Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics

Abstract

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies.

Figure 1.

Acetylcholine synthesis and degradation, and the actions of pharmacological interventions. Acetylcholine (ACh) is synthesized in neurons from choline and acetyl-coenzyme A by the enzyme acetyltransferase. ACh is protected from degradation by packaging within synaptic vesicles. ACh is released into the synaptic cleft where it acts upon pre- and postsynaptic muscarinic and nicotinic receptors, and degraded into choline and acetate by the enzyme acetylcholinesterase (AChE). Choline is recycled back into neurons. AChE inhibitors (AChEIs) such as physostigmine and donepezil prevent the breakdown of ACh. Precursors such as deanol and choline contribute to ACh synthesis. Abbreviations: AcCoA, acetyl coenzyme A; AChR, acetylcholine receptor.

Figure 2.

Sites of action of scopolamine’s rapid antidepressant-like effects within cholinergic circuitry. Rodent studies have shown that acute scopolamine treatment can induce fast-onset antidepressant effects when administered within the mPFC, nAC, and VTA (shown in yellow). Cholinergic innervation of the mPFC and VTA is supplied by the basal forebrain and brainstem cholinergic systems, respectively. The only source of acetylcholine within the nAC comes from local cholinergic interneurons (shown in red). Abbreviations: nAC, nucleus accumbens; mPFC, medial prefrontal cortex; VTA, ventral tegmental area; MS, medial septal nucleus; vDB, vertical diagonal band; NBM, nucleus basalis of Meynert; SI, substantia innominata; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus.