Serotonin and dopamine system interactions in the reinforcing properties of psychostimulants: A research strategy
Manuel Tancer, M.D. and Charles
October 1998 update: This study was begun in September 1998.THE MAIN GOAL of the experiments described in this proposal is to increase our understanding of the interaction between serotonin (5-HT) and dopamine (DA) systems in mediating the subjective, discriminative stimulus, and reinforcing effects of psychostimulant drugs in humans. This proposal will use three primary approaches to study DA/5-HT interactions: first, a drug with mixed DA/5-HT properties, 3,4- methylenedioxymethamphetamine (MDMA), will be compared to drugs with more selective DA (e.g., d- amphetamine) vs. 5-HT (e.g., d-fenfluramine) mechanisms of action; second, d-amphetamine and d-fenfluramine will be co- administered in such a way as to produce mixed DA/5-HT effects which will be compared to the effects of the compounds administered alone; and third, serotonin- mediated effects will be blocked either by fluoxetine or tryptophan depletion in order to isolate the effects of dopamine with the expectation that this blockade will have differential effects on amphetamine, fenfluramine and MDMA.
Although amphetamine and fenfluramine are similar structurally, they have significantly different subjective, discriminative stimulus and reinforcing effects. These differences in dependence-related effects are presumably related to the fact that amphetamine produces prominent effects on DA systems whereas fenfluramine´s effects are mediated primarily by 5-HT systems. Interestingly, MDMA, which structurally is an amphetamine derivative, has prominent effects on both 5-HT and DA brain systems but unlike fenfluramine has abuse potential more like that of amphetamine. Thus, MDMA may be a useful compound for investigating the interactions among neurochemical systems as they relate to effects of drugs that are dependence-related. Although most psychostimulants that are abused alter norepinephrine (NE), DA, and to a lesser degree 5-HT levels, there are compelling data that DA systems play the major role in the reinforcing properties and other dependence- related effects of psychostimulant drugs. On the other hand, DA and 5-HT neurochemical systems are known to interact; for instance, recent studies have demonstrated a potentiation of impulse-dependent DA release by 5-HT. MDMA, whose effects have been attributed to its actions on 5-HT systems as well as DA has been shown in animal studies to share discriminative stimulus and reinforcing effects with amphetamine. On the other hand, humans have also reported that it produces hallucinogenic- like effects. Animal brain dialysis studies have shown that pretreatment with selective 5-HT reuptake inhibitors (SSRIs such as fluoxetine, Prozac) will prevent fenfluramine from producing 5-HT release. Similarly, the 5-HT releasing property of MDMA is blocked by pretreatment with the selective SSRIs. The SSRIs provides us with a useful tool for investigating in humans how the dependence related actions of MDMA are modified by manipulations of its effects on 5-HT.
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Background and Significance
There is compelling evidence for the importance of DA systems in mediating the reinforcing properties of d- amphetamine and cocaine (Giros et al., 1996; Di Chiara and Imperato, 1988; Ritz and Kuhar, 1989). However, in humans, blocking the DA system with pimozide does not reliably block the subjective effects of d-amphetamine, suggesting that the stimulant effects of d-amphetamine are not simply due to activation of DA systems (Brauer and de Wit, 1996). Likewise, Volkow et al. (1996) found that blockade of DA transporter by methylphenidate did not block the "high" from a second dose of methylphenidate and suggested that other neurotransmitter systems may be involved in the "high." Furthermore, manipulation of 5-HT systems have been found to modulate the stimulant and reinforcing properties of d-amphetamine (Porrino et al., 1989; Leccese and Lyness, 1984).
In behavioral paradigms, it appears that increased 5-HT activity does decrease the reinforcing properties of d- amphetamine. For instance, acute administration of the 5-HT precursor L-tryptophan (Leccese and Lyness, 1984), the 5-HT releasing agent d-fenfluramine (Olds and Yuwiler, 1992; Fletcher, 1995), the direct 5-HT agonist quipazine (Leccese and Lyness, 1984), and the 5-HT reuptake inhibitor fluoxetine (Porrino et al., 1989) decreased the rate of amphetamine self- administration, while chemical 5-HT depletions enhance the rate of responding for amphetamine (Leccese and Lyness, 1984). Furthermore, the 5-HT antagonist metergoline (Lyness and Moore, 1983) enhanced d-amphetamine self- administration, while cyproheptidine and methysergide reduced self-administration frequency (Leccese and Lyness, 1984). This inhibitory interaction between 5-HT and DA systems was consistent with a recent drug interaction study in humans in which a mutual antagonism of the mood altering properties of D,L-fenfluramine and phentermine were observed (Brauer et al., 1996). Interestingly, in a drug discrimination paradigm in rats, this combination was discriminated as more cocaine-like than either drug alone. This points to the importance of studying the interaction of d- amphetamine and fenfluramine in humans.
On the other hand, two studies in cocaine abusing human subjects report the opposite interaction. Satel et al., (1995) and Aronson et al. (1995) reported that tryptophan depletion, a procedure which acutely decreases 5-HT levels in the brain (Delgado et al., 1989; 1994) resulted in a decreased subjective response to intranasal administration of cocaine and to decreased cue-induced cocaine craving. Taken together, these different results may be a function of drug (cocaine versus d- amphetamine), different experimental paradigms, different brain regions being examined, different procedures, as well as different species. Nevertheless, this sort of conflicting data speaks to the need to conduct additional research in humans.
The pharmacology of MDMA is well known from animal studies and there have been numerous studies comparing it to prototypic dopaminergic (e.g., amphetamine) and serotonergic (e.g., fenfluramine) drugs (for reviews, see Green et al., 1995; White et al., 1996). There is evidence that MDMA is self-administered in monkeys (Beardsley et al., 1986) suggesting human abuse liability. However, there are no well- controlled studies comparing the subjective (reinforcing) or objective (changes in temperature, heart rate or blood pressure) effects of MDMA in human subjects to other drugs, such as d-amphetamine and/or d-fenfluramine (McCann and Ricaurte, 1993; Grob et al., 1992; Liester et al., 1992). The only data that are available are retrospective subjective reports of symptoms experienced following MDMA ingestion (Greer and Talbert 1986; Downing 1986; Peroutka et al., 1988). In these reports, users describe a wide range of subjective effects ranging from "altered time perception" or a sense of "closeness" with other people, increased alertness, luminescence of objects, and decreased "hostility." It is important to note that the MDMA was usually taken in a social context in which people were told what effects they would experience. These expectations may have been of great importance in modulating the subjective experiences produced by MDMA. Common side effects or adverse effects reported by MDMA users include: insomnia, nausea, tight jaw muscles, dry mouth, diaphoresis, trouble concentrating, palpitations, tremor, and increased body temperature. Much less commonly, there are single case reports of liver failure, accidents, and cerebral hemorrhage (see Green et al., 1995 for review). Grob et al., (1996) have recently reported that low doses of MDMA (1 mg/kg) cause robust increases in prolactin and adrenocorticotropin hormone levels compared with placebo.
MDMA has more serotonergic activity than d- amphetamine and like fenfluramine, high doses have been associated with selective damage to serotonergic systems with a sparing of DA systems (Ricaurte et al., 1985; Ricaurte et al., 1988) in rats and non-human primates. Interestingly, in mice, MDMA caused DA not 5-HT neurotoxicity (Logan et al., 1988). Moreover, unlike other neurotoxins such as 1- methyl-1,2,3,6-tetrahydropyridine [MPTP] (Langston et al., 1983, 1984) which has been associated with severe depletion of dopamine and clinical symptoms of Parkinson´s disease, there is no clear evidence that MDMA use results in any neurotoxicity in humans. Ricaurte and associates (1990) have reported decreased cerebral spinal fluid 5-HIAA (the primary serotonin metabolite) levels in subjects who had previously taken MDMA (as well as other drugs) although there were no physical or psychological symptoms associated with these changes nor was MDMA use verified or the potential influence of others factors controlled. Several human deaths have been reported following MDMA ingestion. The majority of the deaths have been attributed to underlying medical conditions, such as arrhythmias, accidents, and most recently to dehydration and hyperthermia at "rave" parties (Screaton et al., 1992; Henry et al., 1992).
Manuel Tancer, M.D. can be reached at:
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