Alpha7 neuronal nicotinic receptors as a drug target in schizophrenia

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Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 12/2012; 17(2). DOI: 10.1517/14728222.2013.736498
Source: PubMed


Schizophrenia is a profoundly debilitating disease that represents not only an individual, but a societal problem. Once characterized solely by the hyperactivity of the dopaminergic system, therapies directed to dampen dopaminergic neurotransmission were developed. However, these drugs do not address the significant impairments in cognition and the negative symptoms of the disease, and it is now apparent that disequilibrium of many neurotransmitter systems is involved. Despite enormous efforts, minimal progress has been made toward the development of safer, more effective therapies to date.

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The high preponderance of smoking in schizophrenics suggests that nicotine may provide symptomatic improvement, which has led to investigation for selective molecules targeted to individual nicotinic receptor (nAChR) subtypes. Of special interest is activation of the homomeric α7nAChR, which is widely distributed in the brain and has been implicated in the pathophysiology of schizophrenia through numerous approaches.

Expert opinion:
Preclinical and clinical data suggest that neuronal α7nAChRs play an important role in cognitive functions. Moreover, some, but not all, early clinical trials conducted with α7nAChR agonists show cognitive benefits in schizophrenics. These encouraging results suggest that development of compounds targeting α7nAChRs will represent a valuable tool to mitigate symptoms associated with schizophrenia, and open new strategies for better pharmacological treatment of these patients.

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Available from: Tanya Wallace, Apr 24, 2014
    • "Nicotinic receptors have been implicated in a number of neuromuscular, neurological and psychiatric disorders. For example , in recent years, neuronal nAChRs have been identified as important targets for therapeutic drug discovery, in connection with disorders such as Alzheimer's disease and schizophrenia [14] [15]. "
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are receptors for the neurotransmitter acetylcholine and are members of the 'Cys-loop' family of pentameric ligand-gated ion channels (LGICs). Acetylcholine binds in the receptor extracellular domain at the interface between two subunits and research has identified a large number of nAChR-selective ligands, including agonists and competitive antagonists, that bind at the same site as acetylcholine (commonly referred to as the orthosteric binding site). In addition, more recent research has identified ligands that are able to modulate nAChR function by binding to sites that are distinct from the binding site for acetylcholine, including sites located in the transmembrane domain. These include positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent allosteric modulators (SAMs) and compounds that are able to activate nAChRs via an allosteric binding site (allosteric agonists). Our aim in this article is to review important aspects of the pharmacological diversity of nAChR allosteric modulators and to describe recent evidence aimed at identifying binding sites for allosteric modulators on nAChRs. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Biochemical pharmacology
    • "More recently, three weeks of adjunctive treatment with EVP-6124 improved sensory gating and CogState indices of non-verbal learning, memory and executive function in SCZ patients (Preskorn et al., 2014). Reviews of these and other α7 molecules under various stages of clinical development have underscored the promise of positive modulation of α7 nAChRs as an augmentation therapy to antipsychotics, but point to the need for a better quantitative understanding of brain functions regulated by the α7 nicotinic cholinergic system (Bencherif et al., 2012; Geerts, 2012; Wallace and Bertrand, 2013a; Young and Geyer, 2013). Choline, both a metabolite and precursor of acetylcholine, is an essential nutrient with multiple biological functions and, in addition to being a lipid component used in cell membrane protection and repair (Blusztajn, 1998; Zeisel, 2000; Ziesel and Blusztajn, 1994), acts as a selective endogenous activator of α7 nAChRs (Albuquerque et al., 1998; Alkondon et al., 1999; Fayuk and Yakel, 2004; Papke et al., 1996). "
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    ABSTRACT: Diminished auditory sensory gating and associated neurocognitive deficits in schizophrenia have been linked to altered expression and function of the alpha-7 nicotinic acetycholinergic receptor (α7 nAChR), the targeting of which may have treatment potential. Choline is a selective α7 nAChR agonist and the aim of this study was to determine whether cytidine 5'-diphosphocholine (CDP-choline), or citicoline, a dietary source of choline, increases sensory gating and cognition in healthy volunteers stratified for gating level. In a randomized, placebo-controlled, double-blind design involving acute administration of low, moderate doses (500 mg, 1000 mg) of CDP-choline, 24 healthy volunteers were assessed for auditory gating as indexed by suppression of the P50 event-related potential (ERP) in a paired-stimulus (S1, S2) paradigm, and for executive function as measured by the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery. CDP-choline improved gating (1000 mg) and suppression of the S2 P50 response (500 mg, 1000 mg), with the effects being selective for individuals with low gating (suppression) levels. Tentative support was also shown for increased GMLT performance (500 mg) in low suppressors. These preliminary findings with CDP-choline in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with choline as a pro-cognitive strategy.
    No preview · Article · Oct 2014 · Journal of Psychopharmacology
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    • "Finally, it is known that schizophrenia patients participate in heavy nicotine searching behavior, which could compensate for the lower expression of α7 receptors, and that nicotine, in addition to more selective α7 agonists, can improve cognitive functioning in these patients (Olincy et al., 2006; Wallace and Bertrand, 2013). Obviously, another psychiatric disorder associated with nAChRs in particular is addiction. "
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    ABSTRACT: Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is crucial for normal cognitive performance. Despite the fact that many have studied how ACh affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between ACh receptors (AChRs) and behavior and how ACh receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of ACh in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between ACh, neuronal activity and behavior.
    Full-text · Article · Mar 2014 · Frontiers in Neural Circuits
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