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Cocaine produces its reinforcing effects primarily by inhibiting the dopamine transporter (DAT) at the level of presynaptic terminals and increasing extracellular levels of dopamine (DA). Surprisingly, in mice genetically lacking the DAT, cocaine was still able to elevate DA in the nucleus accumbens (NAc). This finding is critically important for explaining the persistence of cocaine reinforcement in DAT knock-out (DAT-KO) mice. However, the mechanism by which cocaine elevates DA is unclear. Here, we tested the recently proposed hypothesis that in the absence of the DAT, the norepinephrine transporter (NET) could provide an alternative uptake site for DA clearance. If true, cocaine could elevate DA levels through its inhibition of the NET. In vitro voltammetry, a technique well suited for evaluating the effects of drugs on DA uptake, was used in the present study. We report that both cocaine and desipramine, a potent NET inhibitor, failed to change DA clearance or evoked release in the NAc of mutant mice. Additionally, fluoxetine, a serotonin transporter (SERT) inhibitor, also had no effect on these parameters. These data rule out the involvement of accumbal NET or SERT in the cocaine-induced increase in extracellular DA in DAT-KO mice. Moreover, the present findings suggest that in the DAT-KO mice, cocaine acts primarily outside the NAc to produce its effects.

Lack of Cocaine Effect on Dopamine Clearance in the Core and Shell of the Nucleus Accumbens of Dopamine Transporter Knock-Out Mice