Potential Antagonism of Cocaine Effects on Extracellular Dopamine: Microdialysis Studies with GBR 12909
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It is well known that cocaine increases striatal extracellular dopamine (ECDA) levels in vivo. Previous studies have also shown that GBR 12909 1-[2-[bis(fluorophenyl)methoxy ]ethyl]-4-[3-pheynyl-propyl]piperazine increases in vivo ECDA levels and pretreatment with GBR 12909 attenuates the ability of cocaine to increase extracellular levels of dopamine (DA) in the rat striatum. In the present study, in vivo microdialysis was utilized to determine the effect of cocaine, GBR 12909, or their combination on ECDA levels after direct infusion into the striatum of anesthetized rats. A 20 minute infusion of artificial cerebrospinal fluid containing either 1 00 ~ cocaine or 100 µM GBR 12909 increased ECDA levels albeit with significantly different efficacies. GBR 12909 increased ECDA levels by 188% and cocaine resulted in a 1063% increase in striatal ECDA levels. In animals exposed transiently to GBR 12909 (20 minutes, 100 µM), the effect of cocaine (administered 1 hr after GBR 12909 exposure) on ECDA was significantly reduced (620% increase over baseline, p <0.05). The results suggest that after a brief exposure to GBR 12909 and a subsequent return of ECDA to basal conditions, the effectiveness of cocaine to elevate ECDA was compromised. The results also demonstrate that although qualitatively similar, the quantitative effects of equimolar doses of cocaine and GBR 12909 are vastly different even when perfused directly into the brain. This suggests that GBR 12909 may be less efficacious than cocaine and thus may act as a partial agonist. Since GBR 12909 binding is highly selective for the DA transporter, the results support the concept that the effect of cocaine on ECDA may include actions distal to the DA transporter, such as its effect on serotonin or norepinephrine. These results may prove GBR 12909 as a potential therapeutic drug for cocaine addiction.