Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: A study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment

Objective: Aberrant cholinergic inputs and synaptic neurotransmission in th e prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M-1 and M -4 receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of s chizophrenia. Method: Using quantitative autoradiography, the authors analyzed the bindin g of the M-1/M-4 receptor selective antagonist [H-3]pirenzepine in prefront al cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients w ho had (N=6) or had not (N=11) been treated with the anticholinergic agent benztropine mesylate and from normal comparison subjects (N=20). Moreover, preliminary studies of [3H]pirenzepine binding in rat frontal cortex follow ing administration of antipsychotic drugs or benztropine mesylate were perf ormed. Results: Relative to those of comparison subjects, the mean levels of [H-3] pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 o f the schizophrenia patients not treated with benztropine mesylate (18% low er in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all fou r examined regions of the patients who had received benztropine (51%-64% lo wer). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [H-3]pirenzepine-labeled receptors in rat frontal cortex. Conclusions: Because M-1 and M-4 receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a function al impairment in cholinergic neurotransmission in schizophrenia and the pos sibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.