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

Am J Psychiatry. 2001 Jun;158(6):918-25. doi: 10.1176/appi.ajp.158.6.918.


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 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 schizophrenia.

Method: Using quantitative autoradiography, the authors analyzed the binding of the M(1)/M(4) receptor selective antagonist [(3)H]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 [(3)H]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 [(3)H]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 [(3)H]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 functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use*
  • Autoradiography
  • Benztropine / analogs & derivatives*
  • Benztropine / pharmacology
  • Benztropine / therapeutic use
  • Cause of Death
  • Female
  • Humans
  • Male
  • Middle Aged
  • Parasympatholytics / pharmacology
  • Parasympatholytics / therapeutic use
  • Pirenzepine / metabolism
  • Prefrontal Cortex / chemistry
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Rats
  • Receptors, Muscarinic / analysis
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / metabolism*
  • Schizophrenia / diagnosis*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism
  • Tritium / metabolism


  • Antipsychotic Agents
  • Parasympatholytics
  • Receptors, Muscarinic
  • Tritium
  • Benztropine
  • Pirenzepine