Some atypical antipsychotics clinically used to treat schizophrenia induce weight gain by unknown mechanisms. The dorsal vagal complex (DVC) of the brainstem and the endogenous cannabinoid system are implicated in the regulation of appetite signalling and food intake. We investigated whether antipsychotic drugs alter cannabinoid receptor-binding density in the DVC. Female Sprague–Dawley rats were treated with olanzapine, haloperidol, aripiprazole or vehicle for 1 wk (short-term) or 12 wk (chronic). Quantitative autoradiographic methods were employed to investigate the binding density of cannabinoid receptors in the DVC using a highly sensitive Beta Imager. Short-term olanzapine induced a significant 39% decrease in cannabinoid receptor binding compared to controls, whilst short-term aripiprazole and haloperidol had no significant effect. Chronic olanzapine treatment induced a significant 46% decrease in cannabinoid receptor binding compared to controls, aripiprazole slightly decreased cannabinoid receptor binding (12%), whilst haloperidol had no effect. Consistent with binding changes, short-term and chronic olanzapine treatment induced significant weight gain, but not aripiprazole or haloperidol. Cannabinoid receptor binding was negatively correlated to weight gain following chronic olanzapine treatment only (r=x0.83, p=0.01). In addition, only chronic olanzapine treatment increased food intake. These results show that olanzapine, an antipsychotic with a high risk of weight gain as a side-effect, significantly decreased cannabinoid receptor binding in the DVC, whilst aripiprazole and haloperidol, antipsychotics with a low risk of weight gain had little or no effect on binding. These results suggest that a mechanism for antipsychotic-induced weight gain may be through the modulation of cannabinoid receptors in the DVC.