Phasic VTA DA neuron activity is induced by reward-predictive cues (Schultz, 1998), implicating a critical role for DA neurons in responding to positive reinforcement. This transition from a tonic spike firing mode to phasic firing can be modulated by glutamatergic afferents onto DA neurons (Mathon et al., 2003; White, 1996). Thus, alterations in glutamatergic input onto VTA DA neurons could significantly alter DA release in terminal regions. Glutamatergic synapses onto VTA DA neurons and NAcb medium spiny neurons (MSNs) are capable of expressing LTP and LTD of evoked AMPAR-mediated synaptic responses (Bellone and Lüscher 2005; Bonci and Malenka 1999; Robbe et al., 2002). Interestingly, following reward-related learning, an NMDA-dependent potentiation of AMPAR-mediated synaptic response of VTA DA neurons is observed (Stuber et al., 2008). Since drug exposure can also enhance AMPAR function in the VTA, these data collectively support the hypothesis that drugs of abuse can co-opt brain circuitry that processes motivationally-relevant non-drug stimuli.
