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Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia

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Abstract

Rationale and objective

Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha7 nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.

Method

This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha7 nicotinic receptor agonists may ameliorate some of these deficits.

Results

Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha7 nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha7 nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures.

Conclusion

Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.

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Acknowledgements

This work was supported by the VA Medical Research Service, USPHS MH-61412, NARSAD, the Stanley Foundation, and the Institute for Children’s Mental Disorders.

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Authors and Affiliations

  1. Department of Psychiatry, Department of Veterans Affairs and University of Colorado Health Sciences Center, 4200 East Ninth Avenue, C268-71, Denver, CO 80262, USA

    Laura F. Martin & Robert Freedman

  2. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, 1600 S.W. Archer Road, PO Box 100267, Gainesville, FL 32610, USA

    William R. Kem

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  1. Laura F. Martin
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  2. William R. Kem
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  3. Robert Freedman
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Correspondence to Laura F. Martin.

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Dr. Martin has nothing to disclose. Dr. Kem holds a patent with the University of Florida on anabaseine-based medicinal compounds. Dr. Freedman has a pending patent application with the VA Medical Research Service on the genomic structure of CHRNA7. He has served as a consultant to Janssen Research Foundation, Abbott Laboratories, and Pharmacia-Upjohn.

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Martin, L.F., Kem, W.R. & Freedman, R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology 174, 54–64 (2004). https://doi.org/10.1007/s00213-003-1750-1

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