The Selective α7 Nicotinic Acetylcholine Receptor Agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide Hydrochloride] Enhances GABAergic Synaptic Activity in Brain Slices and Restores Auditory Gating Deficits in Anesthetized Rats

神经科学 甲基枸杞碱 海马结构 兴奋剂 门控 烟碱激动剂 加巴能 化学 药理学 烟碱乙酰胆碱受体 生物 受体 抑制性突触后电位 生物化学
作者
Mihály Hajós,Raymond S Hurst,William E. Hoffmann,Michael Krause,Theron M. Wall,Nicole R. Higdon,V E Groppi
出处
期刊:Journal of Pharmacology and Experimental Therapeutics [American Society for Pharmacology and Experimental Therapeutics]
卷期号:312 (3): 1213-1222 被引量:223
标识
DOI:10.1124/jpet.104.076968
摘要

Schizophrenic patients are thought to have an impaired ability to process sensory information. This deficit leads to disrupted auditory gating measured electrophysiologically as a reduced suppression of the second of paired auditoryevoked responses (P50) and is proposed to be associated with decreased function and/or expression of the homomeric α7 nicotinic acetylcholine receptor (nAChR). Here, we provide evidence that N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987), a novel selective agonist of the α7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective α7 nAChR antagonist methyllycaconitine (MLA) and enhanced GABAergic synaptic activity when applied to hippocampal slices. Amphetamine-induced sensory gating deficit, determined by auditory-evoked potentials in hippocampal CA3 region, was restored by systemic administration of PNU-282987 in chloral hydrate-anesthetized rats. Auditory gating of rat reticular thalamic neurons was also disrupted by amphetamine; however, PNU-282987 normalized gating deficit only in a subset of tested neurons (6 of 11). Furthermore, PNU-282987 improved the inherent hippocampal gating deficit occurring in a subpopulation of anesthetized rats, and enhanced amphetamine-induced hippocampal θ oscillation. We propose that the α7 nAChR agonist PNU-282987, via modulating/enhancing hippocampal GABAergic neurotransmission, improves auditory gating and enhances hippocampal oscillatory activity. These results provide further support for the concept that drugs that selectively activate α7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.

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