Investigation of M1/M4 Muscarinic Receptors in the Anterior Cingulate Cortex in Schizophrenia, Bipolar Disorder, and Major Depression Disorder

Abstract

Abnormal cholinergic neurotransmission has been suggested to occur in psychiatric illness. Therefore, this study investigated cholinergic muscarinic receptors in the anterior cingulate cortex (ACC) of schizophrenia, bipolar disorder and major depression disorder (n ¼ 15 per group). We used quantitative autoradiography to measure [ 3 H]pirenzepine binding to M1 and M4 receptors. Brain tissue was obtained from the Stanley Foundation Neuropathology Consortium. [ 3 H]pirenzepine binding was higher in superficial laminae (I-II) than in deep laminae (III-VI) of the ACC. There was a significant 24% reduction in the density of [ 3 H]pirenzepine in the deep laminae and a significant 19% reduction in the upper laminae of the ACC in the schizophrenia group compared to the control group. There were no differences in [ 3 H]pirenzepine binding in any laminae of the ACC in the bipolar or major depression groups compared with the control group, except for a trend towards decreased [ 3 H]pirenzepine binding in subjects with major depression relative to control subjects. We also detected a significant effect of suicide on [ 3 H]pirenzepine binding in the ACC in subjects who died as a result of suicide relative to those who did not, which was more evident in patients with schizophrenia. A significant effect of the onset of the disease was also observed that was more evident in patients with bipolar disorder. The study provides evidence of decreased muscarinic receptor density in the ACC in schizophrenia but no evidence for significant changes in these receptors in the bipolar and major depression groups. The changes observed in schizophrenia may contribute to dysfunctional ACC neural circuits.

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

“…The M 1 receptor subtype is the most abundant of the muscarinic receptors in the cortex and hippocampus (Levey et al, 1991;Wei et al, 1994), brain regions crucial to cognitive function. Decreased M 1 receptor binding has been reported in postmortem studies of the prefrontal cortex, hippocampus, and striatum from patients with schizophrenia (Dean et al, 1996;Crook et al, 2000Crook et al, , 2001Katerina et al, 2004); and decreased M 1 -receptor cDNA levels in the frontal cortex have also been reported (Mancama et al, 2003). This has contributed to the suggestion that enhancement of central cholinergic neurotransmission by M 1 agonists might be useful to treat the cognitive impairments of schizophrenia (Sur et al, 2003;Weiner et al, 2004).…”

Towards a muscarinic hypothesis of schizophrenia

“…92 However, this group did report a significant reduction in the levels of M 1 and M 4 muscarinic receptors in the anterior cingulate cortex in schizophrenia. 93 These changes were shown to have some disease-specificity as the density of M 1 and M 4 muscarinic receptors was not altered in the same CNS region from subjects with bipolar disorder or major depression. 93 In the superior temporal gyrus, another relevant brain region for schizophrenia, the density of M 1 and M 4 muscarinic receptors (using pirenzepine) was significantly decreased in schizophrenia.…”

“…93 These changes were shown to have some disease-specificity as the density of M 1 and M 4 muscarinic receptors was not altered in the same CNS region from subjects with bipolar disorder or major depression. 93 In the superior temporal gyrus, another relevant brain region for schizophrenia, the density of M 1 and M 4 muscarinic receptors (using pirenzepine) was significantly decreased in schizophrenia. M 2 and M 4 muscarinic receptor levels in the same brain region (using AF-DX 384) showed a decrease that failed to reach significance.…”

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

“…Nevertheless, postmortem, clinical imaging, and genetic approaches have further implicated mAChR expression and function in the underlying pathophysiology of schizophrenia. Several postmortem [ 3 H]pirenzepine-binding studies have demonstrated decreased levels of M 1 /M 4 mAChRs in specific brain regions of schizophrenic patients, including the prefrontal and anterior cingulate cortices, superior temporal gyrus, hippocampus, and dorsal striatum (Dean et al, 1996(Dean et al, , 2002Crook et al, 1999Crook et al, , 2000Crook et al, , 2001Katerina et al, 2004;Deng and Huang, 2005). These changes in mAChR expression appear to be specific to schizophrenia, as similar decreases were not observed in patients with bipolar disorder or major depression (Zavitsanou et al, 2004).…”