Withdrawal from continuous cocaine administration: time dependent changes in accumbens 5-HT3 receptor function and behavioral tolerance

We have previously reported that continuous cocaine administration function ally down regulates 5-HT3 receptors in the nucleus accumbens. The current e xperiments evaluated the duration of behavioral tolerance to cocaine and wh ether the duration of behavioral tolerance and 5-HT3 receptor down-regulati on covaried. Rats were withdrawn from a pretreatment regimen (40 mg/kg/per day cocaine or 0.9% saline for 14 days) for 1, 7 or 14 days. The rats were either sacrificed, and slices from the nucleus accumbens obtained, or were exposed to behavioral rating procedures. The results indicated that continu ous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-stimulated DA release on days 1 and 7, but not day 14, of wi thdrawal. Furthermore, continuous cocaine administration induced behavioral tolerance to a cocaine challenge on days 1 and 7, but not day 14, of withd rawal. These results suggest that continuous cocaine administration functio nally downregulates 5-HT3 receptors in the nucleus accumbens, and this func tional down-regulation co-varies with the behavioral tolerance induced by c ontinuous cocaine administration. Hence, a functional down-regulation of ac cumbens 5-HT3 receptors may represent a partial mechanism for the tolerance following continuous cocaine administration.