Brain-selective stimulation of nicotinic receptors by TC-1734 enhances ACh transmission from frontoparietal cortex and memory in rodents
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- 作者：Obinu ; Maria Carmen ; Reibaud ; Michel ; Miquet ; Jean Marie ; Pasquet ; Martine ; Rooney ; Thomas
- 关键词：ACh release ; Mice ; Microdialysis ; Nicotinic agonist ; Object recognition test ; Rats ; TC-1734 ; ACh ; acetylcholine ; AChEI ; acetylcholine esterase inhibitor ; AD ; Alzheimer's disease ; nAChR ; nicotinic acetylcholine receptors ; RI ; recognition index
- 刊名：Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 出版年：2002
- 出版时间：June, 2002
- 年：2002
- 卷：26
- 期：5
- 页码：913-918
- 全文大小：141 K
文摘
The authors have described the effect of TC-1734, a brain-selective nicotinic acetylcholine receptor (nAChR) agonist, on acetylcholine (ACh) release in the frontoparietal cortex of rats and on cognitive function in mice. Oral administration of TC-1734 (5, 10 and 20 mg/kg) stimulated ACh release in a dose-dependent manner, as measured by transversal microdialysis. The maximal effect on the amplitude of ACh release was observed at a dose of 10 mg/kg (about 70 % above baseline), whereas the maximal effect on the duration of ACh release was observed at the dose of 20 mg/kg. By contrast, oral administration of nicotine (1, 2.5 and 5 mg/kg) did not stimulate ACh release in a dose-dependent manner but produced the same maximal effect on the amplitude of ACh release (about 50 % above baseline) at all the doses tested. The ability of both TC-1734 (10 mg/kg) and nicotine (1 mg/kg) to increase ACh levels was antagonized by mecamylamine (1 mg/kg sc), suggesting a specific nicotine receptor-mediated effect of both agonists. No tolerance to TC-1734- and nicotine-stimulated ACh release was observed after repeated treatment with TC-1734 (10 mg/kg) or nicotine (1 mg/kg) for 4 days. TC-1734 (1 mg/kg po) improved memory in the object recognition test in mice, and this effect was antagonized by mecamylamine (2.5 mg/kg ip). Taken together, these results show that TC-1734 stimulates nAChR in the brain to induce an increase of ACh release in the cortex of rats and enhance memory in mice.