Contributory role for nornicotine in nicotine neuropharmacology: Nornicotine-evoked [³H]dopamine overflow from rat nucleus accumbens slice

Nornicotine is a tobacco alkaloid and an active nicotine metabolite, which accumulates in brain to pharmacologically relevant concentrations following repeated nicotine administration to rats. Furthermore, nornicotine is self-administered by rats, indicating that it has reinforcing efficacy and may contribute to nicotine dependence. Since drugs of abuse activate the mesolimbic dopamine (DA) system to produce rewarding effects, the present study tested the hypothesis that nornicotine evokes DA release from nucleus accumbens in a nicotinic receptor-mediated manner. Rat nucleus accumbens slices were preloaded with [³H]DA and superfused for 60 min in the absence and presence of a range of alkaloid concentrations. Superfusate samples were collected and alkaloid-evoked [³H]overflow was determined. S(-)-Nornicotine (EC₅₀ value = 3.0 μM), R(+)-nornicotine (EC₅₀ value = 0.48 μM), and S(-)-nicotine (EC₅₀ value = 70 nM) evoked [³H]overflow in a concentration-dependent manner. For each nornicotine enantiomer, 0.3 μM was the lowest concentration to evoke significant [³H]overflow. Dihydro-β-erythroidine (DHβE, 10 μM), a classical nicotinic receptor antagonist, inhibited the S(-)-nornicotine-evoked [³H]overflow, indicating the involvement of nicotinic receptors. Furthermore, the effect of S(-)-nornicotine was calcium-dependent, consistent with a nicotinic receptor-mediated mechanism. Whereas S(-)-nornicotine was found previously to be more potent in the striatum, R(+)-nornicotine was more potent than its enantiomer in nucleus accumbens, suggesting the involvement of different nicotinic receptor subtypes in these brain regions. Thus, the results of the current study indicate that nornicotine stimulated DA release from nucleus accumbens in a nicotinic receptor-mediated manner, further supporting the hypothesis that nornicotine contributes to tobacco dependence.