Prefrontal cortex D1 receptor regulation of mesolimbic dopamine and cocaine self-administration

The prefrontal cortex (PFC) is known to modulate mesolimbic dopamine (DA) activity and has also been implicated in drug abuse. The present study demonstrated that blockade of DA D1 receptors in the PFC had a delayed effect on mesolimbic DA activity and cocaine self-administration. Using in vivo microdialysis, nucleus accumbens (NAcc) DA was found to be elevated 24 hours, but not immediately following intra-PFC infusion of the D1 antagonist SCH 23390, but not the D1 agonist SKF 38393. Tyrosine hydroxylase (TH), phospho-TH, and dopamine transporter (DAT) levels were unchanged one and 24 hours following intra-PFC SCH 23390 or SKF 38393 in the ventral tegmental area (VTA) and NAcc. Neither intra-PFC SCH 23390 nor SKF 38393 had an immediate effect on cocaine self-administration on a progressive ratio (PR) or fixed ratio (FR) of reinforcement. SCH 23390 produced a delayed lowering of breakpoints for 0.25 mg/kg, but not 0.75 mg/kg cocaine on a PR schedule and had no effect on responding for 0.25 mg/kg cocaine on an FR schedule. The present study demonstrates that PFC D1 receptors modulate mesolimbic activity and sensitivity to the reinforcing properties of cocaine.