Chapter 8 Psychostimulants
Compounds, producing excitement, euphoria, reduced sensitivity of fatigue and increased motor activity, belong generally to the psychostimulants. These drugs could be divided into three categories: amphetamines, methylxanthines and cocaine.
8.1. Amphetamines and methylxanthines
• Amphetamines. Repeatedly taken amphetamine may induce, over the course of a few days, a state of "amphetamine psychosis" in men (Caplehorn, 1990) and animals (Balfour, 1990; Lillrank et al., 1991). Human amphetamine users report visual and auditory hallucinations, accompanied by paranoid symptoms. In both men and animals, aggressive behaviour may occur, and at the same time repetitive stereotyped behaviour could develop. When the intake of drugs is stopped there is usually, after a few days, a period of deep sleep and on awakening, the subject feels extremely lethargic, depres sed, anxious, and is often hungry (Swerdlow et al., 1991).
Tolerance develops rapidly to the sympathomimetic and anorectic effects of amphetamine, but much more slowly to the other effects, such as locomotor stimulation and stereotyped behaviour (Lillrank et al., 1991).
Repeated administration of amphetamine to experimental animals may lead to behavioral sensitization, a process in which the dopaminergic (DA-ergic) system seems to be involved (Segal and Kuczenski, 1992).
• Methylxanthines are constituents of various beverages (tea, coffee, cocoa etc.). The main components are caffeine and theophylline, both having common stimulant effects on the CNS. Compared to the amphetamines, the methylxanthines produce less locomotor stimulation, and do not induce euphoria, stereotyped behaviour, or a psychotic state (Swerdlow et al., 1986). Tolerance develops to a small extent, but much less than with amphetamines (Denaro et al., 1991).
Cocaine was used in our experimental study and therefore, more extensively data will be discussed.
Administration route and metabolism. Cocaine is an alkaloid, derived from the plant erythroxylon coca. Two chemical forms of cocaine exist, hydrochloride salt and free base. The salt ("snow" or "coke") dissolved in water, can be taken by vein or in the nose. The free base ("crack") is smoked (Siegel, 1985). In the earlier days coca leaves were chewed, but it appeared that the effects of cocaine occurred later and were less intense compared to the intranasally route. The route of administration determines the rate and peak of blood levels achieved. It takes for cocaine 5-10 seconds by smoking, 30-120 seconds intravenously, and 1-3 minutes intranasally to reach and produce the onset of effects in the brain. Unlike heroin, which tends to be used on daily basis, cocaine (and amphetamine), is characterized by drug consumption in heavy binges (Bozarth and Wise, 1985).
Cocaine is detoxified by liver and plasma esterase enzyme system. Two water soluble metabolites, benzoylecgonine and ecgonine methyl ester, are excreted in the urine (Stewart et al., 1979) and are useful markers of cocaine use. Benzoylecgonine could be detected in the urine for as many as 22 days after the last cocaine intake (Weiss and Gawin, 1988). The plasma half-life of cocaine varies from 30-80 min (Prakash and Das, 1993).
Transporter molecules and neurotransmitters. It has been shown that cocaine primarily acts on monoaminergic systems, by blocking the reuptake of dopamine (DA), noradre naline (NA) and 5-hydroxytryptamine (5-HT, Taylor and Ho, 1978). Recently, it has been demonstrated that cocaine inhibits several monoamine transporter molecules in the mammalian brain, but particular attention was paid to the inhibition of the DA transporter (Hitri et al., 1994). The neurotransmitter transporters terminate synaptic transmission by rapid sodium-dependent reaccumulation of released neurotransmitter in the presynaptic terminal. Not only cocaine is acting by this type of mechanism, also antidepressants and neurotoxins that induce Parkinsonism are shown to act in this way (Meister, 1993).
DA-ergic system. The inhibition of DA reuptake has been demonstrated in several brain nuclei, such as nucleus accumbens (NAc, Bradberry and Roth, 1989; Kalivas and Duffy, 1990), medial prefrontal cortex (Maisonneuve et al., 1990), ventral tegmental area (VTA, Bradberry and Roth, 1989) and striatum (Church et al., 1987). Recently, it has been shown that stereotypy induced by cocaine is mediated by a DA-ergic activation of a glutaminer gic system within the striatum (Karler et al., 1994). In general, the DA-ergic seems to be involved in the behavioral effects of cocaine. D, receptor antagonists block cocaine induced increase of locomotor activity, stereotypy, and decrease of food intake (Spealman, 1990). However, the cocaine/amphetamine induced increase of locomotor activity in mice was blocked by the NA antagonist prazosin, which implies that the underlying mechanism is more complex (Snoddy and Tessel, 1985).
NA-ergic and 5-HT-ergic .system. It was demonstrated, that cocaine blocks the uptake of 5-HT and NA in the dorsal raphe (Cunningham and Lakoski, 1990) and in locus coeruleus (Hadfield and Nugent, 1983; Reith et al., 1986; Lacey et al., 1990). The inhibited firing of these neurons is probably mediated by activation of presynaptic a2-adrenoceptors (Suprenant and Williams, 1987) and 5-HT1a receptors (Cunningham and Lakoski, 1990).
8.3. Cocaine dependence
Similarly to the opioids, the mesocorticolimbic DA-ergic pathway seems to play a major role in the process of reinforcement of cocaine (Woolverton and Johnson, 1992). The 5-HT- and/or NA-ergic pathways seemed not to be involved in reinforcing process (Fibiger et al., 1992). Lesions of the mesocorticolimbic DA-ergic system, induced by 6hydroxydopamine, produced a selective termination of cocaine self-administration in rats (Caine and Koob, 1994), while the administration of 5-HT and NA receptor antagonists was without any effect on the cocaine intake in rats (Fibiger et al., 1992). Microdialysis studies in rats during cocaine self-administration have shown an increased release of DA within the NAc (Hurd et al., 1989) and in the amygdala (McGregor et al., 1994), while the NA and 5-HT levels remained unaffected (McGregor et al., 1994). The involvement of the 13 2 -receptors in cocaine reinforcement was demonstrated by 132- agonists bromocriptine (Hubner and Koob, 1990) and lisuride (Pulvirenti and Koob, 1994), which reduced the intravenous cocaine self-administration intake in rats.
8.4. Withdrawal syndrome
Human and animal studies have shown that there are behavioral consequences of termination of exposure to cocaine (Woolverton and Johnson, 1992). The initial phase of the withdrawal (hours-days) is termed the "crash". During the crash an intense depression, fatigue, hypersomnia, hyperphagia, and drive for repeated cocaine use are present. The later phase (weeks to months) is characterized by mood lability, depression, anhedonia, low energy, sleep disturbances, suspiciousness and anxiety (Gold, 1983; Gawin and Kleber, 1986).
Neurochemically, it appears that a functional reduction of DA neurotransmission may be one important component of cocaine withdrawal. A significant reduction in DA overflow in the NAc of rats withdrawing from unlimited access to cocaine self-administration has been shown (Weiss et al., 1992).
Treatment of cocaine dependence. Having in mind a role of DA in cocaine dependence, several DA receptor agonists in the treatment of cocaine dependence have been used:
• Bromocriptine, agonist at D 2 receptor, was shown to reduce the intake of i.v. cocaine self-administration in rats (Hubner and Koob, 1990). In humans, the results are controversial. Some studies showed that bromocriptine reduced symptoms of cocaine withdrawal, such as dysphoria (Giannini et al., 1987), while others reported no effect of bromocriptine on craving and no alterations of the subjective effects of cocaine, such as "rush" or "good feeling" (Kumor et al., 1989).
• Lisuride, agonist at D 2 receptor, reduced cocaine intake in rats (Pulvirenti and Koob, 1994). In humans, lisuride is involved in the normalization of the disturbed sleep pattern occurring during cocaine withdrawal, however, it did not modify subjective ratings of craving and mood (Gillin et al., 1994).
• Amantadine (Weddington et al., 1991) and pergolide (Malcolm et al., 1991) have been used with some success in treatment of cocaine human addicts.
Besides the DA agonists as adjuncts for the treatment of cocaine dependence two other categories of drugs have been suggested:
• Opioid antagonists. Animal and human studies have revealed that naltrexone, but also the partial opioid agonist/antagonist buprenorphine may have therapeutic value in cocaine addiction (Kosten et al., 1989; Mello et al., 1993).
• Catalytic antibodies have been developed and these compounds combine with cocaine and in the same time destroy the molecules. The antibodies are injected into the bloodstream and could protect a person (at least partially) from the effects of cocaine by destroying the drug more rapidly than do the enzymes already present in the blood. However, these antibodies are not effective by oral administration (Tramontano et al., 1986).
8.5. Tolerance and sensitization
Both tolerance and sensitization to the behavioral effects of chronic administration of cocaine have been demonstrated in man and animal (Post and Contel, 1983). Whether sensitization or tolerance would occur, seems to depend on the method of drug administration (dose, duration and interval). For example, tolerance was induced following continuous infusion of cocaine (Reith et al., 1987), whereas sensitization was observed after intermittent injection of cocaine (King et al., 1994).
It has been suggested, that tolerance induced by continuous cocaine administration is associated with supersensitivity of D 2 autoreceptor and 5-HT1a receptors, but not by changes in 5-HT1b receptor sensitivity (King et al., 1994).
One of the most interesting aspects of sensitization to cocaine is, that it is a relatively long lasting process (Post et al., 1987), like the process of kindling and long-term potentiation. Such long lasting changes imply that cocaine "experience" can induce structural modifications in synaptic architecture that are responsible for the strengthened synaptic circuitry that may underlie behavioral sensitization to cocaine. It seems that glutaminergic neurotransmission, particularly that mediated by the NMDA receptor subtype, is thought to play an important role. Accordingly, the NMDA channel blocker MK-801 blocks the sensitization to cocaine and amphetamine (Karler et al., 1989), indicating a role of the NMDA (glutamate) system in cocaine abuse.
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