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 induction of behavioral sensitization to amphetamine (Amp) and accompanying neurochemical and molecular adaptive responses using a highly selective D4 antagonist, PNU-101387G. Behavioral sensitization to an acute challenge 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. Interestingly, coadministration of PNU-101387G with Amp during pretreatment completely blocked the sensitized response to an acute Amp challenge. 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 behavioral sensitization were two postsynaptic neuroadaptive responses: reduction in the ability of Amp to induce c-fos gene expression in the infralimbic/ventral prelimbic cortex and NT/N mRNA in the accumbal shell. However, concurrent blockade of D4 receptors during Amp pretreatment prevented the refractoriness in c-fos and NT/N responsiveness to acute Amp. We observed also a presynaptic neuroplastic response associated with the behavioral sensitization: a significant augmentation in the ability of Amp to increase extracellular dopamine concentrations in the nucleus accumbens shell. As with the behavioral sensitization and associated postsynaptic adaptive responses, concurrent administration of PNU-101387G with Amp during pretreatment blocked the augmentation in Amp-induced dopamine release. Taken together, these data demonstrate that dopamine D4 receptors play an important role in the induction of behavioral sensitization to Amp and accompanying adaptations in pre- and postsynaptic neural systems associated with the mesolimbocortical dopamine projections.