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.
    Biochemical pharmacology 07/2015; 97(4). DOI:10.1016/j.bcp.2015.07.028 · 5.01 Impact Factor
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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.
    Frontiers in Neural Circuits 03/2014; 8:17. DOI:10.3389/fncir.2014.00017 · 3.60 Impact Factor
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    ABSTRACT: The prefrontal cortex (PFC) is responsible for integrating cortical and subcortical inputs to execute essential cognitive functions such as attention, working memory planning and decision-making. The importance of this brain region in regulating complex cognitive processes is underscored by a decline in PFC-mediated ability observed in ageing and disease. The cholinergic system plays a vital role in cognitive function and treatments (e.g., cholinesterase inhibitors) to improve cholinergic neurotransmission provide the standard-of-care for diseases such as Alzheimer's. Nicotinic receptors (nAChRs) are a primary site of action for acetylcholine (ACh), and the resulting pro-cognitive effects observed by stimulating nAChRs with nicotine has long been appreciated by tobacco users, prompting investigation of therapeutic development for diseases (e.g. schizophrenia, Alzheimer or attention-deficit-hyperactivity disorder) by targeting the neuronal nAChR system. Noteworthy, improvements in attention, working memory and executive processes mediated by the PFC have been reported following nicotinic agonist exposure. Relevance of these ligand gated channels in higher brain function is further supported by the association of cognitive deficits reported in humans with mutations in CHRNB2 or CHRNA7 the genes encoding for the nicotinic receptor β2 and α7 subunits, respectively. In this work we review, in light of the latest findings, how nicotinic agonists may be acting in the PFC to influence cognitive function.
    Biochemical pharmacology 04/2013; 85(12). DOI:10.1016/j.bcp.2013.04.001 · 5.01 Impact Factor
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