Currently available therapeutic agents for treatment of
schizophrenia target signaling by monoaminergic
neurotransmitters; however, these treatments do not adequately treat the range of symptoms observed in patients. While these
therapies treat the positive symptoms, they do not have efficacy in treating the negative symptoms and cognitive deficits that are associated with the disease. Evidence suggests that molecules that modulate signaling by the
neurotransmitter acetylcholine (ACh) could provide a more comprehensive treatment of
schizophrenia than currently prescribed
antipsychotics. Molecules that broadly increase ACh-signaling have been demonstrated to have efficacy in treating numerous
symptom clusters in
schizophrenia patients. Unfortunately, these compounds induce adverse effects via activation of peripheral receptors that limit their clinical utility. One proposed strategy for retaining the efficacy of
cholinergic treatments, without the adverse effects, is to target specific
cholinergic receptor subtypes in the brain. Several
cholinergic receptors are able to modulate brain circuits that are dysregulated in
schizophrenia patients including receptors belonging to both the
muscarinic family (i.e., M1, M4, and M5), and the nicotinic family (i.e., α7, α4β2). Recently, great strides have been made in developing small molecules with high specificity for these receptors, and several of these novel molecules have robust efficacy in several preclinical models predictive of both anti-psychotic and pro-cognitive effectiveness. Promising studies suggest that targeting M1 and α7 may be beneficial for pro-cognitive effects, while molecules that target M4 may be ideally suited to address the positive symptoms. Since these receptor subtypes are distinct from those responsible for the adverse effects observed with non-selective
cholinergic treatments, there is hope that molecules targeting these receptors could provide novel
therapeutics. Further research is needed to examine the utility of such compounds as
therapeutics that could be used either alone, or in combination with existing medications, to better treat
schizophrenia.