Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

Abstract

The group of schizophrenia disorders affects approximately 1% of the population and has both genetic and environmental etiologies. Sufferers report various behavioral abnormalities including hallucinations and delusions (positive symptoms), reduced joy and amotivation (negative symptoms), plus inattention and poor learning (cognitive deficits). Despite the heterogeneous symptoms experienced, most patients smoke. The self-medication hypothesis posits that patients smoke to alleviate symptoms, consistent with evidence for nicotine-induced enhancement of cognition. While nicotine acts on multiple nicotinic acetylcholine receptors (nAChRs), the primary target of research is often the homomeric α7 nAChR. Given genetic linkages between schizophrenia and this receptor, its association with P50 sensory gating deficits, and its reduced expression in post-mortem brains, many have attempted to develop α7 nAChR ligands for treating schizophrenia. Recent evidence that ligands can be orthosteric agonists or positive allosteric modulators (PAMs) has revitalized the hope for treatment discovery. Herein, we present evidence regarding: 1) Pathophysiological alterations of α7 nAChRs that might occur in patients; 2) Mechanistic evidence for the normal action of α7 nAChRs; 3) Preclinical studies using α7 nAChR orthosteric agonists and type I/II PAMs; and 4) Where successful translational testing has occurred for particular compounds, detailing what is still required. We report that the accumulating evidence is positive, but that greater work is required using positron emission tomography to understand current alterations in α7 nAChR expression and their relationship to symptoms. Finally, cross-species behavioral tasks should be used more regularly to determine the predictive efficacy of treatments.

Effects of haloperidol, olanzapine, ziprasidone, and PHA‐543613 on spatial learning and memory in the Morris water maze test in naïve and MK‐801‐treated mice

“…Accumulating evidence indicate that alpha-7 nicotinic acetylcholine receptor, which has a significant effect on cognitive processes, plays an important role in the pathophysiology of schizophrenia and previous studies demonstrated that alpha-7 nicotinic acetylcholine agonists had emerged as a potential treatment target for the treatment of CIAS (Freedman, 2014;Nikiforuk, Kos, Potasiewicz, & Popik, 2015;Young & Geyer, 2013). PHA-543613, an alpha-7 nicotinic partial agonist, has been reported to improve MWM performance in Aβ 25-35 -induced cognitive deficits mice (Sadigh-Eteghad et al, 2015).…”

A-582941, cholinergic alpha 7 nicotinic receptor agonist, improved cognitive and negative symptoms of the sub-chronic MK-801 model of schizophrenia in rats

“…Freedman et al [11] have suggested a link between impaired auditory sensory gating and α7 NAChR gene single-nucleotide polymorphism on the promoter regions of chromosome 15q14 locus. Furthermore, postmortem studies demonstrated that α7 NAChR binding levels and protein expressions decreased in dentate gyrus, hippocampal CA3 region, cingulate cortex, and prefrontal cortex, which are important regions for modulating cognitive function [12][13][14]. In addition to this, the fact that the prevalence of tobacco consumption of schizophrenia patients is higher compared with healthy individuals encourages researchers to examine nicotinic receptors in schizophrenia pathogenesis and treatment [15].…”

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

“…Possibly reflecting single nucleotide changes within promoter regions of CHRNA7 (Leonard et al 2002), diminished numbers of apparently structurally intact α7 nAChRs have been shown in the hippocampus (Freedman et al 1995), frontal cortex (Guan et al 1999) and the nucleus reticularis thalami (Court et al 1999) of SZ postmortem brains. Results from clinical trials of novel α7 molecules in SZ patients have been mixed (Young and Geyer 2013). DMXB-A (a.k.a.…”