Abstract

Background: Cognitive deficits are amongst the most socially debilitating and least effectively treated symptoms of schizophrenia. The cholinergic system is a promising target for the design of novel drugs that can more effectively treat these symptoms. Methods: We review the literature supporting the dysfunction of the cholinergic system in schizophrenia, discuss the preclinical and clinical data showing that modulating the cholinergic system could improve the symptoms of schizophrenia and review the main pharmacological strategies being investigated to treat cholinergic dysfunction in schizophrenia. Results: Post-mortem and neuroimaging studies suggest there are widespread reductions in cholinergic receptor signalling in the cortex as well as subcortical regions, such as the hippocampus and striatum, in individuals with schizophrenia. Potential cholinergic drug targets are being pursued to increase receptor function. These include inhibiting the activity of the enzyme acetylcholinesterase to increase synaptic acetylcholine levels, and increasing the nicotinic receptor and muscarinic receptor activity with agonists or positive allosteric modulators. Conclusion: Amongst the most promising drug targets for treating schizophrenia are the α₇ nicotinic receptor and the CHRM1 and CHRM4 muscarinic receptors. The recent development of allosteric modulators that selectively target these receptors offers the potential to more effectively treat the symptoms of schizophrenia.

Keywords: Schizophrenia, acetylcholine, cholinesterase inhibitors, muscarinic receptors, nicotinic receptors, positive allosteric modulators.