Research reportDecreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects
Introduction
The pathologies of bipolar disorder and major depressive disorder have long been thought to have a cholinergic component (Janowsky et al., 1972, Janowsky et al., 1994). Early studies found that insecticidal cholinesterase inhibitors (Roundtree et al., 1950) induced depression in individuals with bipolar disorder. Further evidence from clinical studies into the effects of drugs that act on the cholinergic and adrenergic neurotransmitter systems lead to a cholinergic–adrenergic hypothesis of mania and depression (Janowsky et al., 1972). Thus, a hypocholinergic–hyperadrenergic state could induce mania while a hypercholinergic–hypoadrenergic state would produce depression. Supporting this hypothesis, clinical studies have shown have shown that scopolamine, a non-selective cholinergic muscarinic receptor antagonist, has antidepressant effects in both bipolar disorder and major depressive disorder (Furey and Drevets, 2006). In addition, it has been shown that the mood stabiliser, lithium, upregulates hippocampal cholinergic muscarinic receptors (Marinho et al., 1998). These observations suggest that muscarinic receptors may have a role in the pathology of bipolar disorder and major depressive disorder.
The potential role of muscarinic receptors in bipolar disorder and major depressive disorder has underpinned genetic studies to determine if these receptors are associated with an increased risk of developing the disorders. Two association studies have identified several non-coding single nucleotide polymorphisms (SNP's) within the cholinergic muscarinic2 receptor (CHRM2) gene associated with the incidence of major depressive disorder (Comings et al., 2002, Wang et al., 2004). The reported association between SNPs within CHRM2 and a combined cohort of subjects with bipolar disorder, major depressive disorder and seasonal affective disorder suggests a potentially broader role for CHRM2 in the pathology of affective disorders (Luo et al., 2005). Conversely, a recent analysis of 19 cholinergic genes, including the five members of the muscarinic receptor family, failed to detect an association between SNP's in CHRM2 incidence of bipolar disorder (Shi et al., 2007). Amongst the other muscarinic receptors, this same study also failed to detect an association between SNP's in any other muscarinic receptor gene and the incidence of bipolar disorder. The lack of association between other muscarinic receptors and the pathology of affective disorders is further supported by linkage studies show, which no association between bipolar disorder and the long arm of chromosome 11, the chromosomal region containing the cholinergic muscarinic1 receptor (CHRM1) gene (Ewald et al., 1995).
Neuroimaging studies have also implicated the cholinergic muscarinic receptors in the pathology of affective disorder. PET studies have reported a decrease in the CHRM2 selective agonist [18F]FP-TZTP in the anterior cingulate cortex of individuals with bipolar disorder but not major depressive disorder (Cannon et al., 2006). By contrast, post-mortem tissue has failed to show any change in binding of the CHRM2/CHRM4 selective antagonist [3H]AFDX-384 or the CHRM1/CHRM4 selective antagonist [3H]pirenzepine in the anterior cingulate cortex from subjects with bipolar disorder or major depressive disorder (Zavitsanou et al., 2004, Zavitsanou et al., 2005). [18F]FP-TZTP selectively binds to the high affinity binding state of CHRM2, compared to the high and low affinity binding of the radioligands employed in the post-mortem studies. Thus the decrease in functional pool of CHRM2 observed in neuroimaging studies are suggestive of an increase in intrasynaptic acetylcholine levels and/or a reduction in the proportion of receptors in their high affinity state associated with bipolar disorder rather than a decrease in receptor expression.
The muscarinic receptor antagonists [3H]pirenzepine, [3H]AFDX-384 and [3H]4-DAMP have been shown to be effective in selectively measuring muscarinic receptor protein expression, whereby [3H]pirenzipine binds with high affinity to CHRM1 and CHRM4, [3H]AFDX-384 binds with high affinity to CHRM2 and CHRM4 and [3H]4-DAMP displays high affinity binding to CHRM3 (Hammer et al., 1980, Michel et al., 1989, Miller et al., 1991). We used the radioligands [3H]pirenzepine, [3H]AFDX-384 and [3H]4-DAMP to examine muscarinic receptors in post-mortem tissue from subjects with bipolar disorder or major depressive disorder. We focused our studies on the frontal cortex, as this region has been shown to be affected by both mania and depression (Blumberg et al., 1999, Drevets et al., 1997, Soares and Mann, 1997). We also measured muscarinic receptors in the parietal cortex as this area has not been shown to be markedly affected by the pathology of bipolar disorder or major depressive disorder; thus we hypothesised that muscarinic receptor expression would be unchanged in this region.
Section snippets
Tissue collection
All tissue was obtained from the Victorian Brain Bank Network, Mental Health Research Institute of Victoria, Parkville, Australia. Approval for the study was obtained from both the Ethics Committee of the Victorian Institute of Forensic Medicine and the Mental Health Research and Ethics Committee of Melbourne Health. Tissue from Brodmann's Area 10 (BA 10), Brodmann's Area 46 (BA 46) and Brodmann's Area 40 (BA 40) of the left hemisphere was obtained post-mortem from 9 subjects diagnosed with
Distribution of radioligand binding within the grey matter
Within all cortical regions examined, binding of [3H]AFDX-384, [3H]4-DAMP and [3H]pirenzepine appeared homogeneous across the cortical laminae (Fig. 1). Thus, an integrated measurement of radioligand binding was taken across the cortical laminae for each section. Using these measures, the radioligand binding data set showed non-Gaussian distribution of the binding data and thus non-parametric analyses were completed.
All binding experiments were performed using radioligand concentrations 3-fold
Discussion
Our data suggests that decreased muscarinic receptor expression in the rostral and dorsolateral and prefrontal cortices is associated with both bipolar disorder and major depressive disorder. There are both similarities and differences in the nature of the cholinergic dysfunctions in these disorders. Binding of the CHRM2/CHRM4 selective radioligand [3H]AFDX-384 was decreased by 37% in subjects with bipolar disorder and by 28% in subjects with major depressive disorder compared to controls
Role of the funding source
This study was supported in part by grants-in-aid from the National Health and Medical Research Council (Project Grant no. 350344), The Rebecca L Cooper Medical Research Foundation and the Wood's Family Research Program. The study was supported by the funding grants; NIH RO1 MH069696-01 and NHMRC project grant 3503441. Brian Dean is a NHMRC Senior Research Follow (400016) and Elizabeth Scarr is the Royce Abbey Postdoctoral Fellow (Australian Rotary Health Research Fund). The funding bodies had
Conflict of interest
No conflict declared.
Acknowledgements
The authors gratefully acknowledge the assistance of Geoffrey Pavey for the preparation of post-mortem tissue, Susan Juzva for her technical assistance and David Copolov, Christine Hill, Nicholas Keks, and Kenneth Opeskin for their roles in tissue collection and diagnostic confirmation.
References (54)
- et al.
Assessing cognitive deficits in bipolar disorder: are self-reports valid?
Psychiatry Res.
(2005) - et al.
Regional brain activity during tasks devoted to the central executive of working memory
Cogn. Brain Res.
(1999) - et al.
The binding of H-3 AF-DX 384 is reduced in the Caudate–Putamen of subjects with schizophrenia
Life Sci.
(1999) - et al.
Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression
Biol. Psychiatry
(2008) - et al.
Basic associated designs: analysis and interpretation
J. Am. Acad. Child Adolesc. Psych.
(2002) - et al.
Regional brain uptake of the muscarinic ligand, [F-18]FP-TZTP, is greatly decreased in M2 receptor knockout mice but not in M1, M3 and M4 receptor knockout mice
Neuropharmacology
(2003) - et al.
A cholinergicadrenergic hypothesis of mania and depression
Lancet
(1972) - et al.
Tissue pH as an indicator of mRNA preservation in human post-mortem brain
Brain Res. Mol. Brain Res.
(1995) - et al.
Localization of muscarinic M3 receptor protein and M3 receptor-binding in rat-brain
Neuroscience
(1994) - et al.
Effects of lithium, alone or associated with pilocarpine, on muscarinic and dopaminergic receptors and on phosphoinositide metabolism in rat hippocampus and striatum
Neurochem. Int.
(1998)
Direct labeling of rat M3-muscarinic receptors by H-3 4DAMP
Eur. J. Pharmacol.
Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward task
Biol. Psychiatry
Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines
Exp. Neurol.
The functional neuroanatomy of mood disorders
J. Psychiatr. Res.
Human postmortem tissue: what quality markers matter?
Brain Res.
Gray matter reduction associated with psychopathology and cognitive dysfunction in unipolar depression: a voxel-based morphometry study
J. Affect. Disord.
M2/M4 muscarinic receptor binding in the anterior cingulate cortex in schizophrenia and mood disorders
Brain Res. Bull.
Diagnostic and Statistical Manual of Mental Disorders
Heterogenous binding of [3H]4-DAMP to muscarinic cholinergic sites in the rat brain: evidence from membrane binding and autoradiographic studies
Synapse
Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder
Am. J. Psychiatry
Function and localization within rostral prefrontal cortex (area 10)
Philos. Trans. R. Soc. Lond. B. Biol. Sci.
Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder
Arch. Gen. Psychiatry
Toward convergence in the medication treatment of bipolar disorder and schizophrenia
Harv. Rev. Psychiatry
Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women
Am. J. Med. Genet.
Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology
Schizophr. Bull.
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
Physostigmine in man
Arch. Gen. Psychiatry
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