title: Epibatidine: a nicotinic acetylcholine receptor agonist releases monoaminergic neurotransmitters: in vitro and in vivo evidence in rats.
abstract: The effect of the neuronal acetylcholine-gated ion channel receptor agonist (+/-)-epibatidine was studied on neurotransmitter release in vitro and motor behavior in vivo. (+/-)-Epibatidine (3-300 nM) caused a concentration- and calcium-dependent release of [3H]-dopamine from striatal slices and [3H]-norepinephrine release from hippocampal and thalamic slices. (+/-)-Epibatidine-induced neurotransmitter release was inhibited in all three regions by mecamylamine (3 microM). In contrast, D-tubocurarine (10-100 microM) inhibited only (+/-)-epibatidine-induced [3H]-norepinephrine release from the hippocampus and the thalamus. Conversely, dihydro beta-erythroidine (3-100 microM) inhibited (+/-)-epibatidine-induced [3H]-dopamine release in the striatum without significantly altering [3H]-norepinephrine release from either the hippocampus or the thalamus. This is consistent with the observation that different nAChRs modulate dopamine release as compared with norepinephrine release. The effect of (+/-)-epibatidine on both [3H]-dopamine and [3H]-norepinephrine release was tetrodotoxin-sensitive, suggesting the involvement of sodium channels. (+/-)-Epibatidine (1-3 micrograms/kg s.c.) produced ipsilateral turning in the unilaterally [6(OH)-DA]-lesioned rat. This effect was mimicked by (-)-nicotine (0.35 mg/kg s.c.). Both (+/-)-epibatidine- and (-)-nicotine-induced turning were significantly inhibited by mecamylamine (3 mg/kg s.c.), indicating that the turning response was mediated by nAChRs. (+/-)-Epibatidine also increased locomotor activity in a dose-dependent manner. (+/-)-Epibatidine-induced hyperactivity was blocked by D1 and D2 receptor antagonists, SCH 23390 and eticlopride, respectively, suggesting that both dopamine receptor subtypes might be required for the locomotor effect of (+/-)-epibatidine. These results demonstrate that (+/-)-epibatidine displays nAChR agonist activity in the rat CNS and that certain effects are mediated via nAChR-stimulated catecholamine release and subsequent activation of corresponding receptors.
authors.affiliation: SIBIA, La Jolla, California, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: F
authors.initials: F
authors.lastname: Menzaghi
authors.forename: J L
authors.initials: JL
authors.lastname: Dunlop
authors.forename: L D
authors.initials: LD
authors.lastname: Correa
authors.forename: K T
authors.initials: KT
authors.lastname: Whelan
authors.forename: G K
authors.initials: GK
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D013779:Tetrodotoxin; C082748:epibatidine; D004298:Dopamine; D009638:Norepinephrine