Cocaine is thought to be rewarding because it elevates dopamine levels in nucleus accumbens. However, cocaine is still habit-forming in mice with the dopamine transporter (DAT), the presumed mechanism of synaptic dopamine clearance, deleted. Cocaine is not a selective blocker of the dopamine transporter, however; it also blocks the norepinephrine and serotonin transporters (NET and SERT). Moreover, NET and SERT can themselves take up dopamine. While they apparently do not do so in the caudate nucleus, we explored the possibility that they may do so in other brain regions by studying dopamine uptake into frontal cortex, caudate, and nucleus accumbens synaptosomes in wild-type and transporter knockout mice. Dopamine uptake was abolished in caudate synaptosomes and greatly decreased in nucleus accumbens synaptosomes from DAT-/- mice; however it was normal in frontal cortex synaptosomes. Dopamine uptake was greatly reduced, however, in frontal cortex synaptosomes from NET-/- mice. It was not decreased in caudate synaptosomes and minimally decreased in nucleus accumbens synaptosomes from NET-/- mice. These data underscore the fact that dopamine uptake depends not only on affinity for the various monoamine transporters but also the relative density of those transporters in different brain regions. These findings suggest the need to assess the roles of the different transporters in dopamine uptake in various subregions of nucleus accumbens since these subregions are thought to play different roles in drug reward.
|Moron, Jose A; Brockington, Alicia; Wise, Roy A et al. (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22:389-95|