Characterization of nicotinic receptors involved in the release of noradrenaline from the hippocampus.

The pharmacological features of putative nicotinic acetylcholine receptor sites involved in the release of [3H]noradrenaline were assessed in rat hippocampus. The effect of nicotinic agonists to induce [3H]noradrenaline release was examined in superfused slices. The nicotinic agonists (-)-epibatidine, (+)-anatoxin-a, dimethylphenylpiperazinium, (-)-nicotine and (-)-lobeline released [3H]noradrenaline. The dose-response curves to nicotinic agonists were bell shaped, and indicated that their functional efficacies and potency vary across agonists. Maximal efficacy was seen with dimethyl-phenylpiperazinium and lobeline (Emax values two to three times higher than other agonists). The rank order of potency for the agonists to release [3H]noradrenaline was (-)-epibatidine > (+)- anatoxin-a > dimethylphenylpiperazinium > cytisine > nicotine > (-)-lobeline. The nicotinic acetylcholine receptor antagonists (n-bungarotoxin > mecamylamine > (+)-tubocurarine > hexamethonium > alpha-bungarotoxin = dihydro-beta-erythroidine) and tetrodotoxin antagonized the effect of dimethylphenylpiperazinium to release [3H]noradrenaline. The results, based on these pharmacological profiles, suggest the possible involvement of alpha 3 and beta 2 nicotinic acetylcholine receptor subunits in the control of [3H]noradrenaline release from hippocampal slices. The absence of effect of alpha-bungarotoxin and alpha-conotoxin-IMI excludes the possible involvement of nicotinic acetylcholine receptors containing the alpha 7 subunit. The release of [3H]noradrenaline by dimethylphenylpiperazinium was Ca2+ dependent. Nifedipine failed to prevent the dimethylphenylpiperazinium-induced release of [3H]noradrenaline, but Cd2+, omega-conotoxin and Ca(2+)-free conditions significantly reduced the dimethylphenylpiperazinium-induced release, suggesting that N-type voltage-sensitive Ca2+ channels are involved in the nicotinic acetylcholine receptor response. These voltage-sensitive Ca2+ channels are activated by the local depolarization produced by sodium influx through the nicotinic channels activated by dimethylphenylpiperazinium. Thus, the observed tetrodotoxin sensitivity of dimethylphenylpiperazinium-induced release of [3H]noradrenaline can be explained either by local depolarization and subsequent generation of action potentials at the preterminal area or that these nicotinic acetylcholine receptors are located on interneurons rather than directly on noradrenergic terminals.