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Psychostimulants

Cocaine, amphetamines, and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects 16–2; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 13). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.

16–2Acute Effects of Psychostimulants and Withdrawal Symptoms

Cocaine and amphetamines produce their psychoactive effects by potentiating monoaminergic transmission 16–2 through actions on dopamine, serotonin, and norepinephrine transporters, although the precise mechanisms underlying this potentiation vary 16–3. These proteins normally transport synaptically released neurotransmitter back into the presynaptic nerve terminal and thereby terminate transmitter action (Chapter 6). Actions at the dopamine transporter (DAT) are the most important for the reinforcing effects of these drugs; for example, mice with a null mutation in the DAT gene are much less sensitive than normal mice to the behavioral effects of cocaine or amphetamines.

16–2

Highly simplified scheme of converging acute actions of drugs of abuse on the VTA–NAc. Stimulants directly increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit GABAergic interneurons in the VTA, which disinhibits VTA dopamine neurons. Opiates also directly act on opioid receptors on NAc neurons, and opioid receptors, like D2 dopamine receptors, signal via Gi; hence, the two mechanisms converge within NAc neurons. The actions of the other drugs remain more conjectural. Nicotine activates VTA dopamine neurons directly via stimulation of nicotinic cholinergic receptors on those neurons, and indirectly via stimulation of its receptors on glutamatergic nerve terminals that innervate the dopamine cells. Ethanol, by promoting GABAA receptor function, may inhibit GABAergic terminals in VTA and hence disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals that innervate NAc neurons. Cannabinoid mechanisms involve activation of CB1 receptors (which, like D2 and opioid receptors, are Gi linked) on glutamatergic and GABAergic nerve terminals in the NAc and possibly on NAc neurons themselves. PCP may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally, evidence suggests that nicotine and ethanol may activate endogenous opioid pathways, and that these and other drugs of abuse (eg, opiates) may activate endogenous cannabinoid pathways (not shown).

16–3

Mechanism of action of cocaine and amphetamine on monoamine nerve terminals. A. Cocaine potentiates the actions of monoamines at the synapse by inhibiting monoamine transporter proteins, which normally carry previously released transmitter back into the nerve terminal. B. Amphetamine serves as a substrate for monoamine transporter proteins and is transported into the nerve terminal. In the nerve terminal, amphetamine disrupts the vesicular storage of monoamine transmitters, which leads to an increase in their extravesicular levels; consequently, these transmitters are pumped out of the nerve terminal by a reverse action of the transporters. Recent research has demonstrated the involvement of dopamine transporter trafficking to and from the nerve terminal plasma membrane in the actions of psychostimulants.

The reinforcing effects of cocaine and amphetamines require an intact mesolimbic dopamine system. Systemic administration of dopamine antagonists, or of the dopamine synthesis inhibitor α-methylparatyrosine (AMPT), decreases self-administration; in contrast, antagonists of various adrenergic or serotonergic receptors have little effect on such behavior. Selective antagonists for multiple dopamine receptor subtypes (D1, D2, and D3) are effective in decreasing the reinforcing actions of cocaine. Dopamine levels are increased in the NAc during self-administration of cocaine or amphetamines, as mentioned previously, and blockade of dopaminergic transmission in the NAc—for example, in response to intra-NAc injections of dopamine receptor antagonists or of the toxin 6-hydroxydopamine (Chapter 6)—dramatically reduces drug reinforcement. Dopamine in the NAc exerts complex effects on γ-aminobutyric acid (GABA)ergic medium spiny projection neurons, with excitation or inhibition seen depending on several factors including the predominant form of dopamine receptor expressed in a particular cell (see the section “Extended Reward Circuitry”). However, how altered excitability of these neurons contributes to drug reinforcement remains unknown.

Methamphetamine is an amphetamine derivative whose pharmacologic effects are very similar to those of amphetamine, but is longer acting due to pharmacokinetic considerations. Methamphetamine is easily synthesized from over-the-counter products (eg, the α-adrenergic agonist, pseudoephedrine), and this has led to its increasing use as an abused drug. Unlike cocaine and amphetamine, methamphetamine is directly toxic at higher doses to midbrain dopamine neurons.

Opiates

The opiates and their synthetic analogs are the most effective analgesic agents known (Chapter 11), yet they are widely abused because of their effects on brain reward circuitry 16–3. Morphine and heroin, along with a host of prescription opiates (eg, oxycontin), are among the most commonly abused opiates. Abuse of these drugs may be driven by a variety of factors, including their reinforcing effects, their ability to relieve both preexisting dysphoria and unpleasant symptoms related to drug withdrawal, and the intense craving they produce after long-term use. Physical dependence on opiates can occur independently of addiction; for example, patients with cancer pain may become physically dependent on these drugs but do not compulsively abuse them. Termination of opiate use is accompanied by emotional–motivational symptoms as well as somatic withdrawal symptoms 16–3.

16–3Acute Effects of Opiates and Withdrawal Symptoms

Immediate effects of opiate drugs result from their binding to endogenous opioid receptors. As discussed in Chapter 7, the three types of opioid receptors—μ, δ, and κ—are distinguished by their pharmacologic profiles and anatomic distributions. These receptors belong to the G protein–coupled receptor superfamily and exhibit significant homology, particularly in transmembrane and intracellular regions. Opioid receptors couple with Gi/o proteins to inhibit adenylyl cyclase, to activate inwardly rectifying K+ channels, and to inhibit voltage-gated Ca2+ channels. They typically mediate inhibitory responses that involve a reduction in excitability and cell firing, and inhibition of neurotransmitter release. Examples of neural and behavioral actions mediated by μ, δ, and κ opioid receptors are listed in 16–4.

16–4Receptor Subtypes Implicated in Actions of Opiates

Opiates activate brain reward circuitry via two main mechanisms: (1) disinhibition of the VTA, which results in dopamine release in the NAc, and (2) dopamine-independent activity in the NAc. For example, reinforcing effects of intravenous heroin can be partly attenuated by administration of an opioid receptor antagonist directly into the VTA or by lesions of VTA dopaminergic neurons. Opiate activation of such neurons results from opiate inhibition of GABAergic interneurons in the VTA that normally inhibit principal dopamine neurons 16–2.

Opiates also produce reinforcement through direct dopamine-independent actions on μ, and perhaps δ, receptors expressed in NAc neurons. These receptors are normally targets of the enkephalinergic (and possibly endorphinergic) neurons that innervate this brain region. Animals will work to self-administer opiates directly into the NAc, even in the presence of dopamine receptor blockade or 6-hydroxydopamine lesions of dopaminergic terminals in this region of the brain. Within the NAc, opiates directly inhibit some of the same populations of medium spiny projection neurons that are inhibited by dopamine. Thus, opioid and dopaminergic systems appear to converge on a common efferent reward pathway in the NAc 16–2.

In contrast to μ and δ opioid receptor subtypes, κ opioid receptor activation is not reinforcing; indeed, it is aversive. Activation of κ receptors decreases dopamine release in the NAc; thus, the mesolimbic dopamine system may mediate aversive effects of opiates as well as their reinforcing properties. See Chapter 11 for a discussion of the use of κ opioid agonists (eg, benzomorphan analgesics) in the treatment of pain. Tonic activation of the different opioid receptors in the reward circuitry by endogenous opioid peptides may modulate responses to natural reinforcers and influence an individual’s motivational state.

Ethanol

Ethanol is a CNS depressant that shares some behavioral effects with sedative–hypnotic drugs such as barbiturates and benzodiazepines (16–5; Chapters 5, 13, and 15). In humans it is clearly reinforcing and addictive, as evidenced by its widespread compulsive use. Ethanol reinforcement can be demonstrated in animals as well. The many serious health problems associated with long-term ethanol use, such as gastritis, cirrhosis, and malnutrition, most likely are related to the extremely large amounts of ethanol that are necessary for its psychoactive effects (as much as 100 mM in tolerant users), and also to the ability of this small molecule to interact with numerous physiologic systems.

16–5Acute Effects of Ethanol and Withdrawal Symptoms

Despite the high concentrations required for its psychoactive effects, ethanol exerts specific actions on the brain. The initial effects of ethanol result primarily from facilitation of GABAA receptors and inhibition of NMDA glutamate receptors. At higher doses, ethanol also inhibits the functioning of many other types of ion channels. Recent evidence supports the view that ethanol selectively affects these channels via direct actions at low-affinity binding sites.

Ethanol allosterically regulates the GABAA receptor to enhance GABA-activated Cl flux. The anxiolytic and sedative effects of ethanol, as well as those of barbiturates and benzodiazepines, result from enhancement of GABAergic function. Facilitation of GABAA receptor function is also believed to contribute to the reinforcing effects of these drugs. Not all GABAA receptors are ethanol sensitive. As mentioned in Chapters 5 and 15, GABAA receptor complexes comprise combinations of five distinct subunit families. The regional distribution and relative abundance of these subunit combinations vary, and thus likely explain differences in the sensitivity of GABAA receptors to ethanol in different brain regions.

Ethanol also acts as an NMDA antagonist by allosterically inhibiting the passage of glutamate-activated Na+ and Ca2+ currents through the NMDA receptor. The sensitivity of NMDA receptors to ethanol, like that of GABAA receptors, may depend on receptor subunit composition. Other NMDA antagonists, such as phencyclidine (PCP) and ketamine, produce profound cognitive deficits and psychotic symptoms; thus, the dissociative and psychotomimetic effects of ethanol (at higher doses) may be mediated by means of such antagonism. Because other NMDA antagonists are reinforcing, some of ethanol’s addicting properties also are likely mediated by this mechanism.

The cellular mechanisms through which ethanol influences reinforcement systems is not yet known, but evidence suggests the involvement of several neurotransmitter systems (see 16–2). The reinforcing effects of ethanol are partly explained by its ability to activate mesolimbic dopamine circuitry, although it is not known whether this effect is mediated at the level of the VTA or NAc. It also is not known whether this activation of dopamine systems is caused primarily by facilitation of GABAA receptors or inhibition of NMDA receptors, or both. Ethanol reinforcement also is mediated in part by ethanol-induced release of endogenous opioid peptides within the mesolimbic dopamine system, although whether the VTA or NAc is the predominant site of such action is not yet known. Accordingly, the opioid receptor antagonist naltrexone reduces ethanol self-administration in animals and is used with modest effect to treat alcoholism in humans. Ethanol affects many other neurotransmitter systems in the brain, which may also contribute to its behavioral actions.

The best established genetic contribution to addiction is the protective effect that mutations in alcohol-metabolizing enzymes have on risk for alcoholism. Mutations that increase alcohol dehydrogenase (ADH) activity and decrease aldehyde dehydrogenase (ALDH) activity are additive and promote accumulation of acetaldehyde following ingestion of alcohol. This produces intoxication at low doses and a flushing reaction that is unpleasant, resembling the reaction to disulfiram, a drug used to prevent relapse (see below). These variants are common among people of East Asian descent, and individuals expressing these variants rarely abuse alcohol.

Nicotine is the main psychoactive ingredient of tobacco and is responsible for the stimulant effects, reinforcement, dependence, and addiction that result from tobacco use 16–6. Cigarette smoking rapidly delivers pulses of nicotine into the bloodstream. Nicotine differs from cocaine and opiates in that it is powerfully reinforcing in the absence of subjective euphoria. The high incidence of carcinogenicity associated with long-term tobacco use is related predominantly to compounds other than nicotine that are either contained in tobacco or generated by its combustion.

16–6Acute Effects of Nicotine and Withdrawal Symptoms

The initial effects of nicotine are caused by its activation of nicotinic acetylcholine (nACh) receptors. nACh receptors are ligand-gated cation channels (Chapters 6 and 9); in the CNS, they are located postsynaptically and also on presynaptic terminals, where they facilitate transmitter release. The reinforcing effects of nicotine, like those of other addictive drugs, depend on an intact mesolimbic dopamine system. nACh receptors located on VTA dopamine neurons are implicated in nicotine reinforcement. Systemic nicotine self-administration is disrupted when antagonists are administered directly into the VTA but not when they are administered into the NAc; moreover, nicotine is rewarding when injected directly into the VTA. Receptors composed of α4β2 subunits are the most important for these actions, as knockout of either receptor abolishes nicotine reward. There is also evidence for the involvement of α7 homomeric receptors being involved. nACh receptors on VTA dopamine neurons are normally activated by cholinergic innervation from the laterodorsal tegmental nucleus or the pedunculopontine nucleus (Chapters 6 and 13). In addition, nicotine may stimulate dopamine release in the NAc through actions on presynaptic nACh receptors located on dopamine terminals within the NAc. Nicotine self-administration also can be blocked by opioid receptor antagonists such as naltrexone. These findings indicate the involvement of endogenous opioid systems in the reinforcing effects of nicotine, and raise the possibility that such antagonists may be of use in the treatment of nicotine addiction.

Variations in the genes that encode several nACh receptor subunits, α3, α5, and β4, all of which cluster in a location on chromosome 15, contribute to the risk for nicotine addiction as well as for some of the health risks associated with tobacco use (eg, chronic obstructive pulmonary disease and lung cancer). Although these genetic variations represent only a very small fraction of the total genetic risk for nicotine addiction, they are among the best established heritable factors yet discovered. Increasing evidence suggests that loss-of-function versions of the α5 subunit promote nicotine addiction by reducing aversive effects of the drug. According to this scheme, nicotine activation of α5-containing nACh receptors in the lateral habenula and that in the medial habenula lead, respectively, to the activation of GABAergic neurons in the ventral midbrain that inhibit VTA dopamine neurons and to the activation of the interpeduncular nucleus, which together produce an aversive response.

Cannabinoids

Delta-9-tetrahydrocannabinol (THC) is one of several cannabinoid compounds contained in marijuana, and is primarily responsible for the psychoactive effects of cannabis preparations 16–7. Although the addictive potential of THC has been a matter of past debate, there is no question that it can be addicting, since there are many compulsive users of marijuana. Withdrawal symptoms typically do not occur with termination of long-term marijuana use, because of the persistence of accumulated THC in the tissues of long-term users. However, cannabinoid dependence can be demonstrated experimentally with the use of cannabinoid receptor antagonists, which precipitate profound withdrawal symptoms that are both physical and emotional–motivational.

16–7Acute Effects of Cannabinoids and Withdrawal Symptoms

THC exerts its primary pharmacologic effects by binding to a G protein–coupled receptor in the brain known as the CB1 receptor—a misnomer because cannabinoids are not natural ligands for this receptor. Rather, endogenous ligands for this receptor are arachidonic acid derivatives termed anandamide and 2-arachidonoylglycerol (2-AG). THC induces dopamine release in the NAc via CB1 receptors, although the mechanism remains obscure. The best defined action of cannabinoids in NAc is induction of a unique form of long-term depression (LTD), which is mediated via activation of CB1 receptors on glutamatergic nerve terminals leading to inhibition of glutamate release (Chapters 5 and 8). The pharmacology and psychoactive effects of cannabinoids are summarized in 16–7. Interestingly, release of endogenous cannabinoids has been demonstrated after administration of several drugs of abuse, which has stimulated interest in the potential utility of CB1 antagonists or inverse agonists (eg, rimonabant) in the treatment of drug addiction. Such antagonists are also being considered for the treatment of obesity (Chapter 10); however, their clinical development has been stalled by the high incidence of depression and suicidal behavior, as might be expected from blockade of an endogenous reward mechanism.

Phencyclidine

PCP (or angel dust) and ketamine (also known as special K) are structurally related drugs 16–4 that are classified as dissociative anesthetics. These drugs are distinguished from other psychotomimetic agents, such as hallucinogens, by their distinct spectrum of pharmacologic effects, including their reinforcing properties and risks related to compulsive abuse (Chapter 17). At lower doses, ketamine has been shown to exert rapid antidepressant effects (Chapter 15).

16–4

Chemical structures of some miscellaneous drugs that are self-administered for psychotropic effects.

The reinforcing properties of PCP and ketamine are mediated by the binding of these drugs to specific sites in the channel of the NMDA glutamate receptor, where they act as noncompetitive antagonists. PCP is self-administered directly into the NAc, where its reinforcing effects are believed to result from the blockade of excitatory glutamatergic input to the same medium spiny NAc neurons inhibited by opioids and dopamine (see 16–2).

Other Drugs of Abuse

Several other classes of drugs are categorized as drugs of abuse 16–4 but rarely produce compulsive use. These include psychedelic agents, such as lysergic acid diethylamide (LSD), which are used for their ability to produce perceptual distortions at low and moderate doses. The use of these drugs is associated with the rapid development of tolerance and the absence of positive reinforcement (Chapter 6). Partial agonist effects at 5HT2A receptors, with the activation of particular downstream signaling pathways, are implicated in the psychedelic actions of LSD and related hallucinogens.

3,4-Methylenedioxymethamphetamine (MDMA), commonly called ecstasy or Molly, is an amphetamine derivative. It produces a combination of psychostimulant-like and weak LSD-like effects at low doses. Unlike LSD, MDMA is reinforcing—most likely because of its interactions with dopamine systems—and accordingly is subject to compulsive abuse. The weak psychedelic effects of MDMA appear to result from its amphetamine-like actions on the serotonin reuptake transporter, by means of which it causes transporter-dependent serotonin efflux. MDMA has been proven to produce lesions of serotonin neurons in animals and humans.

A variety of volatile chemicals are abused as inhalants because of their ability to produce rapid and brief intoxication, which generally consists of some degree of euphoria and light-headedness. Abused inhalants include commercial products that are readily obtained by minors and that consist of diverse chemical classes—for example, aerosol products, formaldehydes, household solvents, adhesives, gasoline, and nitrous oxide. Their pharmacologic effects and toxicity vary, depending on their constituent chemicals; however, their mechanisms of action remain obscure. Compulsive use of inhalants can be severe.

It is difficult for neuropharmacologists and drug enforcement officials to keep up with the production of so-called designer drugs, compounds with unique chemical structures (which hence avoid for a time illegal status) that produce powerful psychotropic effects. Examples are synthetic cannabinoids, most of which activate—with very high affinities—the CB1 receptor and, unsurprisingly, show compulsive patterns of use.

Caffeine and related methylxanthines (eg, theophylline and theobromine) stimulate the CNS, produce increased alertness, improve psychomotor performance, and decrease fatigue. Long-term caffeine use can lead to mild physical dependence. A withdrawal syndrome characterized by drowsiness, irritability, and headache typically lasts no longer than a day. True compulsive use of caffeine has not been documented, and, consequently, these drugs are not considered addictive. The main mechanism responsible for the pharmacologic effects of methylxanthines is competitive antagonism of G protein–coupled adenosine A1 and A2A receptors (Chapter 8).

Role of Reward Circuitry in “Natural Addictions”

As previously indicated, the neural circuitry activated by reinforcing brain stimulation and by addictive drugs is part of an endogenous reward mechanism that motivates individuals to pursue natural reinforcers such as food and sex. Can compulsive eating, shopping, gambling, and sex—so-called “natural addictions”—be related to abnormal regulation of endogenous reward mechanisms in certain individuals? Just as addictive drugs can powerfully activate reward pathways and consequently modify motivated behavior, it is possible that these pleasurable behaviors may excessively activate reward–reinforcement mechanisms in susceptible individuals. As with drugs, such activation may result in profound alterations in motivation that promote the repetition of initially rewarding behavior, despite the impact of negative consequences associated with the resulting compulsion. Indeed, addictions to both drugs and behavioral rewards may arise from similar dysregulation of the mesolimbic dopamine system. While speculative, such a view is supported by brain imaging studies in humans.

Dopaminergic Neurons and Reward-Dependent Learning

How does increased dopaminergic transmission in the NAc, elicited by natural reinforcers, drugs, or rewarding brain stimulation, strengthen the motivated behavior produced by these stimuli? Dopamine’s precise role in reinforcement has been recently reevaluated. Instead of simply mediating subjective pleasure, dopamine may affect motivation and attention to salient stimuli, including rewarding stimuli. Several experimental findings suggest that the pleasure associated with food does not necessarily depend on dopamine; rather, it appears to be more affected by drugs that influence opioid and GABA systems. Dopaminergic lesions of the NAc and caudate nucleus, as well as dopamine receptor antagonists, can alter the motivation to eat, but do not affect the hedonic value assigned to taste. If motivational drive is described in terms of wanting, and hedonic evaluation in terms of liking, it appears that wanting can be dissociated from liking and that dopamine may influence these phenomena differently. Differences between wanting and liking are confirmed in reports by human addicts, who state that their desire for drugs (wanting) increases with continued use even when pleasure (liking) decreases because of tolerance. Moreover, during withdrawal the desire for drugs can be more strongly associated with dysphoria than with pleasure.

The involvement of dopaminergic neurons in the regulation of attention and motivation is suggested by electrophysiologic studies of dopaminergic neurons in the midbrain of the monkey. These neurons respond robustly to reward-predicting stimuli as well as to unexpected—but not expected—rewards. Thus, they appear to signal not a reward per se but salient events that warrant attention. Therefore, it is predictors of reward and unexpected rewarding stimuli that elicit significant responses in dopaminergic neurons of the midbrain; indeed, these neurons respond less to rewards that have become predictable based on previous experience. When predicted rewards fail to occur, dopaminergic neurons signal this deviation from expected events by a decrease in activity at the time the reward was predicted to have occurred. Based on such findings, it appears that these neurons can signal positive and negative outcomes in relation to predicted rewards. It has been suggested that the dopamine signal may constitute a mechanism of learning relevant to rewards. Dopaminergic innervation of the prefrontal cortex has been strongly associated with regulation of executive functions such as working memory (Chapter 14), a finding that further demonstrates the potent effects of dopamine—and of drugs that affect dopaminergic transmission—on attention and planning.

The functioning of midbrain dopamine neurons is, however, more complicated than the scheme outlined above. A subset of VTA dopamine neurons are activated—not suppressed—by a range of negative emotional stimuli and are believed to enhance attention to and memory of such aversive events. One current hypothesis is that distinct subsets of VTA dopamine neurons, with different afferent inputs and efferent projections, differentially signal positive versus negative environmental stimuli.

Extended Reward Circuitry

Dopaminergic neurons of the midbrain are believed to function in reward and reinforcement as part of a neural circuit at the interface between limbic emotional–motivational information and extrapyramidal regulation of motor behavior. The major components of this circuit and the critical substrates for drug reward are represented in 16–1. A macrostructure postulated to integrate many of the functions of this circuit is described by some investigators as the extended amygdala. The extended amygdala is said to comprise several basal forebrain structures that share similar morphology, immunocytochemical features, and connectivity and that are well suited to mediating aspects of reward function; these include the bed nucleus of the stria terminalis, the central medial amygdala, the shell of the NAc, and the sublenticular substantia innominata.

The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.

As stated earlier, the GABAergic medium spiny neurons of the NAc are critical components of the postulated limbic–extrapyramidal interface involved in reward and reinforcement. By analogy with such neurons in the dorsal striatum (Chapter 14), NAc projection neurons integrate glutamatergic inputs from the cerebral cortex, hippocampus, amygdala, and thalamus with dopamine inputs from the midbrain. In contrast to activity in the dorsal striatum, however, cortical inputs to the NAc arise from prefrontal cortex (rather than from motor cortex and other areas) and dopamine inputs originate in the VTA (rather than in the substantia nigra). In both the NAc and the dorsal striatum, the interactions between dopamine and glutamate may underlie learning and presumably involve plasticity at synapses formed between glutamatergic neurons and neurons of the NAc and dorsal striatum. The actions of addictive drugs in these circuits may underlie the acquisition of learned drug-seeking behaviors, in accord with dopamine’s postulated involvement in the prediction of reward in animals.

Both main subtypes of GABAergic medium spiny neurons in the NAc (Chapter 18) are strongly linked to reward-related behaviors. One subtype comprises the direct pathway and projects from the NAc to the VTA. Neurons of this pathway express predominantly D1 dopamine receptors plus dynorphin and substance P. The other subtype comprises the indirect pathway and projects from the NAc to the ventral pallidum. Neurons of this pathway express predominantly D2 dopamine receptors plus enkephalin. Recent optogenetic studies (see Chapter 2) show that activation of the direct pathway stimulates drug reward, while activation of the indirect pathway inhibits drug reward. This is consistent with the notion that drugs of abuse might activate direct pathway neurons via stimulation of D1 receptors, but inhibit the indirect pathway via stimulation of D2 receptors. In reality, however, the effect of drugs on activity of direct and indirect pathway neurons is far more complex and may depend in part on the ambient level of activation of these neurons by glutamatergic innervation. A major goal of current research is to more clearly define the role of these two major cell types in reward behavior and to explicate how regulation of their excitability leads to reward and reinforcement.

The amygdala regulates an individual’s orientation to and memory of emotionally salient stimuli. Projections between the NAc and the amygdala are believed to be important to the formation of stimulus–reward associations. Neurons in the amygdala fire in response to food-related stimuli. Lesions of the amygdala disrupt the ability of experimental animals to remember the pairing of a stimulus with a reward (without disrupting recognition of the stimulus) and can lessen the response to a conditioned reinforcer previously paired with a natural reward. The central nucleus of the amygdala also has been implicated in aversive aspects of drug withdrawal, as described in a subsequent section of this chapter, and is associated with fear, as discussed in Chapter 15.

In addition to the amygdala, other memory circuits in the brain are affected by drugs of abuse. The hippocampus is likely involved in mediating the powerful associations between drug use and environmental cues. Regions of prefrontal cortex, as mentioned earlier, are critical for executive function. Such cortical regions provide control over impulses for destructive behavior, and their impairment, demonstrated in animals and humans after chronic drug exposure, appears to be an important mediator of the loss of control over drug intake that is central to addiction.

Finally, several peptide systems of the hypothalamus (eg, melanocortins, orexins, melanin-concentrating hormone) have been implicated in the actions of drugs of abuse on the brain. These systems, which normally function as an interplay between wanting and physiologically needing food (Chapter 10), may be corrupted by drugs of abuse and contribute to addictive syndromes.

Optogenetic and related tools are now making it possible for scientists to determine with unprecedented precision the influence of each of these brain areas, and specific neuronal cell types within each region, on different aspects of reward and reinforcement as well as on the compulsive behavior that characterizes addiction.

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