The Selective α7 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
| Autor: | Vincent E. Groppi, Nicole R. Higdon, Raymond S. Hurst, Mihály Hajós, William E. Hoffmann, Michael Krause, Theron M. Wall |
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| Rok vydání: | 2004 |
| Předmět: |
Agonist
alpha7 Nicotinic Acetylcholine Receptor Pyridines medicine.drug_class Gating Receptors Nicotinic Hippocampal formation Pharmacology Benzylidene Compounds Hippocampus Rats Sprague-Dawley Bridged Bicyclo Compounds chemistry.chemical_compound medicine Animals Homomeric Nicotinic Agonists Amphetamine Cells Cultured gamma-Aminobutyric Acid Methyllycaconitine Sensory gating Intralaminar Thalamic Nuclei Chemistry Electroencephalography Rats medicine.anatomical_structure Benzamides Synapses Evoked Potentials Auditory Molecular Medicine GABAergic Neuroscience medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 312:1213-1222 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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