Cholinergic connectivity: it's implications for psychiatric disorders

Abstract

Acetylcholine has been implicated in both the pathophysiology and treatment of a number of psychiatric disorders, with most of the data related to its role and therapeutic potential focusing on schizophrenia. However, there is little thought given to the consequences of the documented changes in the cholinergic system and how they may affect the functioning of the brain. This review looks at the cholinergic system and its interactions with the intrinsic neurotransmitters glutamate and gamma-amino butyric acid as well as those with the projection neurotransmitters most implicated in the pathophysiologies of psychiatric disorders; dopamine and serotonin. In addition, with the recent focus on the role of factors normally associated with inflammation in the pathophysiologies of psychiatric disorders, links between the cholinergic system and these factors will also be examined. These interfaces are put into context, primarily for schizophrenia, by looking at the changes in each of these systems in the disorder and exploring, theoretically, whether the changes are interconnected with those seen in the cholinergic system. Thus, this review will provide a comprehensive overview of the connectivity between the cholinergic system and some of the major areas of research into the pathophysiologies of psychiatric disorders, resulting in a critical appraisal of the potential outcomes of a dysregulated central cholinergic system.

Keywords: GABA; acetylcholine; cytokines; dopamine; glutamate; psychiatric disorders; serotonin.

Figure 1

A schematic representation of the human central cholinergic system—striatal interneurons not shown. Adapted from (Felten and Shetty, 2010).

Figure 2

A schematic diagram of the regulation of NMDA receptor activity by G_q protein-coupled muscarinic receptors in the hippocampus. Muscarinic receptors inhibit NMDA receptor activity via the activation of protein tyrosine phosphatase mediated by inositol triphosphate receptor pathways in conjunction with AMPA receptor induced calcium release from intracellular calcium stores. Muscarinic receptors can stimulate NMDA receptor activity via the activation of Src family tyrosine kinase in response to PKC signaling. Activation of the NMDA receptor by glutamate or aspartate and the co-agonist glycine, in turn inhibits muscarinic receptor activity via calmodulin inhibition of G protein coupled receptor kinases. α_q: G_qα subunit; β: Gβ subunit; γ: Gγ subunit; ACh: Acetylcholine; AMPAR; AMPA receptor; Asp: Aspartate; CaM: Calmodulin DAG: Diacyl glycerol; Glu: Glutamate; Gly: Glycine; GPRK: G protein coupled receptor kinase; InsP3: Inositol 1,4,5-trisphosphate; IP3R: Inositol triphosphate receptor; M1R: Muscarinic M1 receptor; M3R: Muscarinic M3 receptor; MEK: Mitogen-activated protein kinase kinase; NMDAR: NMDA receptor; PLCβ: Phospholipase C β; PIP2; Phosphatidylinositol 4,5-bisphosphate; PKC: Phosphokinase C; PTK2B: Protein tyrosine kinase 2β; PTP: Protein tyrosine phosphatase; RTK: Tyrosine kinase receptor; SRC: Src family tyrosine kinase.

Figure 3

Schematic representation of the human central dopaminergic systems. Adapted from (Felten and Shetty, 2010).

Figure 4

Schematic representation of the human central serotonergic systems. Adapted from (Felten and Shetty, 2010).

Figure 5

Schematic showing the complex interactions between cholinergic receptors (α7 nicotinic receptor (α7 CHRN), muscarinic M2 receptor (CHRM2), α4 β2 nicotinic receptor (α4 β2 CHRN) and the α4 β4 nicotinic receptor (α4 β4 CHRN) and the cytokines; tumor necrosis factor α (TNF α), interleukin 1 β (IL1 β) and interleukin 6 (IL6). Current data suggests some of these interactions may involve cholinesterase inhibitors (AChE) and their ability to regulate acetylcholine (Ach) and the interactions of the muscarinic receptor antagonist scopolamine with CHRM2.