title: Nicotinic-receptor mediation of S(-)nornicotine-evoked -3H-overflow from rat striatal slices preloaded with -3H-dopamine.
abstract: Previous results from our laboratory demonstrated that S(-)nornicotine, a major tobacco alkaloid and an active nicotine metabolite present in the CNS, increases dopamine release from rat striatal slices in a concentration-dependent and calcium-dependent manner. The present study determined if S(-)nornicotine-evoked dopamine release was the result of nicotinic receptor stimulation. Stereoselectivity and the ability of classical noncompetitive and competitive nicotinic receptor antagonists (mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), respectively) to inhibit S(-)nornicotine-evoked [3H]overflow from [3H]dopamine-preloaded rat striatal slices were investigated. Nornicotine increased [3H]overflow in a stereoselective manner at concentrations from 1 to 100 microM. MEC (0.01-100 microM) or DHbetaE (0.01-10 microM) alone did not evoke -3H-overflow. However, 100 microM DHbetaE evoked -3H-overflow, and therefore, was not used in experiments investigating antagonism of S(-)nornicotine's effect. MEC and DHbetaE inhibited S(-)nicotine- (10 microM) evoked [3H]overflow in a concentration-dependent manner. Concentrations of MEC (100 microM) and DHbetaE (10 microM) which maximally inhibited S(-)nicotine's effect were chosen for subsequent experiments determining inhibition of the effect of S(-)nornicotine (0.1 microM-3 mM). MEC and DHbetaE significantly inhibited the effect of low concentrations (<100 microM) of S(-)nornicotine; however, higher concentrations (>100 microM) of S(-)nornicotine were not inhibited by either nicotinic antagonist. Taken together, the results suggest that low concentrations of S(-)nornicotine stimulate nicotinic receptors to evoke the release of dopamine from dopaminergic presynaptic terminals. Thus, nornicotine, which acts as an agonist at neuronal nicotinic receptors, may contribute to the neuropharmacological effects of nicotine and tobacco use.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
authors.forename: L
authors.initials: L
authors.lastname: Teng
authors.forename: P A
authors.initials: PA
authors.lastname: Crooks
authors.forename: S T
authors.initials: ST
authors.lastname: Buxton
authors.forename: L P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013237:Stereoisomerism; D014316:Tritium
chemical_list: D011978:Receptors, Nicotinic; D014316:Tritium; D004079:Dihydro-beta-Erythroidine; D008464:Mecamylamine; D009538:Nicotine; C005311:nornicotine; D004298:Dopamine