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Cocaine and Amphetamines Introductory article Article Contents George V Rebec, Indiana University, Bloomington, Indiana, USA . Ephedrine, the First General Stimulant As stimulants, cocaine and amphetamines heighten arousal and increase behavioural activation. More ominously, rapid delivery of a high concentration of these drugs to the brain triggers a state of euphoria (the so-called ‘flash’ or ‘rush’) that creates an alarming potential for abuse. Cocaine and amphetamines are phenylisopropylamines whose stimulant properties have been known for centuries. . General Stimulants and an Increase in the Availability of Norepinephrine (Noradrenaline) . Sympathomimetics as General Stimulants . Stimulation of Behavioural Arousal and Vigilance . Stimulation of Pleasure . Overdoses and Acute Psychosis . Use as Therapeutic Agents . Caffeine and Other Xanthines . Summary Ephedrine, the First General Stimulant The stimulant effects of ephedrine, an alkaloid of the shrub, Ephedra vulgaris, were described in China more than 5000 years ago. Local physicians typically used the plant, also known as ma huang, as a herbal remedy for asthmatic wheezing and other pulmonary problems. These disorders are caused by severe constriction of the bronchial tree, and ephedrine simply relaxes bronchial muscle to improve respiration. Although Western medicine relied on intravenous epinephrine (adrenaline) to treat severe asthma, pharmaceutical firms recognized the value of developing an oral medication for bronchial congestion. By 1935, several ephedrine analogues were synthesized, some of which remain in use as nasal decongestants (e.g. pseudoephedrine). The amphetamines were developed as part of this effort. In fact, the first synthetic ephedrine analogue was a mixture of d- and l-amphetamine. Marketed in 1932 as a decongestant, these amphetamine isomers were the active ingredient in the popular Benzedrine inhaler, which quickly became known for its stimulant properties. The addition of a second methyl group created an even more potent amphetamine variant, methamphetamine, sold as Methedrine. After the amphetamines became available in tablet form, they were used to treat both narcolepsy, a condition characterized by sleep attacks, and attention-deficit hyperactivity disorder (ADHD), an apparent paradoxical effect (see below). Amphetamine tablets also were used as appetite suppressants; d-amphetamine was marketed for this purpose as Dexedrine in 1945, but the anorexiant effect faded rapidly with repeated use. It was during World War II, however, that the stimulant properties of the amphetamines became widely recognized. Many American, German and Japanese soldiers relied on the activating effects of these drugs during prolonged military campaigns. The problem was especially severe in Japan, where civilians used methamphetamine to keep up factory production for the war effort, and large stockpiles of the drug continued to be available after the war. By the 1960s, abuse of amphetamines had spread throughout the industrialized world, and govern- ments placed tight restrictions on the production and distribution of these drugs; the now-infamous Benzedrine inhaler was banned in 1959 as part of this effort. Despite the crackdown, abuse of amphetamines continued, and to make matters worse, authorities were soon confronted with a drug problem they thought had been solved many years earlier: cocaine abuse. Cocaine occurs naturally in the leaves of a shrub, which thrives along the eastern slopes of the Andes (Erythroxylon coca) and other circumscribed regions of South America (Erythroxylon novogranatense). Although natives of the Andean highlands have been known for centuries to chew coca leaves to increase energy and elevate the spirit, it was not until the 1860s ] when cocaine could be extracted from the leaves and refined to a pure form ] that cocaine use spread to Europe and other continents. The coca extract first gained popularity as a ‘feel-good’ additive to wines and other beverages, though some physicians, including a young Sigmund Freud, wrong-headedly recommended intravenous cocaine to treat morphine addiction. The real medicinal value of cocaine resided in its local anaesthetic effects, which allowed it to be used for delicate eye and lung surgery (see below). By the end of the nineteenth century, cocaine’s easy availability and favourable advertising, which included many celebrity endorsements, led to widespread abuse. Laws were passed to control its use and distribution. Cocaine abuse did not resurface on a large scale until the 1970s when snorting cocaine powder became a way to get ‘high’ without needles or other dangerous paraphernalia. In the mid-1980s, the introduction of a cheap, smokable version of the drug known as ‘crack’ led to another surge in cocaine abuse, creating more than 3 million addicts in the United States alone. The amphetamines also experienced an illicit upgrade, resulting in still more dangerous variants, including a smokable and highly addictive form of methamphetamine known as ‘ice’. More than 100 years after the first widespread use of cocaine, stimulant abuse continues to be a major, worldwide problem. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 1 Cocaine and Amphetamines General Stimulants and an Increase in the Availability of Norepinephrine (Noradrenaline) The amphetamines induce many physiological changes, including an increase in heart rate and blood pressure, dilatation of the bronchial tree, and increased respiration. Because these effects mimic activation of the sympathetic nervous system, the amphetamines and other drugs that have these effects, including cocaine, are called sympathomimetics. The sympathetic nervous system is most active in times of danger or stress to prepare the body for ‘fight or flight’. Sympathomimetic drugs mimic this effect by increasing the function of norepinephrine (noradrenaline), the transmitter released by the sympathetic neurons innervating the heart, vasculature, lungs and other internal organs. Many of these drugs also act on epinephrine (adrenaline), which when released into the bloodstream as a hormone reinforces the effects of sympathetic activation. Communication between a sympathetic nerve ending and its target organ was one of the first events studied by researchers interested in nervous system function. The basic principles were established by the mid-1950s. Norepinephrine is released from the transmitting or presynaptic neuron to interact with receptors on the receiving or postsynaptic cell. Almost immediately, the norepinephrine returns to the presynaptic neuron by a process known as reuptake. Under normal conditions, reuptake prevents overstimulation of synaptic receptors and resupplies the neuron with releasable norepinephrine. Drugs like the amphetamines and cocaine activate the sympathetic system by subverting the reuptake mechanism. Reuptake depends on transporter proteins located in the presynaptic membrane. Each transporter is equipped with a specialized site that binds a molecule of norepinephrine. This site normally faces outward in anticipation of norepinephrine release. When the released norpinephrine attaches, ionic gradients across the neuronal membrane cause the transporter to rotate inward. When the norepinephrine enters intracellular fluid, it detaches from the transporter, which then returns to its outward position to repeat the process. In effect, the transporter operates as a kind of revolving door moving norepinephrine from outside to inside the neuron. The amphetamines and cocaine are like norepinephrine in that they attach to the transporter. But their attachment changes the function of the transporter in dramatic, albeit very different, ways. The amphetamines cause the transporter to release rather than take up norepinephrine. This effect begins with an accumulation of amphetamine molecules outside the neuron. The transporter, recognizing them as norepinephrine, springs into action. As amphetamine is carried into the neuron, it detaches from the transporter, and the transporter is now free to return to its 2 extracellular configuration. But because there already is a large concentration of norepinephrine molecules inside the neuron, they can attach to the transporter as it rotates outward and they get deposited in the synapse. Another factor reinforces this effect. As amphetamine accumulates intracellularly, it enters the vesicles that store even more norepinephrine. Under normal conditions, vesicular norepinephrine is held in place by an acidic or low pH, but amphetamine, which is slightly basic, causes the pH to increase and allows norepinephrine to leak from the vesicles into the surrounding cytoplasm. This rise in intracellular norepinephrine means that more is available for outward transport. The amphetamines, therefore, increase sympathetic activation by causing the outward movement of norepinephrine from sympathetic nerve endings. Cocaine also binds to the norepinephrine transporter, but unlike amphetamine, cocaine does not ride the transporter into the neuron. Instead, the relatively large size of the cocaine molecule prevents the transporter from working. Without a functioning transporter, the neuron loses its ability to regulate synaptic transmission. Thus, norepinephrine released into the synapse when the neuron becomes active will not be removed. Unlike the amphetamines, therefore, cocaine does not release norepinephrine but allows it to accumulate in the synapse. Although this action of cocaine contributes to its sympathomimetic effects, the drug also acts on brain circuits that directly control the sympathetic system, further enhancing a sympathomimetic response. Sympathomimetics as General Stimulants Even before the removal of Benzedrine inhalers, it became clear that amphetamine-like drugs were not the ideal treatment for bronchial congestion. The challenge was to develop drugs that could dilate the bronchial tree without interfering with the entire sympathetic system. A step in this direction was made in the 1940s with the synthesis of isoproterenol. Rather than increase synaptic norepinephrine like cocaine and the amphetamines, isoproterenol stimulated a specific group of postsynaptic receptors. At noradrenergic synapses, receptors are classified as either aadrenergic or b-adrenergic. Within each classification, moreover, there are several subtypes. All respond to norepinephrine, but each has a slightly different configuration such that a drug with a slightly different molecular shape may activate only one or a few subtypes selectively. The situation is analogous to locks in a building. A master key may open them all, but individual keys may only open a select few. Isoproterenol stimulates b-adrenergic receptors, which are located on only some sympathetic target organs, including the bronchial muscles. Thus, isoproterenol has a ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Cocaine and Amphetamines more selective sympathomimetic action than the amphetamines. Isoproterenol, moreover, does not readily cross the blood]brain barrier, minimizing its central stimulant properties. Although it is an effective antiasthmatic drug, isoproterenol still has adverse cardiovascular effects because b-adrenergic receptors are also located on heart muscle. Stimulation of the heart, however, mainly occurs via a subgroup of b-adrenergic receptors termed b1. With further refinement of the isoproterenol molecule, it was possible to devise drugs that could act more selectively on the bronchial tree via b2 receptors and thereby reduce b1 cardiovascular effects. In addition, the realization that asthma involves an inflammatory response led to the use of glucocorticoids and other anti-inflammatory compounds as an alternative treatment. Interestingly, nasal decongestion is now treated by drugs that stimulate the a1 subtype of the a-adrenergic receptor. Many sympathomimetics have been developed for the treatment of a variety of ailments involving the heart, lungs and other organs innervated by the sympathetic system. These drugs not only are more selective but also lack the powerful central stimulant actions of the early amphetamine prototypes. Some sympathomimetics, however, have central stimulant effects, albeit less pronounced than cocaine or the amphetamines. Perhaps the best known of these other sympathomimetics is methylphenidate, marketed as Ritalin for the treatment of narcolepsy and ADHD (see below). Stimulation of Behavioural Arousal and Vigilance Research on the sympathetic nervous system provided an important clue for understanding how sympathomimetic drugs could alter brain function to induce a state of mental alertness. Like the sympathetic system in the periphery, the brain contains distinct groups of neurons that use norepinephrine as a transmitter. These neurons, moreover, are active during the same behavioural responses associated with sympathetic activation. It seemed likely, therefore, that the brain noradrenergic system is also active in response to cocaine and the amphetamines. This hypothesis proved to be correct. In the brain, many noradrenergic neurons originate in the locus coeruleus, a brainstem nucleus that sends axons to portions of the cerebral cortex and limbic system. Cortical neurons process a wide range of cognitive, motor and sensory information, whereas the limbic system appears to regulate emotional behaviour. The locus coeruleus, therefore, targets brain regions involved in crucial behavioural outcomes. It influences how these brain regions operate by modulating their level of excitability through the release of norepinephrine. Highly relevant or meaningful environmental events activate locus coeruleus neurons. The resulting increase in norepinephrine release elevates cortical and limbic excitability, which explains why such events increase our state of alertness. Drugs like cocaine and the amphetamines mimic this mental state by directly increasing the synaptic level of norepinephrine in the brain just as they do in the sympathetic nervous system (see above). This state of alertness is manifest as an increase in arousal and vigilance. Stimulation of Pleasure The euphoria associated with the amphetamines and cocaine appears to involve a brain transmitter chemically similar to norepinephrine but found in different groups of neurons. The transmitter is dopamine, and the neurons are located in the ventral tegmental area of the midbrain. These neurons send axons to portions of both the frontal cortex, which plays a role in memory and other complex aspects of information processing, and limbic system. An important limbic target is the nucleus accumbens. Dopamine release in this area of the forebrain occurs in response to naturally occurring pleasures such as food, novelty and sex. The amphetamines and cocaine also increase synaptic dopamine in the accumbens, suggesting that they, too, cause the same neurochemical change as natural pleasures. But because these drugs act directly on dopaminergic transmission, they are likely to pack a much greater dopamine ‘punch’ than pleasurable environmental stimuli, which must travel from peripheral sensory organs through several synaptic relays before activating the accumbal dopamine system. The amphetamines and cocaine increase dopamine transmission in the same way that they influence norepinephrine: by attaching to transporter proteins. Both structurally and functionally, the dopamine transporter closely resembles the norepinephrine transporter. Thus, the amphetamines bind to the dopamine transporter, get carried inside the neuron, promote the leakage of dopamine from intracellular vesicles, and, as the transporter returns to its extracellular configuration, intracellular dopamine is transported outward into the synapse. Cocaine, in contrast, prevents the dopamine transporter from working, which allows synaptic dopamine to accumulate. As with norepinephrine, therefore, both drugs increase the level of synaptic dopamine. This similarity of drug action in different neurons is not surprising in view of the chemical similarity of dopamine and norepinephrine, both of which are known as catecholamines. Although they act by still different mechanisms, heroin and nicotine also facilitate dopamine transmission in the nucleus accumbens. In fact, all drugs of abuse that have been tested produce this same neurochemical change, ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3 Cocaine and Amphetamines suggesting that accumbal dopamine is a key factor in drug addiction. The amphetamines and cocaine are just two ] albeit very dramatic ] examples of drugs that usurp a neuronal system normally involved in promoting behaviour necessary for species survival and turning that system into a mechanism for drug abuse. It is important to stress that dopamine does not act alone. Much like its catecholamine partner, norepinephrine, dopamine acts mainly by modulating the excitability of target cells. In the nucleus accumbens, dopamine helps to strengthen the response of neurons to other synaptic inputs. Thus, the actions of dopamine must be considered in terms of other ongoing neuronal activity. In addition, not all drugs of abuse ] not even the amphetamines and cocaine ] elicit identical behavioural and emotional responses; the differences reflect the different ways that drugs alter brain neurochemistry beyond the catecholamines. It is especially noteworthy that serotonin, a transmitter that shares some molecular features of the catecholamines, also responds to many drugs of abuse including the amphetamines and cocaine. In fact, cocaine is just as effective in blocking the serotonin transporter and thus increasing serotonin transmission as it is in increasing synaptic dopamine and norepinephrine. Serotonin has long been implicated in mood, suggesting that the behavioural effects of cocaine reflect a complex interaction of several transmitter systems. The amphetamines also increase serotonin transmission, and they appear to do so by attaching to the serotonin transporter and causing the same changes as they do in dopamine and norepinephrine neurons. Unlike cocaine, however, the amphetamines have widely variable potencies in altering serotonin transmission. That dopamine is not the sole factor in a possible pleasure circuit underlying addiction is evident in data obtained from genetically engineered mice that lack the gene for the dopamine transporter. If blockade of dopamine reuptake is responsible for the pleasurable properties of a drug like cocaine, then these mice should not show any inclination to take the drug when given the opportunity. Surprisingly, however, these animals will work to obtain intravenous injections of cocaine in the same way as genetically normal mice, suggesting that other transmitters and other brain circuits participate in the rewarding effects of cocaine. Overdoses and Acute Psychosis At high doses, the sympathomimetic effects of cocaine and the amphetamines can be sufficiently severe to cause a hypertensive crisis or even death. In fact, because of its local anaesthetic action, cocaine has the added danger of anaesthetizing heart muscle. With repeated drug use, 4 tolerance develops to the sympathomimetic effects, and drug users are able to increase the dose to generate more pronounced effects in the brain. An amphetamine addict or ‘speed freak’, for example, often takes the drug in binges or ‘runs’ characterized by intravenous injections of escalating doses every few hours for several days. Unfortunately, the drug-induced euphoria also fades with repeated use, and as the dose escalates, an acute psychosis begins to emerge characterized by paranoid delusions and auditory or visual hallucinations. In many respects, the drug-induced psychosis resembles the symptoms of paranoid schizophrenia, which is one reason why the behavioural effects of these drugs are sometimes studied as models of the brain condition underlying schizophrenia and related psychotic states. In fact, the same drugs used to treat schizophrenia ] the socalled antipsychotic drugs ] can also alleviate the stimulant-induced psychosis. The antipsychotic drugs oppose the synaptic action of dopamine by blocking dopamine receptors. This evidence forms the basis for the view that dopamine dysfunction plays a key role in paranoid psychosis. Abuse of stimulant drugs presumably induces this mental condition by elevating synaptic dopamine. Although the mechanism linking dopamine and psychosis is far from settled, dopamine is known to modulate neuronal excitability in areas of frontal cortex and limbic system that process a wide range of cognitive information. Disruption of this modulatory function, therefore, could easily interfere with normal mental operations. It is also interesting to note that apart from increasing cortical and limbic dopamine, cocaine and the amphetamines also elevate synaptic dopamine in the neostriatum, a sensorimotor integration area of the basal ganglia. Neostriatal dopamine arises from the substantia nigra, which lies just medial to the ventral tegmental area of the midbrain. Loss of dopamine axon terminals in the neostriatum, which occurs in Parkinson disease, leads to bradykinesia (slowness of movement) and other profound motor deficits. An increase in neostriatal dopamine transmission, on the other hand, has an activating effect on behaviour, which is often manifest as a series of highly repetitive or stereotyped motor patterns. In both amphetamine and cocaine abusers, these motor patterns may include aimless walking, compulsive sorting, and intense searching such as dismantling clocks, radios or television sets as if looking for something. Perhaps the best-known example of cocaineinduced stereotypy is the searching behaviour of Sherlock Holmes, whose cocaine habit was described by Dr Watson (these characters were created by Arthur Conan Doyle in the late 1800s when cocaine was readily available and Doyle himself may have experienced the effects of the drug). Like the drug-induced psychosis, many of the stereotyped motor patterns become more intense with repeated drug use and may actually become part of the paranoid delusion. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Cocaine and Amphetamines Use as Therapeutic Agents Neither cocaine nor the amphetamines have widespread therapeutic value. Cocaine is most useful in medicine as a local anaesthetic agent. This effect is complemented by a strong vasoconstrictive action, which makes cocaine especially valuable for anaesthetizing organs having a dense vascular supply such as the eye and lungs to permit delicate surgery. Freud’s proposal that cocaine be used to treat morphine addiction seems laughable today. Freud also recommended cocaine for the treatment of clinical depression, but far safer and much more effective antidepressant remedies have been available since the 1950s. Although the amphetamines were developed specifically for the treatment of asthma and related bronchial conditions, the only remaining therapeutic value of these drugs lies in their central stimulant properties. Because d-amphetamine has more pronounced effects in the brain than l-amphetamine, the d isomer is typically used for narcolepsy and ADHD. Other treatments are available, including methylphenidate (Ritalin), another sympathomimetic drug (see above), but these alternatives are not dramatically better or different than d-amphetamine. For narcolepsy, amphetamine prevents sleep attacks but treatment is complicated by the potential for abuse as well as the disruption of normal nighttime sleep. In the case of ADHD, which is typically diagnosed in childhood, it seems paradoxical that a stimulant would have a beneficial effect in treating a condition characterized by excessive motor activity and difficulty in focusing attention. ADHD patients, however, are not really calmed by amphetamine. They respond with an increase in arousal and vigilance just like other individuals. The problem in ADHD appears to be an inability to concentrate, which results in hyperactivity. The drug-induced increase in mental alertness, therefore, helps to overcome the concentration problem, which, in turn, helps to keep the hyperactivity in check. Of course, a relatively high dose would induce stereotyped motor activation, so stimulants are prescribed in low doses for ADHD patients. Even at low doses, however, the long-term consequences of stimulant therapy begun in childhood continues to be a major concern. An early medicinal use for d-amphetamine was the treatment of obesity. Dexedrine tablets were available as appetite suppressants shortly after World War II. Despite their popularity, they really had little lasting effect on food intake because the decrease in appetite faded with continued use. This tolerance meant that higher and more dangerous doses of the drug were necessary to control weight gain, and as the dose increased so too did the possibility of long-term abuse and psychosis. Although the amphetamines may see occasional use as anorectic agents, they have been largely replaced by other drugs, including some that act selectively on the serotonin system. A good example is dexfenfluramine, marketed as Redux (USA), which is a modified version of the original amphetamine molecule but with relatively little ability to alter either dopamine or norepinephrine transmission. Serotonin systems in the brain are known to play a role in food intake, but it is not clear how dexfenfluramine alters this behaviour since the drug also slows the rate of gastric emptying and increases body temperature, both of which tend to suppress appetite. Caffeine and Other Xanthines Another group of drugs that combat fatigue, elevate mood, and increase the capacity for work are the xanthines, perhaps the most popular of which is caffeine. Like the amphetamines, these stimulants have also been used to treat asthma because they relax bronchial muscle, but their therapeutic value is limited by their low potency. Even as stimulants, the xanthines do not pack the wallop nor the euphoria of cocaine or the amphetamines. For coffee drinkers, the major source of caffeine is the coffee bean, which is the fruit or seed of the Coffea arabica plant. Caffeine also is found in Thea sinensis leaves, which are used for making tea and which also contain theophylline, another xanthine. Other common sources of caffeine include: cola drinks, which may contain extracts of the cola nut, Cola acuminata, as well as any caffeine added in production; chocolate, made from Theobroma cacao seeds, which also contain the xanthine and theobromine; and many over-the-counter analgesics and cold preparations, which are made with a dose level of caffeine similar to that in a small (4 oz) cup of coffee. Caffeine, theophylline and theobromine, represent different methylated versions of xanthine, which is a purine compound structurally related to uric acid. All the drugs in this category appear to influence neuronal function by several mechanisms, but most of the research has centred on caffeine. Despite its stimulant properties, caffeine does not act directly on catecholamine neurons. It may act indirectly, however, by inhibiting phosphodiesterase, an enzyme that metabolizes adenosine-3’5’- monophosphate or cyclic AMP. Because most, if not all, dopamine and norepinephrine receptors influence cyclic AMP production, a caffeine-induced change in cyclic AMP levels could influence catecholamine transmission. This cyclic AMP effect, however, occurs only at doses much higher than those required to activate behaviour. A more likely mechanism for the stimulant effect of caffeine involves adenosine receptors. Adenosine is a purine nucleotide that may function either as a transmitter or as a modulator of other transmitters. Unlike caffeine, adenosine depresses behaviour. It also depresses dopamine release via receptors located on the axon terminals of dopaminergic neurons. Caffeine, however, binds to ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5 Cocaine and Amphetamines adenosine receptors and blocks their stimulation. Thus, by acting as an adenosine receptor antagonist, caffeine elevates dopamine release and activates behaviour. Summary Cocaine and the amphetamines are stimulants known for their high risk of abuse. Their physiological effects were first studied on norepinephrine-releasing neurons in the sympathetic nervous system, which innervates the heart, lungs and other internal organs. Both types of drugs attach to the norepinephrine transporter, a protein in the plasma membrane of noradrenergic neurons that removes norepinephrine from the synapse. Cocaine attaches in such a way that the transporter is blocked, allowing synaptic norepinephrine to accumulate. The amphetamines, in contrast, keep the transporter working, but change its mode of operation from removing norepinephrine to releasing it. Both drug effects increase synaptic norepinephrine and thus mimic activation of the sympathetic nervous system; hence, cocaine and amphetamines are called sympathomimetics. In the brain, these drugs increase norepinephrine transmission by the same mechanism, which appears to account for their ability to induce a state of arousal. They also have euphoric effects that can play a role in addiction. These effects have been linked to an increase in dopamine transmission in limbic areas of the brain, although other neurochemical systems are likely to play a role. Dopamine may also be involved in the paranoid psychosis that accompanies cocaine or amphetamine abuse. Therapeuti- 6 cally, cocaine has value as a local anaesthetic, whereas the amphetamines are used to treat narcolepsy. Another sympathomimetic drug, methylphenidate, shares some of the actions of cocaine and amphetamine in the brain and is used to treat attention deficit hyperactivity disorder by improving concentration. Caffeine and other analogues of xanthine are milder stimulants, which block brain receptors for adenosine. Further Reading Cho A and Segal DS (eds) (1994) Amphetamine and its Analogs. San Diego, CA: Academic Press. Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251: 1580]1586. Higgins ST and Katz JL (eds) (1998) Cocaine Abuse ] Behaviour, Pharmacology, and Clinical Applications. San Diego, CA: Academic Press. Hyman SE (1996) Addiction to cocaine and amphetamine. Neuron 16: 901]904. Leschner AI and Koob GF (1999) Drugs of abuse and the brain. Proceedings of the Association of American Physicians 111: 99]108. Seiden LS, Sabol KE and Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annual Reviews of Pharmacology and Toxicology 32: 639]677. Tarter RE, Ammerman RT and Ott PJ (1998) Handbook of Substance Abuse ] Neurobehavioral Pharmacology. New York: Plenum Press. Volknow ND, Wang G-J, Fischman MW et al. (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386: 827]830. White FJ and Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug and Alcohol Dependence 51: 141]153. Wise RA (1996) Addictive drugs and brain stimulation reward. Annual Review of Neuroscience 19: 319]340. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net