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.

Abstract

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.

• Authors: J M Crook, E Tomaskovic-Crook, D L Copolov, B Dean
• Journal: The American journal of psychiatry (Am J Psychiatry) Vol. 158 Issue 6 Pg. 918-25 (Jun 2001) ISSN: 0002-953X [Print] United States
• PMID: 11384900 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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