THE ROLE OF DOPAMINE-D4 RECEPTOR IN THE INDUCTION OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE AND ACCOMPANYING BIOCHEMICAL AND MOLECULAR ADAPTATIONS

Our studies examined the role of dopamine D4 receptors in the inductio n of behavioral sensitization to amphetamine (Amp) and accompanying ne urochemical and molecular adaptive responses using a highly selective D4 antagonist, PNU-101387G. Behavioral sensitization to an acute chall enge of Amp (2 mg/kg, s.c.) was observed in rats pretreated with five daily doses of Amp (2 mg/kg/d, s.c.) followed by 7-day withdrawal. int erestingly, coadministration of PNU-101387G with Amp during pretreatme nt completely blocked the sensitized response to an acute Amp challeng e. The behavioral sensitization and its blockade by the D4 antagonist were observed in the absence of significant differences in cerebellar Amp levels among the various pretreatment groups. Accompanying behavio ral sensitization were two postsynaptic neuroadaptive responses: reduc tion in the ability of Amp to induce c-fos gene expression in the infr alimbic/ventral prelimbic cortex and NT/N mRNA in the accumbal shell. However, concurrent blockade of D4 receptors during Amp pretreatment p revented the refractoriness in c-fos and NT/N responsiveness to acute Amp. We observed also a presynaptic neuroplastic response associated w ith the behavioral sensitization: a significant augmentation in the ab ility of Amp to increase extracellular dopamine concentrations in the nucleus accumbens shell. As with the behavioral sensitization and asso ciated postsynaptic adaptive responses, concurrent administration of P NU-101387G with Amp during pretreatment blocked the augmentation in Am p-induced dopamine release. Taken together, these data demonstrate tha t dopamine D4 receptors play an important role in the induction of beh avioral sensitization to Amp and accompanying adaptations in pre- and postsynaptic neural systems associated with the mesolimbocortical dopa mine projections.