Psychostimulant addiction cocaine

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. 

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. 

Although the role of the increase of DA in the prefrontal cortex for the addictive properties of cocaine and amphetamine is obscure, it is unlikely to be a major one given the lack of addictive liability or psychostimulant properties of antidepressants, that increase DA in the PFCX but not in the NAc (Tanda et al., 1994). Finally, a number of aversive-anxiogenic drugs (e.g. picrotoxin, pentylenetetrazol, beta-carbolines) stimulate in vivo DA transmission in the medial prefrontal cortex but fail to affect DA transmission in the NAc shell (Bassareo et al., 1996). These observations indicate that the property of stimulating DA transmission in the NAc shell is not secondary to generic motivational stimulus properties or to psychostimulant properties of addictive drugs. 

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