The Cholinergic System in Schizophrenia Reconsidered: Anticholinergic Modulation of Sleep and Symptom Profiles

Abstract

Receptors, Cholinergic; Receptors, muscarinic; Parasympathetic nervous system; Sleep, REM; Symptoms, positive; Symptoms, negative The dopamine (DA) hypothesis has dominated biochemical and pharmacological research on schizophrenia for about two decades. Although pharmacological data implicate increased DA activity in the pathogenesis of positive symptoms of schizophrenia, there is minimal association with negative symptoms (Crow 1980;Andreasen and Olsen 1982;Angrist et al. 1980). The poorly elucidated pathogenesis of negative symptoms and the unique properties of the atypical antipsychotic clozapine (Jibson and Tandon 1998) have encouraged a reappraisal of the role of the DA system in schizophrenia. Newer approaches to evaluating neurochemical abnormalities in schizophrenia include consideration of other neurotransmitter systems. Models of DA-serotonin (Meltzer 1989), DA-glutamate (Carlsson and Carlsson 1990), DA-acetylcholine (Tandon and Greden 1989), and DA-norepinephrine (van Kammen et al. 1990) interactions have been proposed. Although these models still accord DA a significant role in schizophrenia pathophysiology, they suggest that altered balance between DA and one (or more) of these other neurotransmitter systems may be the principal neurochemical abnormality related to the production of schizophrenic symptoms. Some of the earliest pharmacological treatments for schizophrenia included cholinergic agents (Cohen et al. 1944;Collard et al. 1946;Pfeiffer and Jenney 1957), and in the 1970s, several investigators suggested that cholinergic activity may be reduced in schizophrenia (Friedhoff and Alpert 1973;Janowsky et al. 1973;Davis et al. 1975;Singh and Kay 1979). There was no direct evidence of altered cholinergic functioning in schizophrenic patients, however, and pharmacological trials with cholinergic agents were generally ineffective (Rowntree et al. 1950;Gerlach et al. 1977;Davis and Berger 1978). With few exceptions (Johnstone et al. 1983;Singh et al. 1987), cholinergic mechanisms were increasingly considered irrelevant to the pathophysiology of schizophrenia and discussed predominantly with reference to the treatment of undesirable extrapyramidal side effects of neuroleptics (Richelson 1984). Indirect evidence from several lines of research, however, suggests that the cholinergic system may differentially influence positive and negative symptoms in schizophrenia (Tandon and Greden 1989).We and others have been conducting various studies to evaluate the role of the cholinergic system in schizophrenia, based on a primary hypothesis that DA-acetylcholine (ACh) interactions are of central importance in the production of positive and negative symptoms of schizophrenia (Tandon and Greden 1989;Tandon and Greden 1991). Based on available data and on observations of the course of positive and negative symptoms during the acute phase of the illness (Donlon and Blacker 1973;Docherty et al. 1978;Tandon et al. 1990a), we posited a role for disruption in DA-ACh balance in the expression of positive and negat...

Anticholinergic Activity and Schizophrenia

“…One is that the appearance of AA is based on a hyperactivity of ACh proposed by Tandon et al [6,16], which is different from our hypothesis. According to their hypothesis, the appearance of AA is a compensation to ACh hyperactivity.…”

“…These reports suggest that downregulation of ACh almost reaching the critical level activates the inflammatory system. The impairments of the cholinergic systems in schizophrenia after onset have been thoroughly investigated; some researchers indicated that cholinergic, especially muscarinic, systems play an important role in the pathogenesis of schizophrenia [15,16]. Postmortem studies have observed a decrease in the levels of muscarinic receptors in large areas of the brain in schizophrenia, and these findings have been well replicated [17,18].…”

“…Subsequently, hyperactivity of the cholinergic system interacts with the dopaminergic system, and the dopaminergic hyperactivity exacerbates psychosis. After treatment with antipsychotic agents, the dopaminergic hyperactivity is improved by blocking D 2 receptors, but the cholinergic hyperactivity may still exist, though it gradually improves the activity; therefore it might be a normal dopaminergic-hypercholinergic state as clinically it appeared for negative symptoms, the so-called postpsychotic depression [6,16]. The chronic cholinergic hyperactivity might lead to cholinergic downregulation of the muscarinic receptors and result in a decreased density of muscarinic receptors in the brain [16].…”

“…After treatment with antipsychotic agents, the dopaminergic hyperactivity is improved by blocking D 2 receptors, but the cholinergic hyperactivity may still exist, though it gradually improves the activity; therefore it might be a normal dopaminergic-hypercholinergic state as clinically it appeared for negative symptoms, the so-called postpsychotic depression [6,16]. The chronic cholinergic hyperactivity might lead to cholinergic downregulation of the muscarinic receptors and result in a decreased density of muscarinic receptors in the brain [16]. Yeomans [34] suggested, in terms of antimuscarinic psychosis, that an increased cholinergic cell (Ch5) tone with genetically increasing tegmental cholinergic cells (Ch5 and Ch6) or fewer Ch5 autoreceptor of schizophrenia might induce Ch5 overactivation, and this overactivation boosts cascades of A10 dopaminergic cell activation, thalamic activation and pontine reticular formation activation.…”

New drug developments in psychosis: Challenges, opportunities and strategies

“…While several agents targeting these receptors are currently in various stages of study, alpha-7 nicotinic and M-1 muscarinic agonists and positive allosteric modulators are of greatest interest (Dineley et al, 2015; Felder et al, 2012). Whereas nicotinic agonists principally target cognitive symptoms (Rowe et al, 2015), muscarinic agonists appear to show promise in addressing positive symptoms (Tandon et al, 1999). Encenicline, an Alpha7 Nicotinic receptor agonist, which had shown promise in early phase trials, has not shown efficacy in phase 3 studies..…”