3 The Chemistry of Behavior Neurotransmitters and Neuropharmacology
Living the Dream As the twentieth century began, scientists knew that neurons were important for brain function, but controversy swirled about how neurons communicated. What happened at those newly discovered synapses between one neuron and another? Did sparks of electricity pass from cell to cell? Or was some unknown chemical substance involved? Some scientists, nicknamed "sparks," favored the idea that electrical signals crossed synapses; other scientists, the "soups," thought neurons released a chemical that flowed across synapses. No one knew how to figure out which account was correct.
Otto Loewi was so consumed with the question of neural communication that he even dreamed about it. One night he suddenly awoke, having dreamed of an experiment that could finally answer whether the "soups" or the "sparks" were right. He made a few notes and went back to sleep, only to discover the next day that he couldn't make any sense of his scribblings from the night before. So when he had the same dream again the following night, he got up and went straight to the lab to do the experiment while it was still fresh in his mind. The result was a discovery that would revolutionize the study of the brain.
Throughout the ages, people have experimented with exogenous substances (substances from outside the body) to try to change the functioning of their bodies and brains. Our ancestors sipped, swallowed, and smoked their way to euphoria, calmness, pain relief, and hallucination. They discovered deadly poisons in frogs, miraculous antibiotics in mold, powerful painkillers in poppies, and all the rest of a vast catalog of helpful and harmful substances. By studying the physiological actions of these substances, modern scientists have been able to unlock many mysteries of brain function. The preceding chapters showed us that the brain is an electrochemical system. Today we know that, in general, each neuron electrically processes information received through many synapses and then releases a chemical to pass the result of that information processing to the next cell. Specifically, a presynaptic neuron releases an endogenous substance (a substance from inside the body), a chemical called a neurotransmitter. The neurotransmitter then communicates with the postsynaptic cell. As you might have guessed, most drugs that affect behavior do so by meddling with this chemical communication process at millions, or even billions, of synapses. So, we open our discussion with a detailed look at the sequence of electrochemical events in synaptic transmission.
exogenous Arising from outside the body. endogenous Produced inside the body. View Animation 3.2: Brain Explorer
3.1Synaptic Transmission Is a Complex Electrochemical Process We open with a detailed look at the sequence of electrochemical events in synaptic transmission. After reading this section, you should be able to: 3.1.1 Review the neuronal processes leading to the release of neurotransmitter into a synapse. 3.1.2 Explain how receptors capture, recognize, and respond to molecules of neurotransmitter. 3.1.3 Give a general overview of the concept of receptor subtypes and how their existence adds complexity to neural signaling.
FIGURE 3.1 A Review of Synaptic Activity EPSP, excitatory postsynaptic potential; IPSP, inhibitory postsynaptic potential.
1 The action potential arrives and spreads over the membrane...
2 ...causing voltage-gated Ca2+ channels to open. Ca2+ 3 The resultant in ux of Ca2+ causes synaptic vesicles to migrate to the presynaptic membrane, fuse, and rupture, releasing neurotransmitter molecules into the synaptic cleft.
5 Neurotransmitter action is rapidly reversed, through reuptake of transmitter and enzymatic breakdown of transmitter molecules.
Transmitter receptor 4 Molecules of neurotransmitter brie y bind to postsynaptic receptors and change the function of the postsynaptic cell. Some receptors cause ion channels to open, resulting in a ow of ions that initiate an inhibitory or excitatory postsynaptic potential. Other types of receptors are linked to second messengers that trigger changes in excitability or metabolism in the postsynaptic cell.
As we learned in Chapter 2, the typical neuron integrates a variety of inputs and, if sufficiently excited (i.e., depolarized), fires a distinctive, brief electrical signal called an action potential that rapidly sweeps down the axon toward the axon terminals, each of which forms the presynaptic side of a synapse. FIGURE 3.1 recaps the events that follow the arrival of the action potential. First, because the arrival of the action potential strongly depolarizes the axon terminal, voltage-gated calcium (Ca2+) channels in the terminal membrane are induced to open. The resulting inflow of Ca2+ ions drives the migration of synaptic vesicles to the nearby presynaptic membrane, where specialized proteins on the walls of the vesicles and corresponding proteins on the synaptic membrane interact and cause the vesicles to release their cargo of molecules of neurotransmitter (or just transmitter) into the synaptic cleft (a process called exocytosis). In Chapter 2 we also saw that following their diffusion across the cleft, neurotransmitter molecules briefly bind to their corresponding neurotransmitter receptors--protein molecules embedded in the postsynaptic membrane that recognize a specific transmitter--which then mediate a response on the postsynaptic side. Eventually the neurotransmitter molecules are either (1) broken down by enzymes into simpler chemicals or (2) brought back into the presynaptic terminal in a process called reuptake (see Figure 3.1). Reuptake of transmitters relies on specialized proteins, called transporters, that bind molecules of neurotransmitter and conduct them back inside the presynaptic terminal. Once inside, the neurotransmitter molecules can be recycled. Neurotransmitter receptors are very selective about the substances that they will respond to: as we saw in Chapter 2, the action of transmitters on receptors is often likened to a key opening a lock. Nevertheless, the various neurotransmitter receptors can all be categorized as belonging to one of two general kinds: ionotropic receptors or metabotropic receptors. An ionotropic receptor is really just a fancy ion channel; when bound by a neurotransmitter molecule, an ionotropic receptor quickly changes shape, opening (or closing) its integral ion channel (FIGURE 3.2). The opening
presynaptic Located on the "transmitting" side of a synapse. synapse The cellular location at which information is transmitted from a neuron to another cell. neurotransmitter Also called simply transmitter. A signaling chemical, released by a presynaptic neuron, that diffuses across the synaptic cleft to alter the functioning of the postsynaptic neuron. neurotransmitter receptor Also called simply receptor. A specialized protein that is embedded in the cell membrane, allowing it to selectively sense and react to molecules of the corresponding neurotransmitter. postsynaptic Located on the "receiving" side of a synapse. reuptake The reabsorption of molecules of neurotransmitter by the neurons that released them, thereby ending the signaling activity of the transmitter molecules. transporter A specialized membrane component that returns transmitter molecules to the presynaptic neuron for reuse. ionotropic receptor Also called ligand-gated ion channel. A receptor protein containing an ion channel that opens when the receptor is bound by an agonist.
A given neurotransmitter may interact with many different receptors in different parts of the brain.
A neurotransmitter may activate an ionotropic receptor (also called a ligand-gated ion channel) at some synapses, opening an ion channel to affect the postsynaptic cell's membrane potential.
The same neurotransmitter may, at another synapse, activate a metabotropic receptor, which activates second messengers (via G proteins) that open other ion channels, and/or cause other changes in the cell.
FIGURE 3.2 The Versatility of Neurotransmitters
excitatory synapse A type of synapse that, when active, causes a local depolarization that increases the likelihood the neuron will fire an action potential. inhibitory synapse A type of synapse that, when active, causes a local hyperpolarization that decreases the likelihood the neuron will fire an action potential. metabotropic receptor A receptor protein that does not contain ion channels but may, when activated, use a second-messenger system to open nearby ion channels or to produce other cellular effects. receptor subtype Any type of receptor having functional characteristics that distinguish it from other types of receptors for the same neurotransmitter. G protein-coupled receptor (GPCR) A type of receptor that, when activated extracellularly, initiates a G protein signaling mechanism inside the cell.
(or closing) of channels in the postsynaptic membrane allows more (or fewer) of the channels' favored ions to flow into or out of the postsynaptic neuron, thus changing the local membrane potential. If the change in the postsynaptic membrane potential is a depolarization, bringing the cell closer to its threshold for producing an action potential, we call it an excitatory synapse. Conversely, if the result is a local hyperpolarization of the postsynaptic cell, making it less likely that the cell will produce an action potential, we call it an inhibitory synapse. But not all receptors contain an ion channel. Receptors belonging to the other major category--the metabotropic receptors--don't pass ions or other substances through the cell membrane. Instead, they provide a link across the cell membrane to complicated chemical machinery--called G proteins--inside the postsynaptic neuron (see Figure 3.2). When activated, metabotropic receptors alter the inner workings of the postsynaptic cell, using internal chemical signals called second messengers that are activated by the G proteins. This two-step signaling process can cause changes in excitability of the postsynaptic cell, or it can cause other, slower but larger-scale responses. For example, the metabotropic receptor may kick off a chain of chemical reactions that will affect gene expression (the use of genes to produce proteins; see the Appendix). Changes in gene expression can have many lasting effects, such as changing the excitability of the postsynaptic neuron, remodeling its connections to other cells, or stimulating the production of more receptors and signaling chemicals. Together, the two major families of transmitter receptors allow not only rapid responses where timing is crucial, but also more complex, integrative, slower behaviors such as emotional responses, social behavior, and so on. Receptors add an important layer of complexity in neural signaling, because any given transmitter may affect various kinds of receptors that differ from one another in structure. This diversity of receptor subtypes is true for both metabotropic receptors and ionotropic receptors. In mammals and almost all other organisms, a gene "superfamily" encodes hundreds of different kinds of G protein-coupled receptors (GPCRs), including the many and various types of metabotropic neurotransmitter receptors that we'll be seeing again later in the book. In the case of ionotropic receptors, a diverse group of genes encodes the various protein subunits that combine to make up the ion channels at the core of the receptors. The characteristics of each subtype of ionotropic receptor--the specific neurotransmitter it recognizes and the type of ions that it selectively conducts--are determined by the unique combination of subunits that make up the receptor. So, the specific response of any postsynaptic neuron to molecules of neurotransmitter is determined by the particular subtypes of receptors present on the postsynaptic membrane. Furthermore, the various subtypes of receptors for any given transmitter may vary widely in their anatomical distribution within the brain (e.g., Beliveau et al., 2017). Shortly we'll look at the ways in which psychoactive drugs exploit this complexity, but first let's see how Otto Loewi made his dream come true.
The first transmitter to be discovered was acetylcholine
Our chapter began with the classic story of Otto Loewi's dream of an experiment that would reveal the first neurotransmitter. After forgetting the details of the dream the first night, Loewi was quick to
get out of bed when the dream returned the following night. He went straight to the lab to conduct the experiment depicted in FIGURE 3.3. Loewi's first step was to electrically stimulate the
vagus nerve in a frog, which he knew would cause its heart to slow down. The question was, Why did the heart slow down? Had electricity jumped from the vagus nerve to the heart, as the "sparks"
believed? Or were the "soups" right? Had the nerve released a chemical to slow the heart? Loewi's critical, dream-inspired experiment was to collect the fluid that surrounded the slowing heart. Then he applied that fluid to the heart of another frog. If the first heart had been slowed by electrical signals from the vagus, then the fluid should have no effect on the second heart. But if activation of the vagus caused it to release a chemical
that slowed the beating of the heart, then the fluid from the first heart should alter the beating of the second. In fact, the transferred fluid caused the second heart to slow its rate, providing Loewi with conclusive evidence of chemical neurotransmission (and a nice shiny Nobel Prize, in 1936). The neurotransmitter was later chemically identified as acetylcholine (ACh for short). The "soups" were vindicated.
Question Do neurons release a chemical to communicate with other cells, or is the communication based on electrical signals?
Experiment Step I: Stimulate the vagus nerve to slow the heart.
The rate and force of heartbeats are reduced almost immediately.
acetylcholine (ACh) A neurotransmitter that is produced and released by the autonomic nervous system, by motor neurons, and by neurons throughout the brain.
Frog heart 1 Step 2: Collect fluid from around the slowed heart and apply the fluid to a second heart. Stimulate Heart 2
Time (s) After a delay as the fluid is transferred into the chamber, this heart also slows down.
Photograph courtesy of Dr. Edward D. Rockstein
Conclusion The vagus nerve uses a chemical neurotransmitter, not a direct electrical connection, to communicate to cells of the heart and cause it to slow down.
FIGURE 3.3 "Soups" versus "Sparks": The First Neurotransmitter
Otto Loewi Following the Nazi annexation of Austria in 1938, Loewi, then a professor at the University of Graz, was forced to flee to the United States, where he remained for the rest of his life. He was photographed in the summer of 1955 by his associate, Dr. Morris Rockstein, at the Woods Hole Marine Biological Laboratory.
1. Distinguish between endogenous and exogenous substances, and give a few examples of each. 2. Review the sequence of events that occurs when an action potential arrives at the axon terminal and causes a release of neurotransmitter. Use the following terms in your answer: exocytosis, receptors, ionotropic, metabotropic, reuptake. 3. Describe how the first neurotransmitter was discovered. Why do you think we selected this discovery for this chapter's "Researchers at Work" feature?
3.2Neurotransmitter Substances Differ in Their Chemical Structure and in Their Distribution within the Brain
amino acid neurotransmitter A neurotransmitter that is itself an amino acid. Examples include GABA, glycine, and glutamate. peptide neurotransmitter Also called neuropeptide. A neurotransmitter consisting of a short chain of amino acids. amine neurotransmitter A neurotransmitter based on modifications of a single amino acid nucleus. Examples include acetylcholine, serotonin, and dopamine. gas neurotransmitter A neurotrans mitter that is a soluble gas. Examples include nitric oxide and carbon monoxide.
Next we survey the major families of neurotransmitters and their distribution in the brain. After reading this section, you should be able to: 3.2.1 Identify general properties shared by most neurotransmitters, summarizing the criteria for establishing that a substance acts as a neurotransmitter. 3.2.2 Name the major neurotransmitters, and briefly describe the chemical families of transmitters to which they belong. 3.2.3 Trace the anatomical distribution of the major transmitters in the brain. 3.2.4 Briefly discuss some of the major functional roles of the classical transmitters. In the years since Loewi's discovery, neuroscientists have agreed on some basic principles for deciding whether a brain chemical qualifies as a classical neurotransmitter. We can conclude that a candidate substance is a transmitter if it meets the following qualifications: · It can be synthesized by presynaptic neurons and stored in axon terminals. · It is released when action potentials reach the terminals. · It is recognized by specific receptors located on the postsynaptic membrane. · It causes changes in the postsynaptic cell. · Blocking its release interferes with the ability of the presynaptic cell to affect the postsynaptic cell. The brain contains many different chemicals that meet these criteria and are therefore considered classic neurotransmitters. Considering the rate at which these substances are being discovered, it would not be surprising if there turned out to be several hundred different neurotransmitters at work in synapses throughout the central nervous system. But for now, let's content ourselves with a look at a few of the best-known neurotransmitter systems in the brain.
TABLE 3.1 summarizes the major neurotransmitters and the chemical families to which they belong. Amino acid neurotransmitters and peptide neurotransmitters (or neuropeptides), as their names suggest, are based on single amino acid molecules or on short chains of amino acids (called peptides), respectively. A different family--the amine neurotransmitters--includes some of the best-known classical transmitters, such as acetylcholine, dopamine, and serotonin. Each year the list of probable neurotransmitters grows, and the search for new transmitters has occasionally yielded surprises like the gas neurotransmitters, soluble gases that diffuse between neurons to alter ongoing processes (and defy several of the criteria for transmitters that we just listed!).
TABLE 3.1 Some Synaptic Transmitters and Families of Transmitters
AMINO ACIDS AMINES Quaternary amines Monoamines NEUROPEPTIDES Opioid peptides Other neuropeptides GASES
Gamma-aminobutyric acid (GABA), glutamate, glycine, histamine Acetylcholine (ACh) Catecholamines: Norepinephrine (NE), epinephrine (adrenaline), dopamine (DA) Indoleamines: Serotonin (5-hydroxytryptamine [5-HT]), melatonin Enkephalins: Met-enkephalin, leu-enkephalin Endorphins: Beta-endorphin Dynorphins: Dynorphin A Oxytocin, substance P, cholecystokinin (CCK), vasopressin, neuropeptide Y (NPY), hypothalamic releasing hormones Nitric oxide, carbon monoxide
The most abundant neurotransmitters are amino acids A majority of synapses in the brain rely on amino acid transmitters for communication. Of this group, the two best studied are glutamate, the most widespread excitatory transmitter in the brain, and gamma-aminobutyric acid (GABA), the most widespread inhibitory transmitter. Both have wide-ranging effects at synapses throughout the central nervous system, and from an evolutionary perspective they are among the most ancient transmitters. GLUTAMATE Glutamate interacts with several subtypes of receptors, which are named after drugs that selectively activate them. Activation of the ionotropic AMPA receptors, the most plentiful receptors in the brain, has rapid excitatory effects. NMDA receptors are another subtype of ionotropic glutamate receptors, with unique characteristics that suggest they play a central role in memory formation (discussed in Chapter 13 and on the website in A STEP FURTHER 3.1). There are also several metabotropic glutamate receptors (mGluRs), which act more slowly because they work through second messengers. GABA Among the subtypes of receptors for GABA, the GABAA receptors have received decades of special scrutiny because of their relationship to anxiety relief. GABAA receptors are ionotropic; when activated, they allow more Cl- ions to flow into the postsynaptic cell, resulting in a rapid-onset local hyperpolarization that inhibits the cell's activity. Compounds that mimic this action of GABAA tend to be effective calming agents because they produce a widespread decrease in neural activity. In fact, drugs belonging to the family of benzodiazepines--examples include Xanax (alprazolam) and Ativan (lorazepam)--potently activate GABAA receptors and are widely used to treat anxiety and panic attacks, as well as to aid muscle relaxation, sleep induction, and the like. GABAB receptors, in contrast, are metabotropic receptors with slower postsynaptic effects (Gassman and Bettler, 2012); GABAB-selective drugs may be helpful for treating diverse chronic problems such as pain and mood disorders (Pin and Bettler, 2016). Four classical neurotransmitters modulate brain activity It is possible to stain brain tissue in such a way that only the neurons that make a particular neurotransmitter end up being labeled (see Box 1.1). Studies of brain sections stained in this way have shown that transmitters are found in complex
glutamate An amino acid transmitter, the most common excitatory transmitter. gamma-aminobutyric acid (GABA) A widely distributed amino acid transmitter, the main inhibitory transmitter in the mammalian nervous system.
FIGURE 3.4 Neurotransmitter Pathways in the Brain
In this midline view, the brain nuclei containing cell bodies of neurons that release four of the major transmitters are shown in different colors. Each system projects widely but arises from a relatively small number of neurons, a vulnerability that accounts for loss of function in degenerative diseases like Parkinson's and Alzheimer's diseases. Although the projections may overlap, each neurotransmitter projects to a distinct set of brain targets.
Basal forebrain to cortex, amygdala, and hippocampus
Mesolimbocortical pathway: ventral tegmental area (VTA) to nucleus accumbens and cortex
Mesostriatal pathway: substantia nigra to basal ganglia
Locus coeruleus to forebrain Lateral tegmental area to brainstem and spinal cord
Midbrain raphe nuclei to forebrain; brainstem raphe nuclei to spinal cord
networks of neurons that extend throughout the brain. In FIGURE 3.4, this com-
plicated anatomy is depicted for acetylcholine plus just three of the most famous
classical amine transmitters: dopamine, serotonin, and norepinephrine (amines are
nitrogen-containing compounds related to ammonia, often derived from an amino
acid). Acetylcholine and the amine transmitters have been implicated in many cate-
gories of behavior and pathology, so these transmitter systems are major targets for
drug development. We'll encounter them in many locations throughout the book.
(To learn more about how neurons synthesize neurotransmitters, see A STEP FUR-
THER 3.2, on the website.) A key point to remember is that each of these classical
neurotransmitters is carried by a different set of axons, and those axons project to
different brain regions. Each type of neurotransmitter is thus talking to a distinct set of brain targets, and there may be overlap as two different transmitters arrive
Foundations of Brain and Behaavtiotrh4ee same target. How those targets respond depends on which neurotransmitter MM4e_03.04.ai 03/06/20 Dragon y Media Group i2s0being released and which kind of receptors the target neurons possess (TABLE 3.2). And despite its gnarly appearance, Figure 3.4 is actually a simplification; there
co-localization The synthesis and release of more than one type of neurotransmitter by a given presynaptic
are many more transmitters at work than the four we have shown here, and they are arranged in much more complicated networks. Furthermore, we now know that some neurons make and release more than one type of transmitter--a phenomenon
known as neurotransmitter co-localization.
TABLE 3.2 The Bewildering Multiplicity of Transmitter Receptor Subtypes
AMPA, kainate, and NMDA receptors (ionotropic); mGluRs (metabotropic glutamate receptors)
Gamma-aminobutyric GABAA (ionotropic) acid (GABA)
Glutamate is the most abundant of all neurotransmitters and the most important excitatory transmitter. Glutamate receptors are crucial for excitatory signals, and NMDA receptors are especially implicated in learning and memory. GABA receptors mediate most of the brain's inhibitory activity, balancing the excitatory actions of glutamate. GABAA receptors are inhibitory in many brain regions, reducing excitability and preventing seizure activity. GABAB receptors are also inhibitory, by a different mechanism.
Muscarinic receptors (metabotropic) Nicotinic receptors (ionotropic)
Both types of receptors are involved in cholinergic transmission in the cortex. Nicotinic receptors are crucial for muscle contraction.
Dopamine (DA) Norepinephrine (NE) Serotonin Miscellaneous peptides
D1 through D5 receptors (all metabotropic) 1, 2, 1, 2, and 3 receptors (all metabotropic) 5-HT1 receptor family (5 members) 5-HT2 receptor family (3 members) 5-HT3 through 5-HT7 receptors (All but one subtype [5-HT3] metabotropic) Many specific receptors for peptides such as opiates (delta, kappa, and mu receptors), cholecystokinin (CCK), neurotensin, neuropeptide Y (NPY), and dozens more (all metabotropic)
DA receptors are found throughout the forebrain. DA receptors are involved in complex behaviors, including motor function, reward, and higher cognition. NE has multiple effects in visceral organs, important in sympathetic nervous system and fight-or-flight responses. In the brain, NE transmission provides an alerting and arousing function. Different subtypes differ in their distribution in the brain. 5-HT2 receptors may be involved in mood, sleep, and higher cognition. 5-HT3 receptors are particularly involved in nausea. Peptide transmitters have many different functions, depending on their anatomical localization. Some important examples include the control of feeding, sexual behaviors, and social functions.
ACETYLCHOLINE We now know that acetylcholine (ACh) plays a major role in neurotransmission in the forebrain. Many cholinergic (ACh-containing) neurons are found in nuclei within the basal forebrain. These cholinergic cells project widely in the brain, to sites such as the cerebral cortex, amygdala, and hippocampus (see Figure 3.4). Widespread loss of cholinergic neurons is associated with Alzheimer's disease, and experimental disruption of cholinergic pathways in rats interferes with learning and memory. DOPAMINE Out of more than 80 billion neurons in the human brain, only about a million synthesize dopamine (DA), but they are critically important for many aspects of behavior. Figure 3.4 shows the paths of the major dopaminergic projections. One of these projections is called the mesostriatal pathway because it originates in the midbrain (mesencephalon) around the substantia nigra and projects axons to regions of the basal ganglia (aka the striatum). There aren't all that many neurons in the system--hundreds of thousands--but keep in mind that a single axon can divide to supply thousands of synapses. Those synapses play a crucial role in motor control. When people lose a significant number of mesostriatal dopaminergic neurons, from either exposure to toxins or just old age, they develop the
cholinergic Referring to cells that use acetylcholine as their synaptic transmitter. basal forebrain A region, ventral to the basal ganglia, that is the major source of cholinergic projections in the brain. dopamine (DA) A monoamine transmitter found in the midbrain--especially the substantia nigra--and in the basal forebrain. dopaminergic Referring to cells that use dopamine as their synaptic transmitter. substantia nigra A brainstem structure that innervates the basal ganglia and is a major source of dopaminergic projections.
ventral tegmental area (VTA) A portion of the midbrain that projects dopaminergic fibers to the nucleus accumbens. serotonergic Referring to cells that use serotonin as their synaptic transmitter. raphe nuclei A string of nuclei in the midline of the midbrain and brainstem that contain most of the serotonergic neurons of the brain. serotonin (5-HT) A synaptic transmitter that is produced in the raphe nuclei and is active in structures throughout the cerebral hemispheres. noradrenergic Referring to cells using norepinephrine (noradrenaline) as a transmitter. norepinephrine (NE) Also called noradrenaline. A neurotransmitter produced and released by sympathetic postganglionic neurons to accelerate organ activity. locus coeruleus A small nucleus in the brainstem whose neurons produce norepinephrine and modulate large areas of the forebrain. lateral tegmental area A brainstem region that provides some of the norepinephrine-containing projections of the brain. opioid peptide A type of endogenous peptide that mimics the effects of morphine in binding to opioid receptors and producing marked analgesia and reward.
profound movement problems of Parkinson's disease (described in Chapter 5), including tremors. Another dopaminergic projection, called the mesolimbocortical pathway, also originates in the midbrain, in a region called the ventral tegmental area (VTA) (see Figure 3.4). From there, the pathway projects to various locations in the limbic system (see Chapter 2) and cortex. The mesolimbocortical system appears to be especially important for the processing of reward; it's probably where feelings of pleasure arise. Thus, it makes sense that the mesolimbocortical dopamine system is important for learning that is shaped by positive reinforcement (which usually involves a reward; see Chapter 13), especially via the D2 dopamine receptor subtype. Abnormalities in the mesolimbocortical pathway are associated with some of the symptoms of schizophrenia, as we discuss in Chapter 12. At the end of this chapter we'll look at the role of this pathway in addictive behaviors. SEROTONIN Dopaminergic neurons may be scarce, but there are even fewer serotonergic neurons in the human brain--just 200,000 or so. Nevertheless, wide expanses of the brain are innervated by serotonergic fibers, originating from neurons sprinkled along the midline of the midbrain and brainstem in the raphe nuclei (raphe is pronounced "rafay" and is Latin for "seam") (see Figure 3.4). Serotonin (5-HT, short for its chemical name, 5-hydroxytryptamine) participates in the control of all sorts of behaviors: mood, vision, sexual behavior, anxiety, sleep, and many other functions. As we'll see a little later, drugs that increase serotonergic activity are often prescribed for depression and anxiety. The precise behavioral actions of serotonergic drugs depend on which of the many 5-HT receptor subtypes are affected (see Table 3.2) (Gorzalka et al., 1990; Carr and Lucki, 2011). NOREPINEPHRINE As Figure 3.4 shows, many of the brain's noradrenergic neurons--given this name because norepinephrine (NE) is also known as noradrenaline--have their cell bodies in two regions of the brainstem and midbrain: the locus coeruleus ("blue spot") and the lateral tegmental area. Noradrenergic axons from these regions project broadly throughout the cerebrum, including the cerebral cortex, limbic system, and thalamic nuclei. They participate in the control of behaviors ranging from alertness to mood to sexual behavior (and many more). Many peptides function as neurotransmitters Peptides are very important signaling chemicals both in the brain and in the other organs of the body. Here are just a few examples of peptides that act as neurotransmitters: · The opioid peptides, a group of endogenous substances with actions that resemble those of opiate drugs like morphine: some key opioids are met-enkephalin, leu-enkephalin, beta-endorphin, and dynorphin. As with morphine, these peptides act as analgesics (painkillers) and have rewarding properties. · A diverse group of peptides originally discovered in the periphery--especially in the organs of the gut (which explains some of their names)--that are also made by neurons in the spinal cord and brain. These peptides may act as synaptic transmitters, and they are often co-localized with classical transmitters. Examples include vasoactive intestinal polypeptide (VIP), substance P, cholecystokinin (CCK), neurotensin, and neuropeptide Y (NPY). · Various peptide hormones, such as oxytocin and vasopressin, that are produced by the hypothalamus and pituitary. These two peptides are involved in an astonishing variety of functions, ranging from basic housekeeping like urine production through to higher-level functions like memory, pair-bonding (see Chapter 8), and social processes.
Some neurotransmitters are gases Neurons sometimes use certain gas molecules to communicate information; the best studied of these is nitric oxide (not to be confused with "laughing gas," which is nitrous oxide). Carbon monoxide also serves as a transmitter in some cells. Although we call them gas neurotransmitters, these substances are different from traditional neurotransmitters in at least three important ways: 1. Gas transmitters are produced in cellular locations other than the axon terminals, especially in the dendrites, and are not held in vesicles; the substance simply diffuses out of the neuron as it is produced. 2. No receptors in the membrane of the target cell are involved. Instead, the gas transmitter diffuses into the target cell to trigger second messengers inside. 3. Most important, these gases can function as retrograde transmitters: by diffusing from the postsynaptic neuron back to the presynaptic neuron, a gas transmitter conveys information that is used to physically change the synapse. This process may be crucial for memory formation (see Chapter 13), but gas transmitters also have been implicated in functions as diverse as hair growth and penile erections (Meldrum et al., 2014). Now that we've surveyed the major neurotransmission mechanisms of the brain, let's turn our attention to chemicals from outside the body that affect the function of the brain: drugs and toxins.
retrograde transmitter A neurotransmitter that diffuses from the postsynaptic neuron back to the presynaptic neuron. View Activity 3.1: Families of Transmitters
1. Identify the criteria that are used to establish whether a substance in the brain can be considered a neurotransmitter. Briefly discuss why each one is important. 2. Name and briefly describe each of the major categories of neurotransmitters. 3. What are the main excitatory and inhibitory amino acid transmitters of the brain, and what importance do they have? 4. Name and describe the anatomical organization of the four major "classical" amine neurotransmitters. What are some of the functions in which each transmitter has been implicated? 5. What is a peptide? Where do peptides come from--give a few examples--and what are some functions they perform? 6. Discuss the ways in which the gas transmitters resemble and differ from traditional amine transmitters.
3.3 Drugs Fit Like Keys into Molecular Locks The effects of drugs depend on the types of receptors they interact with. After reading this section, you should be able to: 3.3.1 Distinguish between agonist, antagonist, and partial agonist drug actions. 3.3.2 Explain the concepts of binding affinity and efficacy, and discuss the general relationship between a drug's dose and its effects. 3.3.3 Summarize the routes of administration of drugs and the ways in which the brain and body adapt to the presence of drugs over time. In everyday English, we use the term drug in different ways. One common meaning is "a medicine used in the treatment of a disease" (as in prescription drug or over-the-counter drug). Many psychoactive drugs--compounds that alter the function of the brain and
ligand A substance that binds to receptor molecules, such as a neurotransmitter or drug that binds postsynaptic receptors. agonist A substance that mimics or potentiates the actions of a transmitter or other signaling molecule. antagonist A substance that blocks or attenuates the actions of a transmitter or other signaling molecule. partial agonist A drug that, when bound to a receptor, has less effect than the endogenous ligand would. View Animation 3.4: Agonists and Antagonists
FIGURE 3.5 Examples of Agonistic and Antagonistic Actions of Drugs on Receptors
thereby affect conscious experiences--fall into this category, and they may be useful in psychiatric settings. Some psychoactive drugs are used recreationally, with varying degrees of risk to the user; these are sometimes referred to as drugs of abuse, although such substances may also have therapeutic value. Some psychoactive drugs affect the brain by altering enzyme action or modifying other internal cellular processes, but as you may have guessed, most of the drugs that are of interest in neuroscience act via receptors. Recall from Chapter 2 that any substance that binds to a receptor is termed a ligand. The natural ligands for receptors are molecules of neurotransmitters, of course. But as you may have guessed, many (but not all) drugs that affect the brain are also receptor ligands. The actions of drugs on ionotropic and metabotropic receptors are illustrated in FIGURE 3.5. Drugs that mimic or potentiate the actions of a transmitter are called agonists. A substance that mimics the normal action of a neurotransmitter on its receptors by binding to the receptors and activating them is thus a receptor agonist. Similarly, drugs that reduce the normal actions of a neurotransmitter system are called antagonists. Drugs classified as receptor antagonists bind to receptors but do not activate them--instead, they block the receptors from being activated by their normal neurotransmitter. For that reason, drugs with this action are sometimes called receptor blockers. Some important drugs, called partial agonists, are useful because they produce only a middling response. And still other drugs have agonistic or antagonistic effects that are not receptor mediated, such as drugs that alter the synthesis or release of transmitter by presynaptic neurons. Many drugs--caffeine, opium, nicotine, and cocaine are just a few examples-- originally evolved in plants, often as a defense against being eaten. Other modern
Receptor bound by transmitter molecule Transmitter molecule
Receptor bound by agonist drug Agonist drug
Receptor bound by antagonist drug Antagonist drug
Drugs can alter the functioning of neurons by directly interacting with receptors, as depicted here, or through less direct mechanisms that alter neuronal metabolism and physiology. In these examples: (A) An ionotropic receptor that is normally closed opens its central ion channel when bound by an endogenous ligand, usually a transmitter molecule. Most endogenous ligands activate their receptors and are thus classi ed as agonists. (B) When bound by a molecule of its neurotransmitter, a metabotropic receptor's G protein system activates a second messenager, signaling a set of ion channels to open. Many variations exist: for example, some iontropic receptors are normally open and close when bound, and some metabotropic receptors alter protein synthesis rather than opening channels.
An exogenous ligand (a drug or toxin) that resembles the endogenous ligand and is able to bind to the receptor and activate it is also classi ed as a receptor agonist.
Some substances bind to receptors but do not activate them. Instead they simply block other drugs and transmitter molecules from binding to the receptors. These are classi ed as receptor antagonists.
drugs are synthetic (human-made) and tuned to target specific transmitter systems. For example, benzodiazepine antianxiety drugs like lorazepam (trade name Ativan) enhance GABA neurotransmission; classic antipsychotics like haloperidol (trade name Haldol) block dopamine receptors; selective serotonin reuptake inhibitors like fluoxetine (Prozac) are antidepressants. So to understand how drugs work, we must perform analyses at many levels--from molecules to anatomical systems to behavioral effects and experiences. Earlier we said that a given neurotransmitter interacts with a variety of different subtypes of receptors. To get a sense of just how diverse the transmitter receptor subtypes can be, take another look at Table 3.2. For example, there are more than a dozen different subtypes of serotonin receptors. Some are inhibitory, some excitatory, some ionotropic, some metabotropic; in fact, the only thing they all really share is that they are normally stimulated by serotonin. They even differ in their anatomical distribution within the brain. This division of transmitter receptors into multiple subtypes presents us with an opportunity because, although the natural transmitter will act on all its receptor subtypes, we humans can craftily design drugs that fit into only one or a few receptor subtypes. Selectively activating or blocking specific subtypes of receptors can produce diverse effects, some of which are beneficial. For example, treating someone with large doses of the neurotransmitter serotonin would necessarily activate all of the different subtypes of serotonin receptors in their brain, producing a confusing welter of different effects. But drugs that selectively block 5-HT3 receptors while ignoring other subtypes of serotonin receptors produce a powerful and specific anti-nausea effect that brings relief to people undergoing cancer chemotherapy. Drugs are administered and eliminated in many different ways Drug molecules aren't magic bullets; they don't somehow know where to go to find particular receptor molecules. Instead, drug molecules just spread widely throughout the body, binding to their selective receptors when they happen to encounter them. This binding triggers a chain of cellular events, but it is usually temporary, and when the drug (or transmitter) breaks away from the receptor, the receptor resumes its unbound shape and functioning. The amount of a drug that gets to the brain, and how fast it gets there, depends in part on the drug's route of administration. Some routes, such as smoking or intravenous injection, rapidly ramp up the amount of drug that is bioavailable: free to act on the target tissue, and thus not in use elsewhere or in the process of being eliminated. With other routes, such as ingestion (swallowing), the concentration of drug builds up more slowly over longer periods of time. The duration of a drug effect also depends on how the drug is metabolized and excreted from the body--via the kidneys, liver, lungs, or other routes. In some cases, the metabolites of drugs are themselves active; this biotransformation of drugs can produce substances with beneficial or harmful actions. The factors that affect the movement of a drug into, through, and out of the body are collectively referred to as pharmacokinetics. The effects of a drug depend on its dose The tuning of drug molecules to receptor subtypes is not absolutely specific. In reality, a particular drug will generally bind strongly to one kind of receptor, more weakly to a few other types, and not at all to many others. This chemical attraction is known as binding affinity (or simply affinity). At low doses, when relatively few drug molecules are in circulation, drugs will preferentially bind to their highest-affinity receptors. At higher doses, enough molecules of the drug are available to bind both the highest-affinity receptors and some of the lower-affinity receptors. It's interesting to note that neurotransmitter molecules are low-affinity ligands: they bind only comparatively weakly to their receptors, so they can rapidly detach a moment later, allowing the synapse to reset in preparation for the next presynaptic signal. Once it is bound to a receptor, the extent to which a drug molecule activates the receptor is termed its efficacy (or intrinsic activity). As you might guess, agonists have
bioavailable Referring to a substance, usually a drug, that is present in the body in a form that is able to interact with physiological mechanisms. biotransformation The process in which enzymes convert a drug into a metabolite that is itself active, possibly in ways that are substantially different from the actions of the original substance. pharmacokinetics Collective name for all the factors that affect the movement of a drug into, through, and out of the body. binding affinity Also called simply affinity. The propensity of molecules of a drug (or other ligand) to bind to receptors. efficacy Also called intrinsic activity. The extent to which a drug activates a response when it binds to a receptor.
The basic dose-response curve (DRC) plots increasing drug doses (usually on a logarithmic scale) against increasing strength of the response being studied. The dose at which the drug shows half of its maximal effect is termed the effective dose 50% (ED50). Drugs with high potency--determined by af nity and ef cacy in concert--have a lower ED50.
FIGURE 3.6 The Dose-Response Curve
The therapeutic index refers to the separation between useful doses of the drug and dangerous doses. This is determined by comparing the ED50 dose of the drug with the dose at which 50% of the animals either show symptoms of toxicity (toxic dose 50%; TD50) or outright die (lethal dose 50%; LD50). In this example, a greater difference between ED50 and LD50 is observed for the anti-anxiety drug lorazepam (Ativan) than for the older anti-anxiety drug phenobarbital, indicating that lorazepam is the safer drug. Many deaths-- accidental and not--have resulted from phenobarbital overdose.
Phenobarbital Narrow therapeutic index 0 ED50 LD50 Log dose
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e Dragon y Media Group dMosMe4-ere_0s3p.0o6n.asi e curv0e3/(0D6R/2C0)20 A formal graph of a drug's effects (on the y-axis) versus the dose given (on the x-axis). blood-brain barrier The protective property of cerebral blood vessels that impedes the movement of some harmful substances from the bloodstream into the brain. drug tolerance Also called simply tolerance. A condition in which, with repeated exposure to a drug, an individual becomes less responsive to a constant dose.
high efficacy: they tend to activate the receptors they bind to. Conversely, antagonists have low or no efficacy (see Figure 3.5). Partial agonists, unsurprisingly, have appreciable but submaximal efficacy. So it is a combination of affinity and efficacy--where it binds and what it does--that determines the overall action of a drug. For example, the classic antipsychotic drugs tend to have high affinity and low efficacy at the D2 subtype of dopamine receptors; in other words, they are D2 blockers. It's a topic we'll revisit in Chapter 12. Giving larger doses of a drug ultimately increases the proportion of receptors that are bound and affected by the drug. Within certain limits, this increase in receptor binding also increases the response to the drug; in other words, greater doses tend to produce greater effects. When plotted as a graph, the relationship between drug doses and observed effects is called a dose-response curve (DRC), typically taking the sigmoidal shape shown in FIGURE 3.6A. Careful analysis of DRCs reveals many aspects of a drug's activity, such as useful and safe dose ranges (FIGURE 3.6B), and it is one of the main tools for understanding the functional relationships between drugs and their targets. Humans have devised a variety of ingenious techniques for introducing substances into the body; these are summarized in TABLE 3.3. In Chapter 1 we described how tight junctions between the cells of the walls of blood vessels create a blood-brain barrier that inhibits the movement of larger molecules out of the bloodstream and into the brain. This barrier poses a major challenge for neuropharmacology because many drugs that might be useful are too large to cross the blood-brain barrier into the brain. To a limited extent this problem can be circumvented by administering the drugs directly into the brain, but that is a drastic step. Alternatively, some drugs can take advantage of active transport systems that normally move nutrients out of the bloodstream and into the brain. Repeated treatments may reduce the effectiveness of drugs Our bodies are well equipped to maintain a constant internal environment, optimized for cellular activities, and to counteract physiological challenges. In the case of drugs, the body's ability to adapt to challenges may result in the development of drug tolerance,
TABLE 3.3 The Relationship between Routes of Administration and Effects of Drugs
INGESTION Tablets and capsules Syrups Infusions and teas Suppositories INHALATION Smoking Nasal absorption (snorting) Inhaled gases, powders, and sprays PERIPHERAL INJECTION Subcutaneous Intramuscular Intraperitoneal (abdominal) Intravenous CENTRAL INJECTION Intracerebroventricular (into ventricular system) Intrathecal (into the cerebrospinal fluid of the spine) Epidural (under the dura mater) Intracerebral (directly into a brain region)
Many sorts of drugs and remedies: ingestion depends on absorption by the gut, which is somewhat slower than most other routes and affected by digestive factors such as acidity of the stomach and the presence of food. Nicotine, cocaine, organic solvents such as airplane glue and gasoline, other drugs of abuse, and a variety of prescription drugs and hormone treatments: inhalation methods take advantage of the rich vascularization of the nose and lungs to convey drugs directly into the bloodstream. Many drugs: subcutaneous (under the skin) injections tend to have the slowest effects because they must diffuse into nearby tissue in order to reach the bloodstream; intravenous injections have very rapid effects because the drug is placed directly into circulation. Central methods involve injection directly into the central nervous system and are used in order to circumvent the blood-brain barrier, to rule out peripheral effects, or to directly affect a discrete brain location.
Typical speed of effects Slow to moderate Moderate to fast Moderate to fast Fast to very fast
where a drug's effectiveness diminishes with repeated treatments. Consequently, successively larger and larger doses of a drug are needed to produce the same effect. Drug tolerance can develop in several different ways. Some drugs provoke metabolic tolerance, in which the body (especially metabolic organs, such as the liver with its specialized enzymes) becomes more effective at eliminating the drug from the bloodstream before it can have an effect. Alternatively, the target tissue may change its sensitivity to the drug--a phenomenon called functional tolerance. One important way in which a cell develops functional tolerance is by changing how many receptors it has on its surface. So, for example, after repeated doses of an agonist drug, neurons may down-regulate their receptors (decrease the number of receptors available to the drug), thereby becoming less sensitive and countering the drug effect. If the drug is an antagonist, target neurons may instead up-regulate (increase) the number of receptors, to become more sensitive and thus counteract the drug effect. Indeed, continual modification of receptor densities is a key feature of synapses and is crucial for neurotransmission and plasticity (Choquet and Triller, 2013). Tolerance to a particular drug often generalizes to other drugs of the same chemical class; this effect is termed cross-tolerance. For example, people who have developed tolerance to heroin tend to exhibit a degree of tolerance to all the other drugs in the opiate category, including codeine, morphine, and methadone. This phenomenon occurs because all those drugs act on the same family of receptors.
metabolic tolerance The form of drug tolerance that arises when repeated exposure to the drug causes the metabolic machinery of the body to become more efficient at clearing the drug. functional tolerance The form of drug tolerance that arises when repeated exposure to the drug causes receptors to be up-regulated or down-regulated. down-regulation A compensatory decrease in receptor availability at the synapses of a neuron. up-regulation A compensatory increase in receptor availability at the synapses of a neuron. cross-tolerance A condition in which the development of tolerance for one drug causes an individual to develop tolerance for another drug.
1. Briefly explain agonist and antagonist actions of a ligand, with respect to effects on receptors. 2. What are receptor subtypes? What is their significance for drug development? 3. Briefly explain how dose-response curves are calculated and why they are useful to pharmacologists. Distinguish between a drug's binding affinity and its efficacy.
4. Provide a review of the different ways in which drugs can be administered, in particular noting some considerations that are taken into account when deciding on a route of administration. 5. How does repeated exposure to a drug alter its effects? (Hint: Use the words tolerance and regulate in your answer.) 3.4Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission Drugs affect many stages of synaptic transmission. After reading this section, you should be able to: 3.4.1 Summarize the ways in which drugs alter presynaptic processes, with examples. 3.4.2 Summarize drug effects on postsynaptic processes, with examples. 3.4.3 Define autoreceptors and explain their function, using caffeine as an example. 3.4.4 Review the processes that terminate transmitter action at synapses. As the saying goes, it takes two to tango. Synaptic transmission involves a complicated choreography of the two participating neurons, and drugs that affect the brain and behavior may act on either side of the synapse. Let's consider these two sites of action in turn. Some drugs alter presynaptic processes One of the ways that a drug may change synaptic transmission is by affecting the presynaptic neuron, changing the system that converts an electrical signal (an action potential) into a chemical signal (secretion of neurotransmitter). As FIGURE 3.7 illustrates, the most common presynaptic drug effects can be grouped into three main categories: effects on transmitter production, effects on transmitter release, and effects on transmitter clearance. TRANSMITTER PRODUCTION In order for the presynaptic neuron to produce neurotransmitter, a steady supply of raw materials and enzymes must arrive at the axon terminals and carry out the needed reactions. Drugs are available that alter this process in various ways (FIGURE 3.7A). For example, a drug may inhibit an enzyme that neurons need in order to synthesize a particular neurotransmitter, resulting in depletion of that transmitter. Alternatively, drugs that block axonal transport prevent raw materials from reaching the axon terminals in the first place, which could also cause the presynaptic terminals to run out of neurotransmitter. In both cases, affected presynaptic neurons are prevented from having their usual effects on postsynaptic neurons, with sometimes profound effects on behavior. A third class of drug (e.g., reserpine) doesn't prevent the production of transmitter but instead interferes with the cell's ability to store the transmitter in synaptic vesicles for later release. The effect on behavior may be complicated, depending on how much transmitter can still reach the postsynaptic cell. TRANSMITTER RELEASE As we saw in Chapter 3, transmitter is released when action potentials arrive at the axon terminal and trigger an inflow of calcium ions. But a number of drugs and toxins can block those action potentials from ever arriving. For example, compounds that block sodium channels (like the toxin that makes puffer fish a dangerous delicacy, called tetrodotoxin) prevent axons from firing action potentials, shutting down synaptic transmission with deadly results. And drugs called calcium channel blockers do exactly as their name suggests, blocking the calcium influx
A Effects on Transmitter Production 1 Inhibition of transmitter synthesis Example: Para-chlorophenylalanine inhibits tryptophan hydroxylase, preventing synthesis of serotonin from its metabolic precursor. 2 Blockade of axonal transport Example: Colchicine impairs maintenance of microtubules and blocks axonal transport. 3 Interference with the storage of transmitters Example: Reserpine blocks the packaging of transmitter molecules within vesicles, thereby allowing the transmitter to be broken down by enzymes.
B Effects on Transmitter Release 4 Prevention of synaptic transmission Example: Tetrodotoxin, found in puffer sh, blocks voltage-gated Na+ channels and prevents nerve conduction. 5 Alteration of synaptic transmitter release through calcium channel blockade Example: Verapamil, a calcium channel blocker, inhibits transmitter release by reducing the infux of calcium ions that drives vesicles to release transmitter. 6 Alteration of transmitter release through modulation of presynaptic activity Example: Caffeine competes with adenosine for presynaptic receptors, thus preventing its inhibitoryeffects. 7. Alteration of synaptic transmitter release through other mechanisms Example: Amphetamine stimulates release of catecholamine transmitters, especially DA and NE. Botox (botulinum toxin) disrupts the proteins that allow the vesicles of motor neurons to release ACh, resulting in local paralysis. C Effects on Transmitter Clearance 8 Inactivation of transmitter reuptake Example: Cocaine and amphetamine inhibit reuptake mechanisms, thus prolonging synaptic 7. activity. Certain antidepressants inhibit serotonin or norepinephrine reuptake. 9 Blockade of transmitter degradation Example: Some drugs (e.g., monoamine oxidase [MAO] inhibitors) inhibit enzymes that normally break down neurotransmitter molecules in the 8. axon terminal or in the synaptic cleft. As a result, transmitter remains active longer and to greater effect.
FIGURE 3.7 Drug Effects on Presynaptic Mechanisms, with Examples
that normally drives the release of transmitter into the synapse (FIGURE 3.7B). The active ingredient in Botox--botulinum toxin--specifically blocks ACh release from axon terminals near the injection site. The resulting local paralysis of underlying muscles reduces wrinkling of the overlying skin, but it may also interfere with the ability to produce normal facial expressions. A different way to alter transmitter release is to modify the systems that the neuron normally uses to monitor and regulate its own transmitter release. For example, presynaptic neurons often use autoreceptors to monitor how much transmitter they have released; it's a kind of feedback system. Drugs that stimulate these receptors provide a false feedback signal, prompting the presynaptic cell to release less transmitter. Drugs that instead block autoreceptors prevent the presynaptic neuron from receiving its normal feedback, tricking the cell into releasing more transmitter than usual. Worldwide, Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e Dragon y Media Group 06/26/20
autoreceptor A receptor for a synaptic transmitter that is located in the presynaptic membrane and tells the axon terminal how much transmitter has been released.
caffeine A compound found in coffee and other plants that exerts a stimulant action by blocking adenosine receptors.
FIGURE 3.8 Drug Effects on Postsynaptic Mechanisms
we drink more than 2.2 billion cups of coffee every day, and the caffeine we get from all that coffee blocks a type of autoreceptor called the adenosine receptor. Adenosine, which is classified as a neuromodulator, is coreleased with the neuron's transmitter and acts to reduce further transmitter release. So, by blocking presynaptic adenosine receptors, caffeine increases the amount of neurotransmitter released, resulting in the enhanced alertness for which coffee is renowned (McLellan et al., 2016). Interestingly, consuming caffeine after a period of studying may improve memory consolidation in humans for some, but not all, learning tasks (Borota et al., 2014; Hussain and Cole, 2015), perhaps thanks to enhanced neural activity. TRANSMITTER CLEARANCE After action potentials have arrived at the axon terminals and prompted a release of transmitter substance, the transmitter is rapidly cleared from the synapse by several processes (FIGURE 3.7C). Obviously, getting rid of the used transmitter is an important step, because until it is gone, new releases of transmitter from the presynaptic side won't be able to have much extra effect. However, researchers think that under certain circumstances, neurons may be too good at clearing the used transmitter and that a significant lack of transmitter in certain synapses may contribute to disorders such as depression. As we'll see shortly, some important psychiatric drugs, called reuptake inhibitors, work by blocking the presynaptic system that normally reabsorbs transmitter molecules after their release; this blocking action allows transmitter molecules to stay a bit longer in the synaptic cleft, having a greater effect on the postsynaptic cell. Other drugs achieve a similar result by blocking the enzymes that normally break up molecules of neurotransmitter into inactive metabolites, again allowing the transmitter to accumulate, having a greater effect on the postsynaptic cell. Some drugs alter postsynaptic processes An alternate way for drugs to change synaptic transmission is by altering the postsynaptic systems that respond to the released neurotransmitter. As illustrated in FIGURE 3.8,
A Effects on Transmitter Receptors 1 Blockade of receptors Example: Antipsychotic drugs like haloperidol block some dopamine receptors. 2 Activation of receptors Example: Nicotine activates ACh receptors. LSD is an agonist at some serotonin receptors.
B Effects on Cellular Processes 3 Alteration of the number of postsynaptic receptors Example: Alcohol increases the number of receptors for the inhibitory transmitter GABA. 4 Modulation of second messengers Example: Lithium, used to treat bipolar disorder, inhibits the second messenger cyclic AMP.
The Chemistry of Behavior 101 there are two major classes of postsynaptic drug actions: (1) direct effects on transmitter receptors and (2) effects on cellular processes within the postsynaptic neuron. TRANSMITTER RECEPTOR ACTIVATION As we discussed earlier in the chapter, selective receptor antagonists bind directly to postsynaptic receptors and block them from being activated by their neurotransmitter (FIGURE 3.8A). The results may be immediate and dramatic. Curare, for example, blocks the nicotinic ACh receptors found on muscles, resulting in immediate paralysis of all skeletal muscles, including those used for breathing (which is why curare is an effective arrow poison). Selective receptor agonists bind to specific receptors and activate them, mimicking the natural neurotransmitter at those receptors. These drugs are often very potent, with effects that vary depending on the particular types of receptors activated. LSD is an example, producing bizarre visual experiences through strong stimulation of a subtype of serotonin receptors (namely, 5-HT2A receptors) found in visual cortex. POSTSYNAPTIC INTRACELLULAR PROCESSES When they bind to their matching receptors on postsynaptic membranes, neurotransmitters can stimulate a variety of changes within the postsynaptic cells, such as the activation of second messengers, the activation of genes, and the production of various proteins. These intracellular processes present additional targets for drug action (FIGURE 3.8B). For example, some drugs induce the postsynaptic cell to up-regulate its receptors, thus changing the sensitivity of the synapse. Other drugs cause a down-regulation in receptor density. Some drugs, like lithium chloride, directly alter second-messenger systems, with widespread effects in the brain. Future research will probably focus on drugs to selectively activate, alter, or block targeted genes within the DNA of neurons. These genomic effects could produce profound long-term changes in the structure and function of neurons.
3.5Some Neuroactive Drugs Provide Relief from Mental Illness and Pain
© Alfred Eisenstadt/Time & Life Pictures/Getty Images
In the next section we look at the major categories of neuroactive drugs used for clinical purposes. After reading this section, you should be able to: 3.5.1 Summarize the two major types of antipsychotic medications, and review their pharmacological actions. 3.5.2 Discuss the major types of actions of drugs for treating depression and anxiety, with examples. 3.5.3 Review the discovery of opiates, and their major actions in the brain. Using the opiate receptors as examples, discuss the significance of the discovery of orphan receptors in the brain. Mental disorders have bedeviled people across the centuries. Historical accounts of sorcery, strange visions, and possession by demons no doubt reflect a misunderstanding of the symptoms of severe mental illness (the topic of Chapter 12) rather than supernatural events. But where the historical response to psychiatric illness was to lock away the afflicted, neuroscience breakthroughs of the last 70 years have revolutionized psychiatry and liberated millions from the purgatory of institutionalized care. In the sections that follow, we will briefly review some of the major categories of psychoactive drugs, based on how they affect behavior.
The Antipsychotic Revolution The introduction of antipsychotic drugs relieved the suffering of millions of patients who had previously required hospitalization in psychiatric institutions like this one. Antipsychotics dramatically curb the striking hallucinations and delusions that are symptomatic of schizophrenia.
102CHAPTER3 first-generation antipsychotics Also called neuroleptics. Any of a class of antipsychotic drugs that alleviate symptoms of schizophrenia, typically by blocking dopamine receptors. second-generation antipsychotic An antipsychotic drug that has actions other than or in addition to the D2 receptor antagonism that characterizes first-generation antipsychotics. antidepressant A drug that relieves the symptoms of depression. monoamine oxidase (MAO) An enzyme that breaks down monoamine transmitters, thereby inactivating them. tricyclic antidepressant An antidepressant that acts by increasing the synaptic accumulation of serotonin and norepinephrine. selective serotonin reuptake inhibitor (SSRI) An antidepressant drug that blocks the reuptake of transmitter at serotonergic synapses. serotonin-norepinephrine reuptake inhibitor (SNRI) Any of a class of drugs that promote the synaptic accumulation of serotonin and norepinephrine by blocking transmitter reuptake. depressant A drug that reduces the excitability of neurons.
Antipsychotics relieve symptoms of schizophrenia It's hard to believe now, but prior to the 1950s about half of all hospital beds were taken up by psychiatric patients (Menninger, 1948), and owing to its debilitating nature, a high proportion of these were people suffering from the delusions and hallucinations of schizophrenia. This awful situation was suddenly and dramatically improved by the development of a family of drugs now called first-generation antipsychotics (or neuroleptics). The first of these drugs, chlorpromazine (Thorazine), and successors like haloperidol (Haldol) and loxapine (Loxitane) all share one crucial feature: they act as selective antagonists of dopamine D2 receptors in the brain. These drugs are so good at relieving positive symptoms of schizophrenia--emergent symptoms and behaviors that were previously absent, such as hallucinations and delusions--that a dopaminergic model of the disease became dominant (see Chapter 12). More recently, second-generation antipsychotics have been developed that have both dopaminergic and additional, nondopaminergic actions, especially the blockade of certain serotonin receptors. These drugs may be helpful in relieving symptoms that are resistant to first-generation antipsychotics--especially the negative symptoms that involve impairment or loss of a behavior, such as social withdrawal and blunted emotional responses--but early hopes that these drugs would generally outperform first-generation antipsychotics have not been borne out (Kane and Correll, 2010). Growing evidence that schizophrenia also involves transmitters other than the classic targets has since prompted an intense research effort aimed at developing third-generation antipsychotics, with novel targets like glutamate and oxytocin, but effective treatments remain elusive (M. C. Davis et al., 2014; O'Tuathaigh et al., 2017). So, although there has been progress in its treatment, schizophrenia remains a difficult, multifaceted disease and a major health problem, with little agreement regarding optimal treatment strategies (Correll et al., 2017). Antidepressants reduce chronic mood problems Disturbances of mood called affective disorders are among the most common of all psychiatric complaints (World Health Organization, 2001). In contrast to the antipsychotic drugs, which reduce synaptic activity by blocking receptors, effective antidepressant drugs act to increase synaptic transmission. Some of the earliest antidepressants were the monoamine oxidase (MAO) inhibitors, which, as their name suggests, block the enzyme responsible for breaking down monoamine transmitters such as dopamine, serotonin, and norepinephrine. This action allows transmitter molecules to accumulate in the synapses (see Figure 3.7, step 9), with an associated improvement in mood. A second generation of drugs, called the tricyclic antidepressants (an example is imipramine), likewise promote an accumulation of synaptic transmitter, by blocking the reuptake of transmitter molecules into the presynaptic terminal (see Figure 3.7, step 8). More recent generations of antidepressants also increase synaptic transmitter availability, but they focus on specific transmitters: selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac) and citalopram (Celexa) are so named because they act specifically to block reuptake at serotonergic synapses. Related compounds called serotonin-norepinephrine reuptake inhibitors (SNRIs), like venlafaxine (Effexor), promote the accumulation of both serotonin and norepinephrine, by blocking reuptake of both, and have therapeutic applications that extend beyond depression to include anxiety disorders. Anxiolytics combat anxiety Severe anxiety, in the form of panic attacks, phobias (specific irrational fears), and generalized anxiety, can spiral out of control and become disabling; many millions of people are affected by anxiety disorders (see Chapter 12). Anything that reduces or depresses the excitability of neurons tends to counter these states, which explains some of the historical popularity of depressants like alcohol and opium. Unfortunately, these substances have a strong potential for intoxication and addiction, so they are not
Deaths due to fentanyl overdose have increased 10-fold in just 5 years.
FIGURE 3.9 An Epidemic of Overdose Deaths (After NIDA [2017], based on data from Natl. Ctr. Hlth. Stat., CDC Wonder database, 2017.)
Other opioids (17,029 deaths) Heroin (15,482 deaths) Cocaine (13,942 deaths) Methamphetamine (10,333 deaths)
0 199 2 9 00 2 0 00 2 1 00 2 2 00 2 3 00 2 4 00 2 5 00 2 6 00 2 7 00 2 8 00 2 9 01 2 2 0 011 01 2 2 01 2 3 01 2 4 01 2 5 01 2 6 017 suitable for therapeutic use. Barbiturate drugs, such as phenobarbital, were originally developed to reduce anxiety, promote sleep, and avoid epileptic seizures. They are still used occasionally for those purposes, but they are also addictive and easy to overdose on, often fatally, as illustrated in Figure 3.6B. Since the 1970s the most widely prescribed anxiolytics (antianxiety drugs) have been the benzodiazepines, which are both safer and more specific than the barbiturates (see Figure 3.6B), although they still carry some risk of addiction. Members of this class of drug, such as alprazolam (trade name Xanax) and lorazepam (Ativan), bind to specific sites on GABAA receptors and enhance the activity of GABA (R. W. Olsen, 2018). Because GABAA receptors are inhibitory, benzodiazepines help GABA to produce larger inhibitory postsynaptic potentials than GABA would produce alone. The net effect is a reduction in the excitability of neurons. The GABAA receptor is large and complex and contains multiple bindings sites through which drugs may act (Masiulis et al., 2019). Hormones that interact with GABA receptors, as well as drugs that subtly alter serotonergic neurotransmission, are examples of these novel anxiolytics (Belelli et al., 2018). Antidepressant drugs are often effective anxiolytics too. Unsurprisingly, given the high prevalence of anxiety disorders in society, the hunt for new antianxiety agents is an area of intense research effort.
barbiturate An early anxiolytic drug and sleep aid that has depressant activity in the nervous system. anxiolytic A drug that is used to combat anxiety. benzodiazepine Any of a class of antianxiety drugs that are agonists of GABAA receptors in the central nervous system. One example is diazepam (Valium). opium An extract of the opium poppy, Papaver somniferum. Drugs based on opium are potent painkillers. morphine An opiate compound derived from the poppy flower. analgesic Having painkilling properties. heroin Diacetylmorphine, an artificially modified, very potent form of morphine. opioid receptor A receptor that responds to endogenous opioids and/or exogenous opiates.
Opiates have powerful painkilling effects WOaptisuomn/,Berxeetdralocvteed from poppy flower seedpods, has been used by humans since The Mind's Machine FaotulenadsattiothnseoSftBornaeinAangde.BMehoavrpiohr i4nee, the major active substance in opium, is a very Defrfaegcotnivey ManeadilageGsroicup(painkiller) that has brought relief from severe pain to many MmMill4ieo_n03s.0o9f.apieople0(3s/e0e6C/2h0a20pter 5). Unfortunately, because it produces powerful feelings of euphoria, morphine also has a strong potential for addiction, as do close relatives like heroin (diacetylmorphine) and opiate painkillers like oxycodone (OxyContin) and fentanyl, a synthetic opiate that is 30 to 40 times stronger than heroin. Accidental opiate overdose is a rapidly growing epidemic: the fatal fentanyl overdose of the musician Prince in 2016 was just one of many thousands every year (FIGURE 3.9). Opiates like morphine, heroin, and codeine bind to specific receptors-- opioid receptors--that are concentrated in various regions of the brain. An
The Source of Opium and Morphine The opium poppy has a distinctive flower and seedpod. The bitter flavor and brain actions of opium may provide the poppy plant a defense against being eaten.
© South West Images Scotland/Alamy Stock Photo
A and B courtesy of Miles Herkenham, Natl. Inst. Ment. Hlth; C courtesy of Bertha K. Madras and Marc J. Kaufman
(A) Opioid binding in rat brain (horizontal section)
(B) Cannabinoid binding in rat brain (horizontal section)
(C) Cocaine binding in monkey brain (coronal section)
Olfactory bulb Caudate nucleus Medial thalamus Hippocampus
Maps of drug binding in the brain reveal that while drugs belonging to these major categories vary signi cantly in their binding patterns - explaining their widely varying subjective effects - some brain regions are affected by almost all such substances. In these radioligand binding studies, radioactive forms of drugs are used to highlight regions showing the highest density of receptor binding (warmer colors correspond to more binding). Many drugs affect cortical sites, and almost all will activate the mesolimbocortical DA pathway, terminating in the basal ganglia, that mediates the pleasurable aspects of drug use.
FIGURE 3.10 Recreational Drugs Bind to Varying Brain Sites
periaqueductal gray A midbrain region involved in pain perception. endogenous opioid Any of a class of opium-like peptide transmitters that have been referred to as the body's own narcotics. The three kinds are enkephalins, endorphins, and dynorphins.
area within the midbrain called the periaqueductal gray (FIGURE 3.10A) contains a very high density of opioid receptors and is an especially important target because it is here that opiates exert much of their painkilling effects (see Chapter 5). As we mentioned earlier in the chapter, we now know that the brain makes its own morphine-like compounds, called endogenous opioids. Researchers have identified three major families of these potent peptides: the enkephalins, from the Greek en, "in," and kephale, "head" (J. Hughes et al., 1975); the endorphins, a contraction of endogenous morphine; and the dynorphins, short for dynamic endorphins, in recognition of their potency and speed of action (see Table 3.1). There are also three main kinds of opioid receptors--delta (), kappa (), and mu (µ)--all of which are metabotropic receptors (see Table 3.2). Powerful drugs that block opioid receptors--naloxone (Narcan) is an example--can rapidly reverse the effects of opiates and rescue people from overdose. Opiate antagonists also block the rewarding aspects of drugs like heroin, so they can be helpful for treating addiction, as we discuss at the end of this chapter.
3.6Some Neuroactive Drugs Are Used to Alter Conscious Experience
In addition to treating illness, humans seek out drugs for recreational use. After reading this section, you should be able to: 3.6.1 Identify the main active ingredients in cannabis, describe their sites of action in the brain, and discuss the effects of cannabinoids on behavior. 3.6.2 Compare and contrast the main families of stimulant drugs, and explain how they interact with neurons, their major effects, and risks they pose to human health. 3.6.3 Review the modes of action of alcohol in the brain, and discuss the prevalence and treatment of alcohol use disorders. 3.6.4 Define hallucinogenic drugs, and summarize the ways in which the major hallucinogens have shared or different actions in the brain, their major behavioral effects, and their potential therapeutic applications.
© Tribune Content Agency LLC/Alamy Stock Photo
Whether to experience pleasurable sensations, to artificially increase vigor and wakefulness, or simply to satisfy curiosity, people have a long history of tinkering with their conscious experience of the world. Some of the most familiar types of drugs that modify consciousness include cannabinoids, stimulants, alcohol, and hallucinogens. Cannabinoids have many effects Cannabis and its related preparations, such as hashish, are derived from the Cannabis sativa plant, which has been widely cultivated and used by human societies for thousands of years (Russo, 2008). (The common alternative name marijuana is considered by some to have dubious, possibly racist origins; see Halperin, 2018.) Typically administered by smoking, by vaping, or via edible products such as cookies and candies, cannabis contains dozens of active ingredients, the best known of which are the compounds delta-9-tetrahydrocannabinol (THC), which is thought to produce the feeling of being "high" most closely associated with cannabis use, and cannabidiol (CBD), which appears to have anxiolytic effects as well as other medicinal actions (Boggs et al., 2018; Freeman et al., 2019). Cannabis use usually produces pleasant relaxation and mood alteration, although the drug can occasionally cause stimulation and paranoia instead. Occasional use of cannabis seems to be mostly harmless, but as with other substances, heavy use can be harmful. For example, persistent heavy use (i.e., ongoing use of cannabis four or more times per week) may be associated with respiratory problems, addiction, cognitive decline, and psychiatric disorders (Meier et al., 2012; Curran et al., 2016). Adolescents who use cannabis appear to be at greater risk of subsequently developing schizophrenia (Marconi et al., 2016; H. J. Jones et al., 2018). However, it remains to be determined whether the cannabis use causes the illness, or conversely whether adolescents who are already experiencing symptoms of mental illness may be more drawn to cannabis use (J. Bourque et al., 2017). As with opiates and benzodiazepines, researchers found that the brain contains specific cannabinoid receptors that mediate the effects of compounds like THC. Cannabinoid receptors are found in the substantia nigra, the hippocampus, the cerebellar cortex, and the cerebral cortex (FIGURE 3.10B) (Devane et al., 1988). Later research revealed that the brain makes several THC-like endogenous ligands for these receptors. The most studied of these endocannabinoids is anandamide (from the Sanskrit ananda, "bliss") (Devane et al., 1992), which produces some of the most familiar physiological and psychological effects of cannabis use, such as mood improvement, pain relief, lowered blood pressure, relief from nausea, improvements in the eye disease glaucoma, and so on. Cannabinoids are thus targets of an intense research effort aimed at developing drugs with some of the specific beneficial effects of cannabis. The documented use of cannabis for recreational and medicinal purposes spans over 6,000 years, but for most of the twentieth century it was subject to widespread legal prohibition. More recently, however, the sale and use of cannabis products is being legalized increasingly in various U.S. states, nationwide in Canada, and to varying extents in other countries, and possession of cannabis for recreational or medical purposes has been "decriminalized" (i.e., tolerated while technically illegal) in many additional jurisdictions. It seems likely that the relaxation of cannabis laws will continue, so a fuller understanding of both the beneficial and adverse effects of cannabis, and potential for cannabis addiction, is a high priority for researchers (Zehra et al., 2018; Freeman et al., 2019). Stimulants increase neural activity Proper functioning of the nervous system involves a fine balance between excitatory and inhibitory influences. A stimulant is a drug that tips the balance toward the excitatory side, with an overall alerting, activating effect. People use many different naturally occurring and synthetic stimulants; familiar examples include nicotine, caffeine, amphetamine, and cocaine. Some stimulants act directly by increasing excitatory
Relaxation Cannabis laws are being relaxed in many jurisdictions. Legal access through licensed shops, like this one in California, acknowledges existing widespread use of cannabis for recreational and medicinal purposes and is expected to reduce criminal activity, but health risks remain for adolescents and heavy users. cannabis Also known as marijuana, although this name is considered pejorative. A psychoactive plant containing numerous active compounds in varying proportions. delta-9-tetrahydrocannabinol (THC) The major active ingredient in cannabis. cannabidiol (CBD) One of the two major types of active compounds found in cannabis. The other is THC. cannabinoid receptor A receptor that responds to endogenous and/or exogenous cannabinoids. endocannabinoid An endogenous ligand of cannabinoid receptors, thus an analog of cannabis that is produced by the brain. anandamide An endogenous substance that binds the cannabinoid receptor molecule. stimulant A drug that enhances the excitability of neurons.
106CHAPTER3 nicotine A compound found in plants, including tobacco, that acts as an agonist on a large class of cholinergic receptors. cocaine A drug of abuse, derived from the coca plant, that acts by enhancing catecholamine neurotransmission.
synaptic potentials. Others act by blocking normal inhibitory processes: we've already seen that caffeine acts as a stimulant by blocking presynaptic adenosine receptors that monitor and inhibit transmitter release. Interestingly, people with attention deficit hyperactivity disorder (ADHD) often find that stimulants like methylphenidate (Ritalin) help them to focus, possibly because of changes in synaptic activity in the frontal lobes (Faraone, 2018). The stimulants thus form a large class of drugs that are exceptionally diverse in their behavioral effects, neurobiological modes of action, and potential for both benefit and harm. NICOTINE Tobacco is native to the Americas, where European explorers first encountered smoking; these explorers brought tobacco back to Europe with them. Tobacco use became much more widespread following technological innovations that made it easier to smoke, in the form of cigarettes (W. Bennett, 1983). Delivered to the large surface of the lungs, the nicotine from conventional or e-cigarettes enters the blood and brain much more rapidly than does nicotine from other tobacco products. Nicotine acts as a stimulant, increasing heart rate, blood pressure, digestive action, and alertness. In the short run, these effects make tobacco use pleasurable. But these alterations of body function, quite apart from the effects of tobacco tar on the lungs, make prolonged exposure to nicotine unhealthful. Smoking and nicotine exposure during development--even as early as in the womb, via the mother--can have a lasting impact on physiology and cognitive development, due to changes in the pubertal development of cholinergic and glutamatergic systems, and possible long-lasting modifications of neural function (Yuan et al., 2015; Rauschert et al., 2019). The nicotinic ACh receptors didn't get their name by coincidence; it is through these receptors that the nicotine from tobacco exerts most of its effects in the body. Nicotinic receptors drive the contraction of skeletal muscles, and the activation of various visceral organs, but they are also found in high concentrations in the brain, including the cortex. This is one way in which nicotine enhances some aspects of cognitive performance. Nicotine also acts directly on nicotinic receptors within the ventral tegmental area to exert its rewarding/addicting effects (Durand-de Cuttoli et al., 2018). (We will discuss the ventral tegmental area in more detail when we discuss positive reward models later in this chapter.) COCAINE For hundreds of years, people in Bolivia, Colombia, and Peru have used the leaves of the coca shrub--either chewed or brewed as a tea--to increase endurance, alleviate hunger, and promote a sense of well-being. The use of coca leaves in this manner does not seem to cause problems. But processing and purifying an extract from this plant produces a much more potent and dangerous drug: cocaine. First isolated in 1859, cocaine was added to beverages (such as Coca-Cola) and tonics for its stimulant qualities, and subsequently it was used as a local anesthetic (it is in the same chemical family as procaine) and as an antidepressant. But people soon discovered that the rapid hit resulting from snorting cocaine (see Table 3.3) has a stimulant effect that is powerful and pleasurable. Cocaine exerts its stimulant effects by blocking the reuptake of monoamine transmitters--especially dopamine and norepinephrine. This action causes transmitters to accumulate in synapses throughout much of the brain (FIGURE 3.10C), therefore boosting their effects. Crack, a smokable form of cocaine that appeared in the mid-1980s, enters the blood and the brain even more rapidly and thus is even more addictive than cocaine powder. However it is consumed, cocaine is highly addictive. Furthermore, heavy cocaine use raises the risk of serious side effects like stroke, psychosis, loss of gray matter in the frontal lobes, and severe mood disturbances (Franklin et al., 2002; Crunelle et al., 2014). Cocaine causes changes in the structure and function of many regions of the brain (Hanlon et al., 2013), which contribute to high rates of relapse in people attempting to quit cocaine use. People who use cocaine along with other substances run the
Mug shots courtesy of the Multnomah County Sheriff's Office and the Faces of MethTM program
added risk of dual dependence, in which the interaction of two (or more) drugs produces another addictive state. For example, cocaine metabolized in the presence of ethanol (alcohol) yields an active metabolite called cocaethylene, to which the user may develop an additional addiction (Y. Liu et al., 2018).
AMPHETAMINE The synthetic stimulant amphetamine ("speed")
and its more potent relatives, like methamphetamine ("meth"),
have a mode of action that superficially resembles that of cocaine,
inducing an accumulation of the synaptic transmitters norepi-
nephrine and dopamine. However, the mechanics of amphet-
amine's actions, involving two steps, are quite different from
those of cocaine. First, amphetamine acts within axon terminals
to cause a larger-than-normal release of neurotransmitter when
the synapse is activated. Second, amphetamine then interferes Faces of Meth These before and after photos, taken just 2½
with the clearance of the released transmitter by blocking its reuptake and metabolic breakdown. The result is that the affected synapses become unnaturally potent, having strong effects on behavior. Over the short term, amphetamine causes increased vigor and
years apart, testify to the heavy toll taken by chronic methamphetamine abuse. Meth causes multiple severe problems such as motor disorders, cognitive impairment, psychosis, rapid changes in appearance due to accelerated tooth decay ("meth mouth"), skin pathology, and excessive weight loss.
stamina, wakefulness, decreased appetite, and feelings of eupho-
ria. For these reasons, amphetamine has historically been used in military applications
and other settings where intense sustained effort is required. However, the quality of
the work being performed may suffer, and the costs of amphetamine use soon out-
weigh the benefits. Addiction and tolerance to amphetamine and methamphetamine
develop rapidly, requiring ever-larger doses that lead to sleeplessness, severe weight
loss, and general deterioration of mental and physical condition.
Prolonged use of amphetamine or methamphetamine may lead to symptoms that
resemble those of schizophrenia: compulsive, agitated behavior and irrational suspi-
ciousness. Users may neglect their diet and basic hygiene, aging rapidly. Users also
experience a variety of peripheral effects, like high blood pressure, tremor, dizziness,
sweating, rapid breathing, and nausea. And worst of all, people who chronically abuse
meth often display symptoms of brain damage long after they quit using the drug
(Moratalla et al., 2017; Wu et al., 2018). As we'll discuss a little later in the chapter, in-
creased activation of the mesolimbocortical dopaminergic reward system of the brain
appears to be crucial for the rewarding aspects of drug use.
Amphetamine-like stimulants called cathinones are released when the African
shrub khat (or qat, pronounced "cot") is chewed. Many types of synthetic cathi-
nones--known collectively as "bath salts"--have been developed and marketed in
recent years (Baumann et al., 2018). These new designer drugs, especially mephedrone
("plant food" or "meow meow"), have shown rapid growth in popularity despite the
potential for damaging effects on the brain, muscular system, and kidneys (Zawilska,
Alcohol acts as both a stimulant and a depressant The most widely consumed psychoactive drug, alcohol, is easily produced by the fermentation of fruit or grains. Taken in moderation (perhaps one or two drinks per day at most), alcohol is probably harmless or maybe even beneficial to the health of adults (e.g., Katsiki et al., 2014; Scarmeas et al., 2018). Heavy alcohol consumption is very damaging and linked to a multitude of serious diseases (O'Keefe et al., 2014; Bell et al., 2017). Alcohol has a biphasic effect on the nervous system: at first it acts as a stimulant, and then it has a more prolonged depressant phase. (Remember, the word depressant relates to a depression or inhibition of neural activity, not an effect on mood.) This complex action is thought to be the result of alcohol's effects on several different
amphetamine A molecule that resembles the structure of the catecholamine transmitters and enhances their activity. khat Also spelled qat. An African shrub that, when chewed, acts as a stimulant.
FIGURE 3.11 Abnormal Brain Development in Fetal Alcohol Spectrum Disorder
Corpus callosum (B) Infant with fetal alcohol spectrum disorder
Compared to MRI images of a healthy infant's brain...
...the MRI of an infant affected by fetal alcohol spectrum disorder--caused by heavy consumption of alcohol by the mother during pregnancy--shows extensive abnormality, including reduced gray matter, complete absence of the corpus callosum, abnormal organization of the brain, and characteristic deformities of the head and face.
fetal alcohol spectrum disorder (FASD) A family of developmental disorders that vary in severity, resulting from fetal exposure to alcohol consumed by the mother. Severe cases, associated with high levels of alcohol abuse by the mother, include characteristic intellectual disability and facial abnormalities.
neurotransmitter systems, such as glutamate and GABA (Roberto and Varodavan,
2017). Like the anxiety-reducing benzodiazepines we discussed earlier, alcohol in-
hibits neural excitability in multiple brain regions via an action on GABA receptors,
resulting in the social disinhibition, poor motor control, and sensory disturbances
that we call drunkenness (Harrison et al., 2017). Alcohol additionally activates dopa-
mine-mediated reward systems of the brain, accounting for some of the pleasurable
Chronic abuse of alcohol damages or destroys nerve cells in many regions of the
brain. Heavy drinking by expectant mothers can cause grievous permanent damage
to the developing fetus, termed fetal alcohol spectrum disorder (FASD), which in
the most severe cases is characterized by facial deformities and stunted brain growth,
sometimes including the absence of the corpus callosum that normally connects the
two hemispheres of the brain (FIGURE 3.11). Furthermore, although it was previously
thought that low levels of alcohol consumption were safe during pregnancy, as few as
one or two drinks per week may be associated with lower fetal weight and preterm birth
(Mamluk et al., 2017), changes in craniofacial development (Muggli et al., 2017), and
later behavioral problems (Murray et al., 2016). Such findings, combined with a paucity
of information on the impact of light drinking on other aspects of fetal health, such as Watson/Breedlove TchoegMniintdiv'seMfuanchcitnioen, and clear evidence of fetal risks from alcohol in studies with lab anFiomunadlsat(iVonasleonf BzuraeinlaaentdaBle.,h2a0v1io2r),4eencourage an abundance of caution: the Centers for Dis-
DeraasgeonCoynMtreodliaanGdroPurpevention (CDC) currently advises that there is no known safe level of
alcohol use in pregnancy (CDC, 2016). In adults, chronic alcohol abuse is associated with
pathological changes in white matter pathways, widespread cortical atrophy, and dam-
age of the diencephalon and cerebellum (de la Monte and Kril, 2014), resulting in a host
of behavioral symptoms including cognitive decline, memory impairment, and move-
ment disorders. Happily, some of the anatomical changes associated with chronic alco-
holism may be reversible with abstinence. In humans recovering from alcoholism, MRI
studies show increased volumes of gray matter throughout multiple cortical regions,
along with improvements in subcortical sites like the thalamus, amygdala, and cerebel-
lum, within days of giving up alcohol (Cardenas et al., 2007) (FIGURE 3.12), along with
at least partial reversal of alcohol-induced atrophy of white matter pathways (Zahr and
Pfefferbaum, 2017). Even in the absence of clear-cut alcoholism, periodic binge drinking,
which is defined as four (female) or five (male) or more drinks on a single occasion by the
Substance Abuse and Mental Health Services Administration (SAMHSA, 2018) and is a
FIGURE 3.12 Immediate Changes in Brain Volume in Recovering Alcoholics (After V. A. Cardenas et al. 2007. NeuroImage 34: 879-887.)
After just one week of abstinence, the average volume of several brain regions was noticeably increased in a group of alcoholics, compared with alcoholic and nonalcoholic control groups. It's not yet clear how much cognitive improvement accompanies these changes, but the results clearly illustrate the potential bene ts of reduced intake in heavy drinkers.
common mode of alcohol use in young people, can harm the brains and alter the behavior of adolescents in ways that last into adulthood (Crews et al., 2016). Hallucinogens alter sensory perceptions Humans have long prized hallucinogens (also called psychedelics or entheogens), substances that produce powerful sensory alterations, often finding the resultant experiences to have deep spiritual or psychological meaning. The effects of lysergic acid diethylamide (LSD, or acid) and related substances like mescaline (from the peyote cactus) and muscarine and psilocybin (both from mushrooms) are predominantly visual, producing bizarre and mysterious sensory experiences, but the term hallucinogen is really a misnomer: a hallucination is a novel perception that takes place in the absence of sensory stimulation (hearing voices, or seeing something that isn't there), but drugs in this category mostly alter or distort existing perceptions (mainly visual in nature). Users may see fantastic images (FIGURE 3.13), often with intense colors, but often they are aware that these strangely altered perceptions are not real events. Hallucinogenic agents are diverse in their neural actions. Whereas muscarine affects the ACh system, mescaline acts via noradrenergic and serotonergic systems.
hallucinogen Also called psychedelics or entheogens. A drug that alters sensory perception and produces peculiar experiences.
These images are portraits produced by a professional artist just after taking LSD (leftmost drawing) and then at three successive time points as the drug took effect. The model for all four drawings is the same man (the researcher, in fact).
20 minutes FIGURE 3.13 Perceptual Alterations with LSD
TABLE 3.4 Possible Clinical Applications for Hallucinogens
Drug name and date of discovery Action in brain
Psilocybin/psilocin (Psilocybe mushroom) (according to archaeological evidence, used in prehistory)
Is a partial agonist of 5-HT receptors, especially 5-HT2A receptors that occur in high density in visual cortex. Modifies activity of frontal and occipital cortex.
Art by Wes Black, courtesy of www.blotterart.com
The Father of LSD Albert Hofmann discovered LSD by accidentally taking some in 1943, and he devoted the rest of his career to studying it. A prohibited drug in most jurisdictions, LSD is distributed on colorful blotter paper. This example, picturing Hofmann and the LSD molecule, is made up of 1,036 individual doses, or "hits." LSD Also called acid. Lysergic acid diethylamide, a hallucinogenic drug. MDMA Also called Ecstasy or Molly. 3,4-Methylenedioxymethamphetamine, a drug of abuse.
Lysergic acid diethylamide (LSD)(1938) Ketamine (1962) 3,4-Methylenedioxymeth amphetamine (MDMA) (1912/1970s)
Activates many subtypes of monoamine receptors, especially DA and 5-HT, resulting in heightened activity in many cortical regions, especially frontal, cingulate, and occipital cortex. Has widespread effects in the brain, especially blockade of NMDA receptors, and stimulates opioid and ACh receptors. Stimulates release of monoamine transmitters and the prosocial hormone oxytocin.
The herb Salvia divinorum is unusual among hallucinogens because it acts on the opioid kappa receptor. But research with LSD and related drugs suggests that perhaps the most important shared neural action of hallucinogens is the stimulation of serotonin receptors. Discovered by Albert Hofmann in the 1940s, LSD (lysergic acid diethylamide, or more simply acid) structurally resembles serotonin. Even in tiny doses, LSD strongly activates serotonin 5-HT2A receptors that are found in especially heavy concentrations in the visual cortex. Other hallucinogens, such as mescaline and psilocybin, share this action. Research with psilocybin has also demonstrated disinhibition of emotion-processing regions in the limbic system (Carhart-Harris et al., 2012), perhaps accounting for some of the drug's emotional, mystical qualities. In addition to their impressive perceptual effects, LSD, psilocybin, and other hallucinogens can produce mood changes, introspective states, and feelings of creativity that have led to renewed interest in the possibility of using hallucinogens to treat specific psychiatric disorders, including depression, anxiety, and obsessive-compulsive disorder (Kyzar et al., 2017). Ketamine (known as Special K) is already in widespread use in medical settings as a component of anesthesia but also has pronounced hallucinogenic properties. Acting principally (but not exclusively) to block NMDA receptors, ketamine increases activity in the prefrontal cortex and hippocampus and produces feelings of depersonalization and detachment from reality. Ketamine increases activity in the prefrontal cortex (Breier et al., 1997; Zorumski et al., 2016), and while high doses produce transient hallucinogenic effects and occasional psychotic symptoms in volunteers, low doses have a potent and rapid antidepressant effect that may help ease symptoms in resistant cases (Carlson et al., 2013; Williams and Schatzberg, 2016). Ecstasy is the street name for the hallucinogenic amphetamine derivative MDMA (3,4-methylenedioxymethamphetamine). Like LSD, MDMA stimulates visual cortical 5-HT2A receptors, but it also changes the levels of dopamine and certain hormones, such as prolactin and oxytocin, that have been associated with prosocial feelings and behaviors. Exactly how these physiological actions of MDMA account for its subjective effects--positive emotions, empathy, euphoria, a sense of well-being, and colorful visual phenomena--remains uncertain. Complications due to hallucinogen use are quite varied. The major hallucinogens seem to have comparatively low addiction potential. LSD has relatively few negative side effects (although some users report long-lasting visual changes). Long-term MDMA use may cause problems with mood and cognitive performance (Sumnall and Cole, 2005; Parrott, 2013) and long-lasting changes in patterns of brain activation,
Recreational use Users of "shrooms" often report spiritual experiences and feelings of transcendence, along with intense visual experiences and alterations in the perception of time. The exact effects are strongly influenced by the expectations and surroundings of the user. "Acid" produces pronounced perceptual changes that resemble hallucinations. Intense colors in geometric patterns, novel visual objects, and an altered sense of time are common. "Special K" creates a detached, trancelike state, in keeping with its routine medical use as an anesthetic. It may also produce hallucinogenic perceptual alterations. Users of "Ecstasy" experience intense visual phenomena, empathy, strongly prosocial feelings, and euphoria.
Possible clinical application Recent studies suggest that psilocybin--administered in controlled settings--can offer substantial and enduring improvements in the symptoms of obsessive-compulsive disorder (OCD), cluster headache (a type of migraine), treatment-resistant depression, and debilitating anxiety and anguish (as in a sample of terminal cancer patients) (Grob et al., 2011;Schindler et al., 2015; Carhart-Harris et al., 2016). LSD may be an effective treatment for alcoholism and other addictions and may also be an effective treatment for some types of debilitating anxiety (Gasser et al., 2014; Bogenschutz and Johnson, 2016). Recent experiments have revealed a potent antidepressant effect of ketamine at lower doses, even in cases that resist other types of treatments (Williams and Schatzberg, 2016). MDMA treatment may reduce symptoms of post-traumatic stress disorder (PTSD), especially in combination with conventional psychotherapy, but concerns remain regarding drug safety (Parrott, 2014; Sessa, 2017).
even at low doses (de Win et al., 2008). However, short-term MDMA treatment is also being investigated as a possible treatment for persistent post-traumatic stress disorder (Feduccia et al., 2019). The neural actions, recreational properties, and possible psychiatric uses of some of the major hallucinogens are summarized in TABLE 3.4.
1. Compare and contrast the three major categories of presynaptic effects of psychoactive drugs. Give examples of each kind of action. (Hint: The words production, release, and clearance will be important for your discussion.) 2. Compare and contrast the main postsynaptic actions of psychotropic drugs, with examples. Be sure to distinguish between actions at receptors and actions within the postsynaptic neuron. 3. At least four general categories of psychoactive drugs are used to relieve disorders. Describe these categories, and give some examples of each class of drugs. Be sure to discuss the modes of action of the drugs you cite. 4. Identify and discuss the major categories of drugs that people use to alter their consciousness. In what ways are the major categories similar, and in what ways do they differ? What are some of the threats to health that these compounds present? 5. Discuss the renewed scientific interest in the therapeutic use of hallucinogens. How might they help in psychiatric disorders?
3.7Substance Abuse and Addiction Are Global Social Problems In the final section of the chapter we turn to the urgent public health problem posed by substance abuse. By the end of this section, you should be able to: 3.7.1 Provide a formal definition of substance abuse, and distinguish between mild, moderate, and severe forms. 3.7.2 Summarize the major theoretical models of substance abuse. 3.7.3 Describe some individual differences that affect susceptibility to addiction. 3.7.4 Review leading categories of treatments for addiction, briefly explaining the logic of each.
Feeding the Monkey Addiction exerts a powerful grip on the lives of people from all walks of life, leading them to go to sometimes extreme lengths to obtain larger and more frequent doses. Author and entertainer Russell Brand has documented his personal descent into addiction, and road to recovery, in several books and documentaries.
The habitual use of drugs to alter consciousness can be costly to the user and to society. Governments attempt to minimize these costs by controlling (or preventing) the production and distribution of designated drugs, but the division of drugs into licit and illicit categories is largely a matter of historical accident. Some classes of drugs--the opiates, for example--span both categories, being both useful medicines and harmful drugs of abuse. And some substances, like tobacco, are legal only because they have been cultivated for centuries and are backed by powerful economic interests. In terms of illness, death, lost productivity, and sheer human misery, some of the legal drugs may be the worst offenders. Just one example reveals the extent of the problem: in the United States each year, more men and women die of smoking-related lung cancer than of colon, breast, and prostate cancers combined. In addition to the personal impact of so much illness and early death, there are dire social costs: huge expenses for medical and social services; millions of hours lost in the workplace; elevated rates of crime associated with illicit drugs; and scores of children who are damaged by their parents' substance abuse behavior, in the uterine environment as well as in the childhood home. Males are more likely than females to engage in substance abuse, but it is unclear whether this sex difference is related to biological differences between the sexes or to differences in social influences on males versus females. For medical purposes, addiction is defined as "substance use disorder" (SUD) in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5; American Psychiatric Association, 2013). SUD can take multiple forms, and it varies in severity from mild to severe. The DSM-5 criteria for a diagnosis of alcohol use disorder appear in TABLE 3.5; about 7% of adults in the USA (approximately 17 million people) currently meet these criteria (SAMSHA, 2018). Identical criteria are used for diagnosis of all other types of substance use disorders, including opioids like heroin,
TABLE 3.5 DSM-5 Diagnostic Criteria for Alcohol Use Disorder
A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: 1. Alcohol is often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. 3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects. 4. Craving, or a strong desire or urge to use alcohol. 5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol. 7. Important social, occupational, or recreational activities are given up or reduced because of alcohol use. 8. Recurrent alcohol use in situations in which it is physically hazardous. 9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. 10. Tolerance, as defined by either of the following: a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. b. A markedly diminished effect with continued use of the same amount of alcohol. 11. Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for alcohol [listed elsewhere in DSM-5 as an alcohol-induced disorder]. b. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms. Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition © 2013. American Psychiatric Association. All rights reserved.
stimulants like cocaine and meth, tobacco, cannabis, hallucinogens, and so on. Almost everyone will meet some of the criteria some of the time; a diagnosis of a specific substance use disorder requires more-sustained problems and a pattern of use that interferes with normal daily functioning. A mild substance use disorder is diagnosed if two or three of the listed criteria are met. People meeting four or five criteria are classified as having moderate substance use disorder, and severe substance use disorder is diagnosed in cases where six or more of the criteria are met. In the discussion that follows, we will look at some of the most prevalent perspectives on addiction: what it is, where it comes from, how it can be treated. Some of these models stem from social forces; others are more deeply rooted in scientific observations and theories. But for any model of drug abuse, the challenge is to come up with a single account that can explain the addicting power of substances as seemingly dissimilar as cocaine (a stimulant), heroin (an analgesic and euphoriant), and alcohol (largely a sedative). We will focus primarily on addiction to cocaine, the opiate drugs (such as morphine and heroin), nicotine, and alcohol because these substances have been studied the most thoroughly. According to the 2016 National Survey on Drug Use and Health, some 20.1 million people in the United States alone have substance-related disorders (SAMHSA, 2017). Worldwide, the number is probably in the hundreds of millions. Sex differences are evident in multiple aspects of drug abuse and dependence (Becker et al., 2017), but although historically men have been more likely than women to engage in substance abuse, in young people rates are now roughly equivalent for the sexes (SAMHSA, 2017). Competing models of substance abuse have been proposed Any comprehensive model of substance abuse has to answer several difficult questions: What social and environmental factors cause someone to start abusing a substance? What factors cause the person to continue abusing? What physiological mechanisms make a substance rewarding? What is addiction, physiologically and behaviorally, and why is it so hard to quit? Four major models attempt to answer at least some of these questions: 1. The moral model blames substance abuse on weakness of character and a lack of self-control. Proponents of this view may apply exhortation, peer pressure, and/or religious intervention in an attempt to curb abusive practices. These approaches have historically had limited success, probably because they aren't founded in a scientific framework that addresses the neurobiological roots of addiction. The temperance movement that commenced in the early 1800s did seem to reduce alcohol consumption for a time, but despite good intentions, high hopes, and multibillion-dollar budgets, there remains little evidence that modern morality-based campaigns--Project D.A.R.E., for example--have a substantial effect on rates of drug abuse (S. L. West and O'Neil, 2004; Vincus et al., 2010). 2. The disease model takes the view that the person who abuses drugs requires medical treatment rather than moral exhortation or punishment. The problem is that substance abuse is not like any other disease we know about. We generally reserve the term disease for cases involving a physical abnormality, and no such condition has been found in the case of drug addiction (although some people are genetically more susceptible to addiction than others). Furthermore, the disease model offers no clue about how addiction initially arises. Nevertheless, this model continues to appeal to many, and much research is focused on looking for pathological states that create addiction after initial exposure to a drug. 3. The physical dependence model argues that people keep taking drugs in order to avoid unpleasant withdrawal symptoms. The specific withdrawal symptoms depend on the drug, but they are often the opposite of the effects produced by the drug itself. For example, withdrawal from morphine causes irritability, a
withdrawal symptom An uncomfortable symptom that arises when a person stops taking a drug that they have used frequently, especially at high doses.
114CHAPTER3 A drug's rewarding properties and addictive potential are re ected in the number of lever presses performed to receive a dose. Lab animals will press the lever thousands of times to receive a single small dose of highly addictive compounds like cocaine and methamphetamine. Catheter Lever Syringe pump Computerized controls A syringe pump is controlled by a computer, delivering a small dose of drug after a certain number of lever presses. FIGURE 3.14 Experimental Setup for Drug Self-Administration
The Mind's Machine FounddyastiponhsoorfiaBraiUnnapnldeaBseahnatvfieoer l4inegs;
insula A region of cortex lying below the surface, within the lateral sulcus, of the frontal, temporal, and parietal lobes.
racing heart, and waves of goose bumps (that's where the term cold turkey comes from--the skin looks like the skin of a plucked turkey). And of course, the opposite of the euphoria caused by many drugs is dysphoria: strongly negative feelings that can be rapidly relieved by administration of the withdrawn drug. So the model does a good job of explaining why addicts will go to great lengths to obtain the drug they are addicted to, but it has an important shortcoming: the model is mute on how the addiction becomes established in the first place. Why do some people, but not all, start to abuse a drug before physical dependence (tolerance) has developed? And how is it that some people can become addicted to some drugs even in the absence of clear physical withdrawal symptoms? A striking example is cocaine, which is powerfully addictive and produces intense drug craving, yet cocaine withdrawal is not accompanied by the shaking and vomiting and other physical symptoms that are seen during withdrawal from equally addictive substances like heroin. 4. The positive reward model proposes that people get started with drug abuse, and become addicted, because the abused drug provides powerful reinforcement. Using an apparatus that allows animals to administer drugs to themselves (FIGURE 3.14), researchers have collected plenty of evidence for this view. Laboratory animals will quickly learn to press a lever repeatedly in order to receive a small dose of an addictive drug like cocaine or morphine (T. Thompson and Schuster, 1964; McKim, 1991). We can infer that the more lever presses animals will perform for a single dose, or the smaller the dose that will support the lever-pressing behavior, the more rewarding and addictive the drug must be. For example, it turns out that animals will self-administer doses of morphine that are so low that no signs of physical dependence ever develop (Schuster, 1970). Animals will also furiously press a lever to self-administer tiny doses of cocaine and other stimulants (Pickens and Thompson, 1968; Koob, 1995; Tanda et al., 2000). In fact, cocaine supports some of the highest rates of lever pressing ever recorded. Experiments using drug self-administration suggest that, by itself, the physical dependence model is inadequate to explain drug addiction, although physical dependence and tolerance may contribute to drug hunger. The more comprehensive view of drug self-administration interprets it as a behavior controlled by a powerful pattern of positive and negative rewards (a variant of operant conditioning theory; see Chapter 13), without the need to implicate a disease process. Many--but not all--addictive drugs cause the release of dopamine in the nucleus accumbens, just as occurs with more conventional rewards, such as food, sex, and gambling (Nutt et al., 2015; Volkow et al., 2017). As we mentioned previously, dopamine released from axons originating in the ventral tegmental area (VTA), part of the mesolimbocortical dopaminergic pathway illustrated in Figure 3.4, has been widely implicated in the perception of reward (FIGURE 3.15). If the dopaminergic pathway from the VTA to the nucleus accumbens serves as a reward system for a wide variety of experiences, then the addictive power of drugs may come from their extra strong stimulation of this pathway. When the drug activates this system, providing an abnormally powerful reward, the user learns to associate the drug-taking behavior with that pleasure and begins seeking out drugs more and more until life's other pleasures fade into the background. If natural activities like conversation, food, and even sex no longer provide appreciable reward, addicts may seek drugs as the only source of pleasure available to them. Tucked deep within the folds of the frontal cortex, the insula (Latin for "island"; FIGURE 3.16) likewise appears to play an important role in addiction, craving, and pleasure. For example, people with damage to the left insula reportedly lose their urge to smoke tobacco and are able to effortlessly quit smoking (Naqvi et al., 2007), and
addiction to numerous substances is associated with abnormalities of the insula (Mackey et al., 2018). It is thought that through its rich interconnections with prefrontal and sensory cortex and the VTA, the insula interacts with several large brain networks to mediate multiple features of addiction (Droutman et al., 2015; Ibrahim et al., 2019). Interestingly, abnormality of the insula is also evident in people whose compulsive use of social media resembles addiction (Turel et al., 2018). Not everyone who uses an addictive drug becomes addicted, of course. For example, most hospitalized patients treated with opiates for pain relief do not go on to abuse opiates after their pain has resolved. However, modern prescription painkillers are highly effective at activating the dopamine reward system, so the use of these drugs outside of medical contexts carries a high risk of addiction. The individual and environmental factors that account for differential susceptibility are the subject of active investigation (Karch, 2006). Some of the major risk factors include biological factors (being male, heritable tendencies to addiction), poor family life, personality factors (poor emotional control), and environmental factors (living in a neighborhood with high rates of addiction). Simply returning to a neighborhood where drugs were previously used can trigger drug craving in an addict (Ciccocioppo et al., 2004); this cue-induced drug use is thought to rely on long-lasting associations that involve remodeling of the brain's reward circuitry (M. E. Wolf, 2016; J. Wang et al., 2018). Let's conclude the chapter considering strategies to treat addiction in Signs and Symptoms, next. Frontal lobe pulled up
FIGURE 3.15 A Neural Pathway Implicated in Drug Abuse (After H. O. Pettit and J. B. Justice Jr. 1991. Brain Res. 539: 93.)
A variety of pleasurable activities, like the ones suggested here, probably activate the dopaminergic pathway that produces rewarding sensations. Drugs of abuse powerfully activate this system and may eclipse other sources of pleasure.
Buried deep within the frontal lobe, changes in insular cortex are associated with the development of drug craving. Shrinkage of the left insula is observed in individuals addicted to various substances.
FIGURE 3.16 The Insula and Addiction
Medical Interventions for Substance Abuse
Some people can overcome their dependence on substances by themselves. For example, the great majority of ex-smokers,
· Directly blocking the actions of the addictive drug Specific receptor antagonists can prevent an abused
and about half of ex-alcoholics, appear to have quit on their own
drug from interacting with its receptors. For example, the
(S. Cohen et al., 1989; Institute of Medicine, 1990). Many others
opiate receptor antagonist naloxone (Narcan) blocks her-
have benefited from counseling and social interventions such
oin's actions, but it also may produce harsh withdrawal
as the 12-step program developed by Alcoholics Anonymous in
the 1930s. However, overcoming addiction may require stronger measures in some cases, especially for the most powerfully addictive substances. An intensive research effort has identified a variety of medicines that can help lessen the grip of addiction through the following strategies: · Lessening the discomfort of withdrawal and drug craving Benzodiazepines and other sedatives, anti-nausea medications, and drugs that promote sleep all help reduce withdrawal symptoms. Other medications help reduce uncomfortable cravings for the abused substance; for example, acamprosate (trade name Campral) eases alcohol-associated withdrawal symptoms. Preliminary evidence indicates that noninvasive stimulation of prefrontal cortex using rTMS (repetitive transcranial magnetic stimulation; see Chapter 2) can reduce drug hunger and relapse rates in people with addiction (Diana et al., 2017). · Providing an alternative to the addictive drug Agonist or partial agonist analogs of the addictive drug weakly activate the same mechanisms as the addictive drug, to help wean the individual. For example, the opioid receptor agonist methadone reduces heroin appetite; nicotine patches work in a similar fashion to reduce cravings for cigarettes.
· Altering metabolism of the addictive drug Changing the breakdown of a drug can reduce or reverse its rewarding properties. Disulfiram (Antabuse) changes alcohol metabolism such that a nausea-inducing metabolite (acetaldehyde) accumulates. · Blocking the brain's reward circuitry When a person takes medicine (e.g., dopamine receptor blockers) to blunt the activity of the mesolimbocortical dopamine reward system, the addictive drugs lose their pleasurable qualities (but at the cost of a general loss of pleasurable feelings, called anhedonia). · Immunization to render the drug ineffective Vaccines against such drugs as cocaine, heroin, and methamphetamine have been developed and are being tested (Hicks et al., 2011; Nguyen et al., 2017). Here the strategy is to prompt the individual's immune system to produce antibodies that remove the targeted drugs from circulation before they ever reach the brain (FIGURE 3.17). The economic impact of substance abuse--the costs of law enforcement, medical care, and lost productivity--exceeds $700 billion per year in the USA alone (National Institute on Drug Abuse, 2017). The social costs of abuse and addiction, furthermore, are incalculable. Unfortunately, no single approach so far appears to be uniformly effective, and rates of relapse remain high. Research
breakthroughs are therefore badly needed.
FIGURE 3.17 The Needle and the Damage Undone (After M. J. Hicks et al. 2011. Mol. Ther. 19: 612.)
In clear contrast to the behavior of normal animals (left), animals that receive cocaine show agitated, hyperstimulated behavior (middle). However, animals that receive cocaine long after being treated with an experimental anticocaine vaccine show no such behavioral change (right).
Resting/ other activities Running Repetitive motions
1. Define substance abuse. How prevalent is drug abuse in the population? 2. Summarize the major models of drug abuse and addiction, highlighting the strengths and shortcomings of each perspective. 3. Describe an experimental setup for measuring the rewarding properties of a drug. 4. Provide a survey of the anatomical system that mediates reward. What happens when this system is activated? What are some triggers that can activate the system, and how does activity of the reward system relate to drug addiction? 5. Provide a thorough overview of medical approaches and interventions in substance abuse.
Recommended Reading Advokat, C. D., Comaty, J. E., and Julien, R. M. (2014). Julien's Primer of Drug Action (13th ed.). New York, NY: Worth. Erickson, C. K. (2018). The Science of Addiction: From Neurobiology to Treatment (2nd ed.). New York, NY: Norton. Grilly, D. M., and Salamone, J. (2011). Drugs, Brain and Behavior (6th ed.). Boston, MA: Allyn & Bacon. Karch, S. B., and Drummer, O. (2015). Karch's Pathology of Drug Abuse (5th ed.). Boca Raton, FL: CRC Press. Meyer, J. S., and Quenzer, L. F. (2018). Psychopharmacology: Drugs, the Brain, and Behavior (3rd ed.). Sunderland, MA: Oxford University Press/Sinauer. Nestler, E., Hyman, S., and Malenka, R. (2014). Molecular Neuropharmacology (3rd ed.). New York, NY: McGraw-Hill. Nutt, D. (2012). Drugs without the Hot Air. Cambridge, UK: UIT Cambridge. Thombs, D. L., and Osborn, C. J. (2013). Introduction to Addictive Behaviors (4th ed.). New York, NY: Guilford Press.
3 · VISUAL SUMMARY You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material.
2 Neurotransmitters exert their effects via neurotransmitter receptors; these are also the site of action for many psychoactive drugs. Most transmitters have several different subtypes of receptors, which may be individually targeted by drugs. A given neurotransmitter may normally bind several different subtypes of receptors. Review Figure 3.2, Table 3.2
3 The major categories of neurotransmitters are amine, amino acid, peptide, and soluble gas neurotransmitters. Neurotransmitter systems form complex, overlapping patterns of projections throughout the brain. Review Figures 3.3 and 3.4, Table 3.1, Animation 3.3, Activity 3.1
4 Drugs classified as agonists activate transmitter pathways, and antagonists block transmitter pathways. Repeated exposure to drugs may cause a compensatory down-regulation (decrease) or up-regulation (increase) in the number of receptors. Changes in receptor density are one mechanism of drug tolerance. Review Figure 3.5, Animation 3.4
5 The dose-response curve (DRC) quantifies the relationship between doses of a drug and its physiological effects, and it can be used to deduce characteristics such as drug potency and safety. Review Figure 3.6
7 Many psychoactive drugs have postsynaptic effects, especially activation or blockade of postsynaptic receptors. Most antipsychotic medications block postsynaptic dopamine (DA) receptors, but some also block serotonin (5-HT) receptors. Other drugs affect metabolic processes within the postsynaptic neuron, such as by altering second-messenger systems, or change the production of crucial proteins (e.g., transmitter receptors). Review Figure 3.8
9 The active ingredient in cannabis-- delta-9-tetrahydrocannabinol, or THC--acts on cannabinoid receptors to produce its effects. Anandamide is an endocannabinoid that acts at these receptors to affect mood, pain sensitivity, blood pressure, and other functions. Review Figure 3.10B 11 Alcohol acts on gamma-aminobutyric acid (GABA) receptors to produce some of its effects. In moderation, alcohol has beneficial effects; in higher doses it is very harmful, damaging neurons in many areas of the brain. Review Figures 3.11 and 3.12
13 Substance abuse and dependence (addiction) are studied intensively, and several explanatory models have been proposed. The positive reward model, based on the observation that animals will work very hard to self-administer highly addictive drugs, has received the most support from research. Review Figure 3.14, Table 3.5
6 Psychoactive drugs have three main presynaptic actions: some drugs alter transmitter synthesis, others alter transmitter release, and some block the clearance of transmitter after it has been released. Review Figure 3.7
8 Opiates such as morphine are potent painkillers; the brain also makes its own endogenous opioids with a variety of effects. Opiates act on specific opioid receptors, especially in a major pain pathway that includes the periaqueductal gray. Review Figure 3.10A
10 Some stimulants, such as nicotine, imitate an excitatory synaptic transmitter. Others, such as amphetamine, cause the release of excitatory synaptic transmitters and block the reuptake of transmitters. Cocaine causes the release of transmitters, especially dopamine, in wide regions of the brain. Review Figure 3.10C
12 Some drugs are called hallucinogens because they alter sensory perception and produce extraordinary visual and emotional experiences. Although hallucinogens vary in their actions, many act upon serotonin receptors in the visual cortex, perhaps explaining their effects on visual perception. Review Figure 3.13
14 A dopamine-based neural pathway from the ventral tegmental area to the nucleus accumbens appears to be a system for experiencing pleasure and reward. Researchers believe that this reward system plays an important role in the formation of addictions. The cortical region called the insula also plays a special role in drug cravings; lesions here reduce the addictive qualities of some drugs. Some experimental treatments for addiction involve blocking the reward signal from drugs. Review Figures 3.15-3.3.17
The Mind's Machine digital resources include additional videos, flashcards, and other study tools. Watson/Breedlove The Mind's Machine