Cholinergic Modulation of Affective Disorders

The cholinergic system, encompassing nicotinic and muscarinic acetylcholine receptors, plays a pivotal role in the regulation of mood, anxiety and stress responses. Dysregulation of cholinergic transmission in limbic structures such as the hippocampus, amygdala and prefrontal cortex contributes to the development and maintenance of affective disorders. Preclinical models have demonstrated that aberrant activation or desensitisation of nicotinic acetylcholine receptors (nAChRs) can precipitate anxiety- and depression-like behaviours, while muscarinic acetylcholine receptors (mAChRs) within ventral hippocampal circuits influence stress-induced anxiogenesis. Cholinesterase inhibitors, by elevating synaptic acetylcholine, exhibit dose-dependent effects on mood: low concentrations may produce antidepressant-like responses, whereas higher levels can exacerbate depressive phenotypes. Basal forebrain cholinergic neurons further modulate hippocampal output, with specific septo-hippocampal pathways implicated in stress-induced hyperactivation of pyramidal cells and ensuing depressive behaviours. Together, these findings underscore the therapeutic potential of targeting cholinergic signalling to treat major depressive disorder, anxiety disorders and stress-related psychopathology, offering routes to novel rapid-acting agents and adjunctive strategies to augment existing monoaminergic treatments.

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Cholinergic Modulation of Affective Disorders publication trend

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Technical terms

Nicotinic acetylcholine receptor (nAChR): A ligand-gated ion channel activated by acetylcholine or nicotine, mediating fast synaptic transmission in central and peripheral neurons.

Muscarinic acetylcholine receptor (mAChR): A G-protein-coupled receptor subtype responsive to acetylcholine, modulating slower neuromodulatory and intracellular signalling pathways.

Cholinesterase inhibitor: A pharmacological agent that inhibits acetylcholinesterase, thereby increasing acetylcholine levels in the synaptic cleft and prolonging cholinergic transmission.

Basal forebrain cholinergic neurons: ChAT-expressing cells in the medial septum and diagonal band that project widely to cortical and limbic regions, regulating arousal, attention and mood.

Anhedonia: A core symptom of depression characterised by diminished capacity to experience pleasure or interest in rewarding activities.

References

1. Pathophysiology of nAChRs: Limbic circuits and related disorders. Pharmacological Research (2023).
2. Acetylcholine Muscarinic Receptors in Ventral Hippocampus Modulate Stress-Induced Anxiety-Like Behaviors in Mice. Frontiers in Molecular Neuroscience (2020).
3. The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test. Translational Psychiatry (2020).
4. Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities. Frontiers in Behavioral Neuroscience (2021).
5. Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral Subiculum Hyperactivation. Neuroscience Bulletin (2022).