There is increasing evidence supporting the involvement of the muscarinic-cholinergic system in schizophrenia. We examined the M1 muscarinic receptor density and mRNA expression in brains of a rat amphetamine model of schizophrenia. We also assessed the effect of the model and chronic treatment with haloperidol and clozapine on brain M1 receptor density and gene expression. A significant decrease of about 20% in the density of M1 receptor was detected in the cortex and in the striatum of amphetamine model rats. A significant increase of 33% in the density of the M1 receptor was found in the cortex and striatum of rats treated chronically with clozapine (0.5 mg/kg), but not with haloperidol (25 mg/kg). Chronic clozapine, but not haloperidol, normalized the decrease in M1 receptors observed in amphetamine model rats, in both cortex and striatum. Regulation of the M1 receptor may occur in a post-transcriptional phase. Our findings suggest involvement of both dopaminergic and cholinergic-muscarinic systems in the pathophysiology and pharmacotherapy of schizophrenia.