Dysfunction of the Cholinergic Muscarinic Receptors and Bipolar Disorder

Andrew Stuart Gibbons
European Psychiatric Review, 2011;4(2):97-100
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Abstract

The underlying molecular cause of bipolar disorder remains poorly understood. Observations of increased symptoms of depression in individuals following prolonged exposure to anticholinesterase insecticides led to the proposal that the manic and depressive symptoms of bipolar disorder result from imbalances in the cholinergic and adrenergic neurotransmitter systems – a hypothesis that has been supported by subsequent pharmacological studies, which have highlighted the involvement of the muscarinic receptor family of cholinergic receptors. Candidate gene studies that have looked for polymorphisms within the muscarinic receptor gene sequences have failed to provide conclusive evidence of mutations in the gene sequence associated with the incidence of bipolar disorder. However, recent studies using radioligands that selectively bind to specific muscarinic receptors have reported deficits in the expression of cholinergic receptor muscarinic-2 (CHRM2) and CHRM3 proteins in subjects with bipolar disorder, significantly advancing our understanding of which receptors are affected in the disorder, while providing evidence against proposed common causes of bipolar disorder and other psychiatric disorders, such as major depression and schizophrenia. Regional variations in the expression of CHRM2 and CHRM3 implicate their involvement in aspects of mood, cognition and decision-making that are commonly affected in bipolar disorder. The growing realisation of the role CHRM2 plays in inflammatory responses may also offer insight into the activation of pro-inflammatory cytokine networks that has been reported in individuals with bipolar disorder.
Keywords
Cholinergic system, muscarinic receptors, mood disorders, bipolar disorder, depression
Disclosure The author has no conflicts of interest to declare.
Received: September 22, 2011 Accepted October 24, 2011
Correspondence: Andrew Stuart Gibbons, Rebecca L Cooper Research Laboratories, Mental Health Research Institute of Victoria, Locked Bag 11, Parkville, VIC 3052, Australia. E: a.gibbons@mhri.edu.au

The underlying molecular aetiology of bipolar disorder remains poorly understood. However, there is growing evidence to implicate the involvement of cholinergic dysfunction in the pathology of the disease. Early reports of increased depressive symptoms associated with chronic exposure to organophosphorus anticholinesterase insecticides, which inhibit the degradation of acetylcholine, provided some of the first evidence of the involvement of the cholinergic system in the symptomatology of bipolar disorder.1,2 Subsequent pharmacological studies supported this role. The cholinesterase inhibitor physostigmine was shown to reverse the symptoms of mania in individuals with bipolar disorder.3,4 Conversely, anticholinergic compounds, such as scopolamine, have been reported to reduce the symptoms of depression in individuals with bipolar disorder.5

This association between cholinergic dysfunction and affective state is complemented by the antagonistic balance between cholinergic and adrenergic signalling.6 Taken together, such observations led to the development of the cholinergic/adrenergic hypothesis of mood disorders, whereby a hypocholinergic/hyperadrenergic state could induce a manic affect, while a hypercholinergic/hypoadrenergic state would produce depression.7

Role of Cholinergic Receptor Muscarinic-2
Acetylcholine mediates its effect through two classes of receptors: the ligand-gated ion channel nicotinic receptor, and the G protein-coupled receptor family – i.e., the muscarinic receptors. The higher incidence of smoking among individuals with bipolar disorder8 and clinical observations showing improvement of the symptoms of bipolar disorder following administration of nicotinic receptor antagonists9 are suggestive of nicotinic receptor involvement. Molecular evidence of the involvement of the nicotinic receptor has, to date, centred on genetic association studies of the genes coding for the subunits of the nicotinic receptor. However, there has been little conclusive evidence to implicate polymorphisms within the nicotinic receptor subunit genes in the pathology of bipolar disorder.10–13 Furthermore, there is a paucity of data regarding whether the expression of the nicotinic receptor is altered in bipolar disorder. However, messenger RNA expression of the nicotinic receptor subunit CHRNA7 has been reported to be unaltered in the prefrontal cortex of post-mortem subjects who had suffered from bipolar disorder.14

Greater progress has been made with regard to our understanding of the muscarinic receptors in the pathology of bipolar disorder. The muscarinic receptor family consists of five receptors that mediate signal transduction of acetylcholine through G proteins. The receptors differ both in their localisation and in their signal transduction pathways – cholinergic receptor muscarinic-1 (CHRM1), CHRM3 and CHRM5 signal through Gq-protein signalling pathways, while CHRM2 and CHRM4 signal through Gi/o protein-mediated pathways. The antidepressant effects of muscarinic receptor antagonists, such as scopolamine,5 have implicated the muscarinic receptors in the pathology of bipolar disorder. The identification of a single nucleotide polymorphism (SNP) in the 3’-untranslated region of the CHRM2 gene associated with major depression in women provided the first evidence to pinpoint the cholinergic involvement in depressive symptoms to a single muscarinic receptor.15 Subsequent studies reported two SNPs in intron 4 of the 5’-untranslated region of the CHRM2 gene associated with major depression.16 The identification of SNPs in the CHRM2 gene associated, in an undifferentiated cohort of subjects, with major depression, bipolar disorder and seasonal affective disorder supported the possibility that CHRM2 could be involved in the broader pathology of mood disorders.17 However, analysis of SNPs in 19 cholinergic genes failed to find any association between CHRM2 or any other muscarinic receptor gene and the incidence of bipolar disorder.11

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