Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice

A large body of evidence supports the hypothesis that the reinforcing effects of cocaine depend on its ability to block the dopamine transporter (DAT), thereby increasing dopamine extracellular concentration within the mesocorticolimbic system. However, the fact that cocaine similarly binds to the serotonin and norepinephrine transporters (SERT and NET, respectively), raises the possibility that modulation of mesocorticolimbic dopaminergic transmission might be achieved through alternate pathways. The successful disruption of the genes coding for the DAT, the SERT and the NET offered ideal tools to determine the extent of the participation of these transporters and respective monoaminergic systems in the reinforcing effects of cocaine. Studies of cocaine-induced motor activation and maintenance of intravenous (i.v.) self-administration in DAT- and in NET-knockout (KO) mice are reviewed here, and discussed in light of new observations obtained from double monoamine transporters KO mice (i.e., DAT-KO/SERT-KO, NET-KO/SERT-KO). The reinforcing potency of cocaine is maintained in the absence of the DAT but decreased in the absence of the NET; its motivational rewarding effect is observed in the absence of the SERT, but not when both DAT and SERT are lacking. Moreover, a dichotomy between cocaine motor activating and reinforcing effects is reported. Such dichotomy is suggestive of independent mechanisms underlying the psychomotor stimulant and reinforcing effects of cocaine. Overall, these studies provide evidence that cocaine dynamically acts at multiple sites through pathways that might be exchangeable under certain circumstances.