Differential Reinforcing Effects of Cocaine and GBR-12909: Biochemical Evidence for Divergent Neuroadaptive Changes in the Mesolimbic Dopaminergic System

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Abstract
The dopamine (DA) transporter is thought to be the primary mediator of reinforcing effects of cocaine. In the present study, an intravenous drug self-administration procedure,in vitroautoradiography, and HPLC methods were used to investigate possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse. Drug-naive rats readily acquired and subsequently maintained cocaine self-administration behavior during 2 hr daily sessions over a prolonged period. In contrast, although GBR-12909 was initially self-administered, both cocaine-naive and cocaine-trained rats failed to maintain self-administration behavior for GBR-12909 over prolonged periods of time. After self-administration responding decreased with GBR-12909, rats showed a delay of 6.6 ± 1.3 sessions in reacquiring consistent cocaine self-administration. Moreover, when GBR-12909 was again substituted for cocaine, they failed to self-administer GBR-12909, even during the initial days of testing. In contrast, after extinction of self-administration responding by water substitution, rats readily self-administered both cocaine and GBR-12909. Cocaine self-administration upregulated DA transporters, whereas water-substituted cocaine withdrawal upregulated both DA transporters and D1 receptors. Unlike cocaine, GBR-12909 self-administration by itself altered neither DA transporters nor D1 or D2 receptors. Nevertheless, substitution of GBR-12909 for cocaine reversed the cocaine-induced upregulation of DA transporters and reduced DA and dihydroxyphenylacetic acid levels in the mesolimbic system. These data suggest that cocaine and GBR-12909 differentially affect dopaminergic systems and also cause different reinforcing and neuroadaptive effects. GBR-12909-like compounds may be useful pharmacotherapeutic agents for cocaine addiction. Upregulation of DA transporters and D1 receptors might play important roles in the neuroadaptive cascade that leads to cocaine addiction and withdrawal.

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