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.
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.
Hajós
M
M
Department of Neuroscience, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA. mihaly.hajos@pfizer.com
Hurst
R S
RS
Hoffmann
W E
WE
Krause
M
M
Wall
T M
TM
Higdon
N R
NR
Groppi
V E
VE
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*
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