We have recently shown that the stimulatory effect of nicotine on dopamine output in the nucleus accumbens is largely dependent upon an enhanced glutamate transmission via N-methyl-D-aspartate receptors, possibly through stimulation of nicotinic receptors localized presynaptically on glutamatergic afferents in the ventral tegmental area. Given that nicotinic alpha7 receptors have been proposed to be involved in presynaptic regulation of glutamate release, we investigated whether alpha7 receptors underlie such a mechanism in the ventral tegmental area. For this purpose, by utilizing microdialysis we measured dopamine release in the nucleus accumbens in response to systemic nicotine, with, or without, concomitant infusion into the ventral tegmental area of the selective alpha7 receptor antagonist methyllycaconitine. To test also whether alpha7 nicotinic receptor antagonism within the ventral tegmental area affected a natural reward-mediated increase in dopamine release in the nucleus accumbens, we employed a model of schedule-induced feeding. Intrategmental administration of methyllycaconitine decreased both the nicotine-induced and the food-induced dopamine release in the nucleus accumbens. We suggest that alpha7 nicotinic receptors in the ventral tegmental area are involved in the acute effect of nicotine on dopamine release in the nucleus accumbens and conclude that the mechanism, by which nicotine stimulates the mesolimbic dopaminergic system, may be an essential constituent of the natural reward-related circuits in brain.