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NEUROPHARMACOLOGY
7 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
Department of Neuroscience and CNS Molecular Sciences, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (M.H., R.S.H., W.E.H., M.K., T.M.W., N.R.H.), and Ann Arbor, Michigan (V.E.G.)
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 
7 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 7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective 7 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 
oscillation. We propose that the 7 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 7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.
Address correspondence to: Dr. Mihály Hajós, Department of Neuroscience, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340. E-mail: mihaly.hajos{at}pfizer.com
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