Nicotinic Acetylcholine Receptor-Mediated [H-3]Dopamine Release From Hippocampus

The mechanism of nicotinic acetylcholine receptor ( nAChR)induced hippocampal dopamine (DA) release was investigated using rat hippocampal slices. nAChRs involved in hippocampal DA and norepinephrine ( NE) release were investigated using prototypical agonists and antagonists and several relatively novel compounds: ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], (+/-)- UB-165 [(2-chloro-5-pyridyl)-9-azabicyclo [4.2.1] non2-ene], and MG 624 [N, N, N-triethyl-2-[4-(2 phenylethenyl) phenoxy]- ethanaminium iodine]. (+/-)-Epibatidine, (+/-)- UB-165, anatoxin-a, ABT-594, (-)-nicotine, 1,1-dimethyl-4-phenyl-piperazinium iodide, and (-)- cytisine ( in decreasing order of potency) evoked [H-3] DA release in a mecamylamine-sensitive manner. Aside from (+/-)-UB-165, all the agonists displayed full efficacy relative to 100 muM (-)-nicotine in [H-3] DA release. In contrast, (+/-)- UB-165 was a partial agonist, evoking 58% of 100 muM (-)-nicotine response. Mecamylamine, MG 624, hexamethonium, d-tubocurare, and dihydro-beta-erythroidine (in decreasing order of potency), but not alpha-conotoxin-MII, methyllycaconitine, alpha-conotoxin-ImI, or alpha-bungarotoxin, attenuated 100 muM (-)nicotine- evoked [H-3] DA release in a concentration-dependent manner. (+/-)- UB-165, ABT-594, and MG 624 exhibited different pharmacologic profiles in the [H-3] NE release assay when compared with their effect on [H-3] DA release. ABT-594 was 4.5-fold more potent, and (+/-)- UB-165 was a full agonist in contrast to its partial agonism in [H-3] DA release. MG 624 potently and completely blocked NE release evoked by 100 muM (-)-nicotine and 10 muM (+/-)- UB-165, whereas it only partially inhibited (-)nicotine- evoked [H-3] DA release. In conclusion, we provide evidence that [H-3] DA can be evoked from the hippocampus and that the pharmacologic profile for nAChR-evoked hippocampal [H-3] DA release suggests the involvement of alpha3beta4* and at least one other nAChR subtype, thus distinguishing it from that of nAChR-evoked hippocampal [H-3] NE release.