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 (EC(50) value = 3.0 microM), R(+)-
nornicotine (EC(50) value = 0.48 microM), and S(-)-
nicotine (EC(50) value = 70 nM) evoked [3H]overflow in a concentration-dependent manner. For each
nornicotine enantiomer, 0.3 microM was the lowest concentration to evoke significant [3H]overflow.
Dihydro-beta-erythroidine (DHbetaE, 10 microM), 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.