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 the prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M1 and M4 receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of schizophrenia.
Method: Using quantitative autoradiography, the authors analyzed the binding of the M1/M4 receptor selective antagonist [3H]pirenzepine in prefrontal cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients who 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 following administration of antipsychotic drugs or benztropine mesylate were performed.
Results: Relative to those of comparison subjects, the mean levels of [3H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [3H]pirenzepine-labeled receptors in rat frontal cortex.
Conclusions: Because M1 and M4 receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.