Addiction psychostimulant

Pulvirenti L., Koob G. Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends Pharmacol. Sci. 15 374, 1994. 

Brebner K., Childress A.R., Roberts D.C. A potential role for GABA(B) agonists in the treatment of psychostimulant addiction. Alcohol Alcohol. 37 478, 2002. 

Slow-onset, long duration dopamine reuptake inhibitors with reduced potential for substance abuse have been suggested as therapies for psychostimulant addiction [33-35]. A series of slow-onset, long duration N-alkyl analogues of methylphenidate were recently reported to have enhanced selectivity for the dopamine transporter [34]. A representative compound is 13, an RR/SS diastereomer (DAT K, = 16nM, SERT K = 5900 nM, NET K-, = 840 nM). In a locomotor activity assay in mice, 13 has a slow onset of activity (20-30 min) with peak activity occurring between 90 and 120 min. In contrast, both methylphenidate and cocaine are active within 10 min and reach peak activity within 30 min. 

Pulvirenti, Luigi, and George F. Koob. 1994. "Dopamine Receptor Agonists, Partial Agonists, and Psychostimulant Addiction." Trends in Pharmacological Sciences 15 374-79. 

Koob GF, Caine SB, Parsons L, Markou A, Weiss F (1997) Opponent process model and psychostimulant addiction. Pharmacol Biochem Behav 57 513-521. 

Howell LL, Kimmel HL (2008) Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 75 196-217... 

Drug addiction is defined as a syndrome in which drug use (e.g., psychostimulants, opiates, alcohol) pervades all life activities of the user. Life becomes governed by the drug and the addicted patient can lose social compatibility (e.g., loss of partner and friends, loss of job, crime). Behavioral characteristics of this syndrome are compulsive drug use, craving, and chronic relapses that can occur even after years of abstinence. 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

Consistent with these observations, there is some evidence that caffeine may act, in part, on dopaminergic fibers that project into the medial forebrain bundle. Other psychostimulants also appear to act on this system, which may be at least one of the neural mechanisms involved in the development of dependence.271 Further work has suggested a parallel between caffeine and another highly addictive drug, alcohol. Many of the same factors that enter into the development of alcoholism may also influence the development of dependence on caffeine.272... 

There are differences in vulnerability to addiction in general, and there is growing evidence that this difference is particularly pronounced in psychostimulant abuse (e.g., Brady and Randall 1999 Brecht et al. 2004). In human subjects, although the dissimilar influence of social and environmental pressures on males and females cannot be overlooked, biological factors are also evident and suggest similarities to the differences observed in animal models of addiction. 

As mentioned in the previous section, we have observed greater impact of nicotine on locomotor activity in female than in male rats (Kanyt et al. 1999). The psychostimulant theory of addiction also proposes that the locomotor stimulant and rewarding effects of addictive drugs have a common neuronal substrate, although there are some studies that do not support this hypothesis (Carr et al. 1988 Villegier et al. 2006). Species differences or methodological differences in the studies may underlie the discrepancies. 

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