WITHDRAWAL FROM CONTINUOUS OR INTERMITTENT COCAINE ADMINISTRATION - CHANGES IN D-2 RECEPTOR FUNCTION

Intermittent cocaine administration produces sensitization, whereas th e continuous administration of cocaine produces tolerance to the effec ts of subsequent cocaine administration during withdrawal. The present study examined whether the effects of these two dosing regimens are r elated to alterations in the functional status of dopamine (DA) D-2 re ceptors. In all experiments, rats were withdrawn for 7 days from a 14- day pretreatment regimen involving either continuous or intermittent c ocaine administration. Experiments examined changes in the behavioral response to an autoreceptor-selective dose of apomorphine, the effects of sulpiride on electrically stimulated DA release in striatal brain slices and striatal D-2 receptor binding, and mRNA levels. The results indicate that the continuous administration of cocaine produces findi ngs consistent with D-2 autoreceptor supersensitivity; there was enhan ced inhibition of behavior after the autoreceptor-selective dose of ap omorphine, decreased electrically stimulated DA release in the absence of sulpiride, and enhanced electrically stimulated DA release in the presence of sulpiride. However, there were no changes in postsynaptic D-2 receptor binding or mRNA levels. Intermittent cocaine administrati on did not produce evidence of D-2 autoreceptor subsensitivity: there was no decrease in inhibition of behavior after the autoreceptor-selec tive dose of apomorphine, no changes in electrically stimulated DA rel ease in the absence or presence of D-2 receptor blockade, and no chang e in the levels of D-2 receptor binding; however, D-2 mRNA levels were decreased by 22%. Overall, the present results are consistent with th e hypothesis that the expression of tolerance induced by continuous co caine administration is associated with D-2 autoreceptor supersensitiv ity.