(+ -)-EPIBATIDINE ELICITS A DIVERSITY OF IN-VITRO AND IN-VIVO EFFECTSMEDIATED BY NICOTINIC ACETYLCHOLINE-RECEPTORS/

(+/-)-Epibatidine, -(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane, is a novel, potent analgesic agent that acts through nicotinic acetylc holine receptor (nAChR) mechanisms. This study sought to establish whe ther (+/-)-epibatidine, like (-)-nicotine, also displays a wide divers ity of behavioral responses that are known to be elicited by nAChR act ivation or whether it demonstrates subtype selectivity for its interac tions with nAChRs. (+/-)-Epibatidine displaced [H-3](-)-cytisine bindi ng to the alpha 4 beta 2 nAChR subtype in rat brain membranes with hig h affinity (K-i, 43 pM). The compound was approximately 5000-fold less potent (K-i = 230nM) in the displacement of [I-125] cu-bungarotoxin b inding from the a-bungarotoxin-sensitive nAChR subtype present in rat brain but was a potent inhibitor (K-i, 2.7 nM) of [I-125] alpha-bungar otoxin binding to the nAChR subtype in Torpedo electroplax, which is s imilar to that present in the neuromuscular junction. Functionally, (/-)-epibatidine enhanced Rb-86(+) flux in IMR 32 cells with an EC(50) value of 7 nM. It was some 3000-fold more potent than (-)-nicotine (EC (50) value, 21,000 nM) and was approximately 150-fold more potent (EC( 50) value, 0.4 nM) than (-)-nicotine (EC(50) value = 60 nM) in increas ing [H-3]dopamine release from rat striatal slices. Remarkably, (+/-)- epibatidine was 40% to 50% more efficacious than (-)-nicotine in both functional assays. Both functional effects were blocked by the nAChR c hannel blocker, mecamylamine (100 mu M) (+/-)-Epibatidine was 300 to 1 000 times more potent than (-)-nicotine in the reduction of body tempe rature and locomotor activity in mice. Substantial reductions in both measures were evident at 0.019 mu mol/kg, effects that were also block ed by mecamylamine (15 mu mol/kg i.p.). However, motor impairments wer e not evident on the rotorod at doses of (+/-)-epibatidine (0.019 mu m ol/kg) and (-)-nicotine (6.2 and 19 mu mol/kg) that markedly reduced s pontaneous locomotor activity. (+/-)-Epibatidine, at doses that ranged from 0.05 to 0.1 mu mol/kg i.p., elicited a significant analgesic res ponse on the hot plate, an effect blocked by mecamylamine. Morphine wa s approximately 80-fold less potent than +/-)-epibatidine in this para digm. Collectively, these results demonstrate that (+/-)-epibatidine i s a potent nAChR agonist in vitro and in vivo with differential activi ty to evoke responses elicited by putative subtypes of nAChRs. Therefo re, (+/-)-epibatidine may serve as a novel pharmacological tool to pro be nAChR function further.