NICOTINIC-RECEPTOR MEDIATION OF S(-)NORNICOTINE-EVOKED [H-3] OVERFLOWFROM RAT STRIATAL SLICES PRELOADED WITH [H-3] DOPAMINE

Previous results from our laboratory demonstrated that S(-)nornicotine , a major tobacco alkaloid and an active nicotine metabolite present i n the CNS, increases dopamine release from rat striatal slices in a co ncentration-dependent and calcium-dependent manner. The present study determined if S(-)nornicotine-evoked dopamine release was the result o f nicotinic receptor stimulation. Stereosetectivity and the ability of classical noncompetitive and competitive nicotinic receptor antagonis ts (mecamylamine (MEC) and dihydro-beta-erythroidine (DH beta E), resp ectively) to inhibit S(-)nornicotine-evoked [H-3]overflow from [H-3]do pamine-preloaded rat striatal slices were investigated. Nornicotine in creased [H-3]overflow in a stereoselective manner at concentrations fr om 1 to 100 mu M. MEC (0.01-100 mu M) Or DH beta E (0.01-10 mu M) alon e did not evoke [H-3]overflow. However, 100 mu M DHPE evoked [H-3]over flow, and therefore, was not used in experiments investigating antagon ism of S(-)nornicotine's effect. MEC and DH beta E inhibited S(-)nicot ine- (10 mu M) evoked [H-3]overflow in a concentration-dependent manne r. Concentrations of MEC (100 mu M) and DH beta E (10 mu M) which maxi mally inhibited S(-)nicotine's effect were chosen for subsequent exper iments determining inhibition of the effect of S(-)nornicotine (0.1 mu M-3 mM). MEC and DH beta E significantly inhibited the effect of low concentrations (<100 mu M) of S(-)nornicotine; however, higher concent rations (>100 mu M) of S(-)nornicotine were not inhibited by either ni cotinic antagonist. Taken together, the results suggest that low conce ntrations of S(-)nornicotine stimulate nicotinic receptors to evoke th e release of dopamine from dopaminergic presynaptic terminals. Thus, n ornicotine, which acts as an agonist at neuronal nicotinic receptors, may contribute to the neuropharmacological effects of nicotine and tob acco use.