The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem worldwide for which there is no accepted medication. Numerous lines of investigation indicate that elevation of dopamine (DA) in the nucleus accumbens (NAC) is largely responsible for the reinforcing (rewarding) effects of many classes of drugs including cocaine and methamphetamine. Although the precise mechanism of DA elevation in the NAC differs among drug classes, medications that suppress or deplete such elevation of DA may thus be useful in the treatment and prevention of diverse, destructive self-administration behaviors including excessive eating. We have pursued the chemical synthesis and identification of biogenic amine agonists and their antagonists as research tools and potential medications. In one example, we developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is enabling numerous studies requiring this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. In another study, we showed that MDL 100,907 significantly attenuated drug- and cue-induced reinstatement of cocaine but had no significant effects on cocaine self-administration in rhesus macaques. MDL 100,907 attenuated cocaine-induced dopamine overflow in the caudate nucleus but not in the nucleus accumbens as measured by in vivo microdialysis. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways.

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National Institute on Drug Abuse
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