CLOZAPINE AND HALOPERIDOL BLOCK THE INDUCTION OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE AND ASSOCIATED GENOMIC RESPONSES IN RATS

Behavioral sensitization resulting from repeated, intermittent exposur e to psychostimulants such as amphetamine (Amp) is hypothesized to mod el pathophysiology of psychotic disorders. The present study was desig ned to characterize the effects of a typical and an atypical antipsych otic drug, haloperidol and clozapine, respectively, on the induction o f context-independent sensitization to Amp. Peripheral Amp treatment f or five days (2 mg/kg/day, s.c.) produced an augmented stimulant respo nse to an acute Amp challenge (2 mg/kg, s.c.) given seven days after t he last pretreatment injection. Interestingly, preexposure to high dos es of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone als o led to a sensitized behavioral response to an acute Amp challenge. T he cross-sensitization between Amp and high doses of the haloperidol a nd clozapine may have occluded any blockade of Amp behavioral sensitiz ation by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the pr eexposure phase clearly blocked the induction of behavioral sensitizat ion. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c-fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked t he initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c-f os and NT/N gene expression. These data lend support to the psychostim ulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon. (C) 1998 Elsevier Science B.V. All rights reserved.