Molecular and regional targets of cocaine in primate brain: liberation from prosaic views

The neurochemical processes underlying initial exposure to and reinforcing effects of cocaine are not fully understood. An enduring hypothesis of coca ine addiction is based on an underlying premise that dopamine is the acute mediator of the rewarding effects of cocaine and this nefarious role extend s through each phase of addiction. Cocaine is an effective inhibitor of the dopamine transporter, thereby increasing extracellular dopamine levels. Eu phoria is attributed to the cocaine-induced inundation of extracellular dop amine and the withdrawal and craving for cocaine after cessation of drug us e are attributed to neuroadaptive processes to dampen dopaminergic transmis sion. Nevertheless, our understanding of the role of dopamine transporter b lockade in cocaine addiction is not fully understood. The objectives of thi s laboratory are to investigate the primary targets of cocaine in the brain , those associated with the initial phase of cocaine use and that can provi de leads for investigating neuroadaptive processes that may trigger addicti on. Two prosaic views of the neurobiology of cocaine addiction are examined in this review. The first is based on the assumption that the dopamine tra nsporter contributes significantly to the stimulant and reinforcing effects of cocaine, and focuses on how stimulant drugs of abuse such as cocaine bi nd to the dopamine transporter We present evidence that the widespread assu mption that dopamine transporter blockers require an amine nitrogen in thei r structure is incorrect as non-amines are effective blockers of transporte rs. The second prosaic view based on the assumption that the dopamine trans porter fulfills a paramount role in cocaine addiction, is assessed in view of mounting evidence that the transporter may not account for the full spec trum of cocaine's effects. Other targets of cocaine, which may be relevant to the acute and chronic effects of cocaine, are presented.