Figure 1: Schematic representation of nicotine effects on dopaminergic neurotransmission in the mesolimbic pathway. Nicotine indirectly regulates dopaminergic signaling in mesolimbic pathways. Nicotine activates nAChRs located on GABAergic and glutamatergic neurons that synapse on dopaminergic neurons in the VTA. GABA exerts hyperpolarizing effects (through GABA receptor activation), whereas glutamate exerts depolarizing effects (through NMDA receptor activation) on dopaminergic neurons. (A) Initially, increased secretion of both GABA and glutamate occur in the VTA in response to nicotine. (B) However, nAChRs located on GABAergic neurons are thought to rapidly desensitize, resulting in increased dopaminergic neurotransmission due to unopposed glutamate signaling in the VTA [11,15-17]. Differential desensitization rates of nAChRs on glutamatergic and GABAergic neurons may be due to differences in subunit composition of the receptors at the two locations [78].