Brain-selective stimulation of nicotinic receptors by TC-1734 enhances ACh transmission from frontoparietal cortex and memory in rodents.
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 s.c.), 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 p.o.) improved memory in the object recognition test in mice, and this effect was antagonized by mecamylamine (2.5 mg/kg i.p.). 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.
D000109:Acetylcholine / Q000819:agonists / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D010296:Parietal Lobe / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D000109:Acetylcholine