Differential region-specific regulation of central alpha 1-adrenoceptor binding following chronic haloperidol and clozapine administration in the rat.

RATIONALE: Many antipsychotics exhibit potent anti-alpha(1)-adrenergic receptor activity, which has been suggested to contribute to typical and atypical antipsychotic effects and to the production of centrally mediated side effects.
OBJECTIVES: To assess the relative contribution of alpha(1)-adrenoceptors to the mechanism of action of haloperidol and clozapine and to identify possible sites of action.
METHODS: We examined the effect of chronic haloperidol and clozapine treatment on alpha(1)-adrenoceptor characteristics in several rat brain regions. For comparison, D(2)-like dopamine receptor density in the striatum was also determined.
RESULTS: Clozapine administration (25 mg/kg/day i.p., 21 days) significantly increased alpha(1)-adrenoceptor density in the frontal cortex (44%), remaining cortex (49%) and thalamus (93%) but binding levels in the hippocampus and spinal cord were unchanged relative to vehicle. Haloperidol treatment (1.5 mg/kg/day i.p., 21 days) also significantly increased the density of alpha(1)-adrenoceptor binding in the thalamus (73%), but had no effect on alpha(1)-adrenoceptor levels in any other region examined. alpha(1)-Adrenoceptor affinity in the cortex was not significantly altered by either antipsychotic treatment. Haloperidol, in contrast to clozapine, significantly upregulated dopamine D(2)-like binding in the striatum.
CONCLUSIONS: Central alpha(1)-adrenoceptors are differentially regulated after chronic haloperidol and clozapine treatment. It is suggested that thalamic alpha(1)-adrenoceptors may represent a common anatomical locus contributing to the antipsychotic activity and/or alpha(1)-adrenoceptor centrally mediated side effects of both drugs, whereas the selective upregulation of cortical alpha(1)-adrenoceptor density by clozapine may contribute, in part, to its superior atypical properties.