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.

Keywords: Cognition; Positron emission tomography; Translational research.

Figure 1. Graphical representation of year-by-year publications involving the α7 nAChR when searched on Pubmed using the terms “alpha7 AND nicotinic”

From few publications early on, maintaining between 0–10 until 1996, there has been a steady increase in publications citing the α7 nAChR. The figures for 2013 are only recorded as far as June 25^th, 2013.

Figure 2. Schematic representation of the α7 nAChR and its associated binding sites

The homomeric α7 nAChR consists of 5 transmembrane spanning α7 subunits. The conjunction of each subunit is a potential binding site (4 in total) for orthosteric agonists, which includes the natural ligands acetylcholine and choline. When the ion channel is opened by an agonist, calcium (Ca²⁺) can enter the cell (see [68] for further downstream effects). The discovery of type I and II positive allosteric modulators (PAMs) has led to the hypothesis that they bind at different sites since they potentiate or prolong the effects of natural ligands (respectively).

Figure 2. Schematic representation of the α7 nAChR and its associated binding sites

The homomeric α7 nAChR consists of 5 transmembrane spanning α7 subunits. The conjunction of each subunit is a potential binding site (4 in total) for orthosteric agonists, which includes the natural ligands acetylcholine and choline. When the ion channel is opened by an agonist, calcium (Ca²⁺) can enter the cell (see [68] for further downstream effects). The discovery of type I and II positive allosteric modulators (PAMs) has led to the hypothesis that they bind at different sites since they potentiate or prolong the effects of natural ligands (respectively).