Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects

Abstract

Background: Dysfunction of the cholinergic muscarinic receptors has been implicated in the pathology of bipolar disorder and major depressive disorder. However, there is conflicting evidence regarding the association between individual muscarinic receptors and the two disorders.

Methods: We used the muscarinic receptor selective radioligands [3H]pirenzepine, [3H]AFDX-384 and [3H]4-DAMP to measure the levels of muscarinic(1) (CHRM1) and muscarinic(4) (CHRM4) receptors, muscarinic(2) (CHRM2) and muscarinic(4) (CHRM4) receptors and muscarinic(3) (CHRM3) receptor, respectively. Radioligand binding was measured in Brodmann's area (BA) 10 of the rostral prefrontal cortex, BA 46 of the dorsolateral prefrontal cortex and BA 40 of the parietal cortex in the post-mortem CNS from subjects with bipolar disorder or major depressive disorder and control subjects.

Results: [3H]AFDX-384 binding was decreased in BA 46 in both bipolar disorder (p<0.01) and major depressive disorder (p<0.05). [3H]4-DAMP binding was decreased in BA 10 in bipolar disorder (p<0.05) but not major depressive disorder (p>0.05). [3H]AFDX-384 and [3H]4-DAMP binding were unaltered in any other cortical region examined for either disorder (p>0.05). [3H]pirenzepine binding was not significantly altered in either disorder in any cortical region examined (p>0.05).

Limitations: 9 bipolar disorder, 9 major depressive disorder and 19 control subjects were used in the study.

Conclusion: Our data is consistent with previously published data implicating a role for CHRM2 receptors in the pathology of bipolar and major depressive disorder. The demonstration of a novel association between decreased CHRM3 receptor expression and bipolar disorder suggests bipolar and major depressive disorder differs in the underlying nature of their cholinergic dysfunction.

Figure 1

Representative autoradiographs showing (A) [³H]AFDX-384, (B) [³H]4-DAMP and (C) [³H]pirenzipine binding in Brodmanns area (BA) 10 from the same subject. The signal intensity of the bound radioligand was corrected non-specific background signal by subtracting the binding levels of the radioligand in the presence of a displacing agent (non-specific binding) from the total binding level of the radioligand. The displacing agents used to correct for [³H]AFDX-384, (B) [³H]4-DAMP and (C) [³H]pirenzipine background signal were quinuclidinyl xanthene-9-carboxylate hemioxilate, tropicamide and 4-diphenylacetoxy-N-methylpiperidine methiodide mustard hydrochloride, respectively. Non-specific binding of the radioligands in the presence of displacing agents are shown in the inset images.

Figure 2

(A) [³H]AFDX-384, (B) [³H]Pirenzepine and (C) [³H]4-DAMP binding in the post-mortem cortex of bipolar disorder (BPD) (n=9), major depressive disorder (MDD) (n=9) and control (n=19) subjects. A significant decrease in [³H]AFDX-384 binding was seen in BA 46 of subjects with bipolar disorder (F_2,36=8.80; p_corrected=0.001) and major depressive disorder (F_2,36=8.80; p_corrected=0.014). A significant decrease in [³H]4-DAMP binding was seen in BA 10 of subjects with bipolar disorder (F_2,36=3.69; p_corrected=0.022). While changes in [³H]AFDX-384, [³H]Pirenzepine and [³H]4-DAMP binding did not reach significance in any other region, there appeared to be a trend towards a greater decrease in [³H]AFDX-384 and [³H]4-DAMP binding in bipolar disorder compared to major depressive disorder in all cortical regions examined. Values are expressed as fmol of bound radioligand per mg of estimated tissue equivalent. * =p<0.05; ** = p<0.01