Cocaine self-administration alters the locomotor response to microinjection of bicuculline into the ventral tegmental area of rats

Several studies indicate that repeated administration of cocaine can alter GABA_A receptor function, particularly in the mesolimbic pathway. The purpose of the present study was to assess the effect of cocaine self-administration on GABA_A receptor activity in the ventral tegmental area (VTA), measured by bicuculline-induced rotational behavior. In order to test whether the hypothesized alteration in GABA_A receptor function persisted during withdrawal, rats were tested when drug-naïve and at two time points after cocaine self-administration. Eighteen rats were implanted with intrajugular catheters and unilateral guide shafts aimed at the VTA. Microinjection of the GABA_A receptor antagonist bicuculline (10, 25 and 50 ng) produced a dose-dependent turning behavior in a direction ipsilateral to the side of the injection. A subset of six rats was given up to 2 weeks exposure to intravenous cocaine by self-administration and was tested for bicuculline-induced rotations early in withdrawal (24 h) and again at a late withdrawal time point (between 11 and 14 days after the last cocaine session). Cocaine self-administration reduced sensitivity to bicuculline-induced rotations at the early but not at the late withdrawal point, when compared to sensitivity in drug-naive animals. A separate control study that was conducted in seven rats determined that repeated injections of bicuculline in the cocaine self-administration animals was not the cause of the decrease in behavioral response to bicuculline at the early withdrawal time point. These results suggest that exposure to cocaine via self-administration reduces the function of GABA_A receptors in the ventral midbrain, but this reduction in receptor sensitivity did not persist beyond 10 days of withdrawal from cocaine.