Effects of repeated cocaine administration on dopamine D1 receptor modulation of mesocorticolimbic GABA and glutamate transmission

Abstract

Repeated cocaine exposure alters medial prefrontal cortex (mPFC) function to allow for enhanced excitatory transmission to the nucleus accumbens and ventral tegmental area (VTA). Previous studies have demonstrated changes in receptor function in the mPFC in animals repeatedly exposed to cocaine that produced increased excitatory output. The present report tested the hypothesis that daily injections of cocaine would enhance D1 receptor responsiveness by infusing the D1 receptor agonist SKF 38393 into the mPFC and monitoring glutamate and/or GABA release in the mPFC, nucleus accumbens and VTA of saline- and cocaine-pretreated animals using in vivo microdialysis. The data demonstrated that intra-mPFC SKF 38393 reduced GABA and glutamate levels in the mPFC in control animals. Intra-mPFC SKF 38393 had no effect on glutamate levels in animals 1 day after daily cocaine treatments, increased mPFC glutamate at 7 days of withdrawal and reverted to decreasing glutamate at 30 days of withdrawal. SKF 38393 induced reduction in mPFC GABA is lost at 7 and 30 days of withdrawal. Intra-mPFC SKF 38393 did not alter glutamate levels in the nucleus accumbens or VTA of control animals. Infusion of SKF 38393 into the mPFC of animals previously exposed to cocaine increased and reduced glutamate release in the nucleus accumbens after 7 and 30 days of withdrawal, respectively and increased glutamate levels in the VTA 7 and 30 days after daily cocaine injections. The data suggest that repeated cocaine exposure alters D1 receptor function in the mPFC that could contribute to enhanced behavioral responses that occur following repeated cocaine.