Antipsychotic-induced alterations in CB(1) receptor-mediated G-protein signaling and in vivo pharmacology in rats

Abstract

Dysregulation of the endocannabinoid and dopamine systems has been implicated in schizophrenia. The purpose of this study was to examine the effects of sub-chronic treatment with two antipsychotics on CB(1) receptor-mediated in vitro and in vivo effects. Adult and adolescent male and female rats were injected twice daily with haloperidol (0.3 mg/kg), clozapine (10 mg/kg), or saline for 10 days. Subsequently, CB(1) receptor number and function were assessed by [(3)H]SR141716 and WIN55,212-2-stimulated [(35)S]GTP gamma S binding, respectively. The effects of sub-chronic antipsychotic treatment on the in vivo actions of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) were also evaluated. In adult female rats, antipsychotic treatment attenuated maximal stimulation of CB(1) receptor-mediated G-protein activity in the striatum (clozapine) and prefrontal cortex (both antipsychotics), but not in the ventral midbrain. Associated changes in CB(1) receptor number were not observed, suggesting that this attenuation was not due to downregulation. In vivo, sub-chronic treatment with clozapine, but not haloperidol, attenuated Delta(9)-THC-induced suppression of activity in adult females, whereas neither drug altered hypothermia or catalepsy. In contrast, antipsychotic treatment did not change CB1 receptor-mediated G-protein activation in any brain region in adult male rats and in adolescents of either sex. In vivo, haloperidol, but not clozapine, enhanced Delta(9)-THC-mediated suppression of activity and hypothermia in adult male rats whereas neither antipsychotic affected Delta(9)-THC-induced in vivo effects in adolescent rats. These findings suggest that modulation of the endocannabinoid system might contribute in a sex- and age-selective manner to differences in motor side effects of clozapine versus haloperidol. (C) 2008 Elsevier Ltd. All rights reserved