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 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.
Footnotes
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↵1 Current address: Baylor College of Medicine, Division of Neuroscience, Houston, TX.
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↵2 Current address: MPI-CardIon Laboratories, Kalamazoo, MI.
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doi:10.1124/jpet.104.076968.
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ABBREVIATIONS: nAChR, α7 nicotinic acetylcholine receptor; nRT, reticular thalamic nucleus; PNU-282987, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride; GTS-21, 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA); CNQX, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate 6-cyano-7-nitroquinoxaline-2,3-dione; DMSO, dimethyl sulfoxide; T, test; C, conditioning; PSTH, peristimulus time histograms; MLA, methyllycaconitine; PBS, phosphate-buffered saline.
- Received August 31, 2004.
- Accepted October 18, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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