Subunit composition of functional nAChRs expressed by DA neurons. The relative proportion of the different nAChR subtypes mediating nicotine-induced DA release in striatal synaptosomes or ACh-elicited currents in SN/VTA are indicated (gray insets). The contribution of subunits in brackets to functional α6^* nAChRs remains to be fully established. In addition to its direct actions on nAChRs expressed by DA neurons, nicotine might increase DA concentration in the Nac by at least two other mechanisms. By acting on α7 nAChRs located on cortical glutamatergic terminals, nicotine stimulates intra-VTA glutamate release and alters the firing pattern of DA neurons via NMDA receptor activation (Nomikos et al., 2000). At concentrations close to those found in smokers' blood, nicotine desensitizes α4β2 nAChRs on GABAergic interneurons, thus relieving the inhibitory control they exert on DA neurons (Mansvelder et al., 2002). Both direct and indirect mechanisms are likely to play a role in nicotine reinforcement.