Nicotine produces rewarding and aversive motivational effects in humans and other animal species. Here, we report that the mammalian ventral tegmental area (VTA) represents a critical neural substrate for the mediation of both the rewarding and aversive properties of nicotine. We demonstrate that direct infusions of nicotine into the VTA can produce both rewarding and aversive motivational effects. While the rewarding effects of higher doses of nicotine were not attenuated by dopamine (DA) receptor blockade, blockade of mesolimbic DA signalling with either systemic or intra-nucleus accumbens (NAc) neuroleptic pretreatment potentiated the sensitivity to nicotine's rewarding properties over a three-order-of-magnitude dose range. Furthermore, the behavioural effects of lower doses of intra-VTA nicotine were reversed, switching the motivational valence of nicotine from aversive to rewarding. Our results suggest that blockade of mesolimbic DA signalling induced by neuroleptic medications may block selectively the aversive properties of nicotine, thus increasing the vulnerability to nicotine's rewarding and addictive properties by inducing a unique, drug-vulnerable phenotype.