As already noted, all drugs of abuse activate dopaminergic input to the NAc and related limbic brain regions (Volkow et al., 2004; Wise, 2004; Nestler, 2005). For instance, psychostimulants such as cocaine or amphetamine act directly on the dopaminergic reward pathway by interfering with the dopamine transporter: cocaine blocks the transporter and amphetamine reverses the transporter, both actions resulting in a build up of dopamine in the synapse which can activate downstream dopamine receptors on target neurons (Figure 1). The two MSNs are most notably differentiated by their enrichment of D1 vs. D2-receptors although single-cell RT-PCR studies reveal that D1+ MSNs express low levels of the D2-like receptor, D3 and D2+ MSNs express low levels of the D1-like receptor, D5 (Surmeier et al., 1996). The two MSNs require glutamatergic innervation to drive neural activity; dopamine oppositely modulates these functional responses via stimulation of distinct dopamine receptor subtypes: by positively modulating excitatory glutamatergic input through D1 receptor signaling via Gs or Golf, which stimulates adenylyl cyclase leading to increased PKA activity, whereas dopamine negatively modulates this input through D2-receptor signaling via
