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The Selective α7 Nicotinic Acetylcholine Receptor Agonist PNU-282987 [ N -[(3 R )-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

2005; American Society for Pharmacology and Experimental Therapeutics; Volume: 312; Issue: 3 Linguagem: Inglês

10.1124/jpet.104.076968

1521-0103

Mihály Hajós, Raymond S Hurst, William E. Hoffmann, Michael Krause, Theron M. Wall, Nicole R. Higdon, V E Groppi,

Memory and Neural Mechanisms

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 -[(3 R )-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.