CONDITIONED PLACE AVERSION FOLLOWING THE CENTRAL ADMINISTRATION OF A NOVEL DOPAMINE RELEASE INHIBITOR CGS 10746B

Numerous drugs of abuse that elevate brain extracellular dopamine concentrations by either increasing the firing rate of dopaminergic neurons or producing dopamine release have been shown to reliably condition a preference for place. If dopamine release is a necessary component for conditioned place preference (CPP), one reciprocal hypothesis may be that inhibition of dopamine release will result in conditioned place aversion (CPA). This hypothesis has been tested pharmacologically by employing CGS 10746B (CGS), a novel neuroleptic known to inhibit the release of dopamine via presynaptic mechanisms. In previous work the peripheral administration of CGS (1.25-20 mg/kg) produced place aversion at doses above 5 mg/kg. However, the contribution of peripheral mechanisms of the production of CGS-induced CPA is unknown. To test whether central administration of CGS would also result in CPA, rats were fitted with chronic intraventricular cannula. Groups of rats subsequently received four conditioning trials with one of four intraventricular (ICV) doses of CGS (1-30-mu-g) when confined to their preferred side of a place conditioning apparatus. Vehicle was similarly administered on four interspersed days prior to confining these same rats to their nonpreferred side of the apparatus. At the conclusion of these eight conditioning trials, the rats were tested, on separate days, in a nondrugged and a CGS-drugged state. The highest dose of CGS (30-mu-g) produced a CPA as evidenced by rats spending less time in the environment initially found to be preferred. Locomotor activity was also measured over a 30-min period with and without ICV injection of CGS (1-30-mu-g). Activity was not reliably decreased at any dose tested in comparison to baseline. In conclusion, centrally administered CGS produces a CPA suggesting that inhibition of dopamine release contributes to place aversion conditioning.