title: The selective alpha7 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.
abstract: 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 alpha7 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 alpha7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective alpha7 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 alpha7 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 alpha7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.
authors.affiliation: Department of Neuroscience, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA. mihaly.hajos@pfizer.com
authors.forename: M
authors.initials: M
authors.lastname: Hajós
authors.forename: R S
authors.initials: RS
authors.lastname: Hurst
authors.forename: W E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: M
authors.initials: M
authors.lastname: Krause
authors.forename: T M
authors.initials: TM
authors.lastname: Wall
authors.forename: N R
authors.initials: NR
authors.lastname: Higdon
authors.forename: V E
authors.initials: VE
authors.lastname: Groppi
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D004569:Electroencephalography / Q000187:drug effects; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D020646:Intralaminar Thalamic Nuclei / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D001549:Benzamides; D001597:Benzylidene Compounds; D001643:Bridged Bicyclo Compounds; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; C498513:PNU-282987; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid; C088936:3-(2,4-dimethoxybenzylidene)anabaseine