Different forms of behavioral flexibility are facilitated by interactions between separate regions of the prefrontal cortex and their striatal outputs. However, the contribution of ventral striatal dopamine (DA) to these functions is unclear. The present study assessed the involvement of DA receptors in the nucleus accumbens (NAc) core on either between-or within-strategy shifts using operant chamberbased tasks. Strategy set-shifting required rats initially to learn a visual-cue discrimination and, on the following day, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were initially trained on a response discrimination and then required to select the opposite lever to receive food reward. Intra-NAc microinfusions of D 1 (SCH23390) but not D 2 (eticlopride) receptor antagonists impaired set-shifting, disrupting the maintenance of a new strategy. Conversely, supranormal activation of D 2 (quinpirole) but not D 1 (SKF81297) receptors also impaired set-shifting, inducing perseverative deficits. However, only infusions of the D 2 agonist impaired reversal learning, but did so without disrupting initial response learning. Thus, mesoaccumbens DA, acting on D 1 receptors, selectively facilitates complex forms of flexibility requiring shifts between different strategies, but does not appear to contribute to simpler forms of flexibility entailing shifts of specific stimulus-reward associations. In contrast, abnormal increases in D 2 receptor activity cause a more general impairment in behavioral flexibility. These findings suggest that deficits in these forms of executive functioning observed in disorders linked to dysfunction of the DA system may be attributable in part to aberrant increases or decreases in mesoaccumbens DA activity.

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Enhanced glutamatergic neurotransmission in dopamine (DA) neurons of the ventral tegmental area (VTA), triggered by a single cocaine injection, represents an early adaptation linked to the more enduring effects of abused drugs that characterize addiction. Here, we examined the impact of in vivo cocaine exposure on metabotropic inhibitory signaling involving G protein-gated inwardly-rectifying K+ (Girk) channels in VTA DA neurons. Somatodendritic Girk currents evoked by the GABAB receptor (GABABR) agonist baclofen were diminished in a dose-dependent manner in mice given a single cocaine injection. This adaptation persisted for 3-4 days, was specific for DA neurons of the VTA, and occurred in parallel with an increase in spontaneous glutamatergic neurotransmission. No additional suppression of GABABR-Girk signaling was observed following repeated cocaine administration. While total Girk2 and GABABR1 mRNA and protein levels were unaltered by cocaine exposure in VTA DA neurons, the cocaine-induced decrease in GABABR-Girk signaling correlated with a reduction in Girk2-containing channels at the plasma membrane in VTA DA neurons. Systemic pre-treatment with sulpiride, but not SCH23390, prevented the cocaine-induced suppression of GABABR-Girk signaling, implicating D2/3 DA receptor activation in this adaptation. The acute cocaine-induced weakening of somatodendritic Girk signaling complements the previously-demonstrated cocaine-induced strengthening of glutamatergic neurotransmission, likely contributing to enhanced output of VTA DA neurons during the early stages of addiction.