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Nicotinic Receptors and Mental Illness

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Nicotinic Receptors

Part of the book series: The Receptors ((REC,volume 26))

Abstract

The prevalence of smoking in the mentally ill, particularly in schizophrenic patients, is much higher than in the general population. While smoking demographics are altered in these patients, nicotinic receptors are implicated in the disorder. Nicotine normalizes several sensory processing deficits in schizophrenia, as well as improving cognition and disease symptomatology. Smoking has a large effect on gene expression in human brain, and many genes abnormally expressed in schizophrenic nonsmokers are brought to control levels in schizophrenic smokers. The α7 nicotinic receptor gene, CHRNA7, is genetically linked to the disorder in multiple studies. Deletion of Chrna7 in mice results in several traits found in schizophrenic individuals. The expression of α7nAChRs is decreased in postmortem brain of schizophrenic subjects, as measured by α-bungarotoxin binding. Nicotine binding is also decreased in schizophrenic brain, suggesting that high-affinity nicotinic receptor expression is reduced as well. Regulation of the CHRNA7 gene is complex. Promoter methylation and several transcription factors have been identified that affect transcription. The human CHRNA7 gene is unusual in that it is partially duplicated. The duplicated sequences are expressed with exons from a second partial duplication, forming a new, chimeric gene, CHRFAM7A. The duplicated gene is human specific, not being found in rodents or primates. The duplicated sequences in CHRFAM7A are nearly identical to exons 5–10 of the full-length gene, CHRNA7. Thus, exons 5–10 cannot be accurately queried for CHRNA7 in genome-wide association studies. Further, the duplicated gene product, dupα7, is a dominant negative regulator of α7nAChR function, reducing current in response to acetylcholine application. Functional mutations in the CHRNA7 gene promoter and in CHRFAM7A have been identified and are associated with schizophrenia. Several agonists of the α7nAChR have been identified as possible therapeutic drugs, including DMXB-A and choline. Type II allosteric modulators appear to potentiate function of the human heteromeric receptor, containing both CHRNA7 and CHRFAM7A gene products.

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  1. Department of Psychiatry, University of Colorado, Anschutz Medical Campus, 12800 East 19th Avenue, RC-1, Room 8107, Aurora, CO, 81230, USA

    Sherry Leonard Ph.D.

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  1. Department of Neurobiology SHEL 1006, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Robin A.J. Lester

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Leonard, S. (2014). Nicotinic Receptors and Mental Illness. In: Lester, R. (eds) Nicotinic Receptors. The Receptors, vol 26. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1167-7_20

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