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.

J. Neurochem. (2010) 114, 1487–1497. Abstract Mice lacking the Girk2 subunit of G protein‐gated inwardly rectifying K+ (Girk) channels exhibit dopamine‐dependent hyperactivity and elevated responses to drugs that stimulate dopamine neurotransmission. The dopamine‐dependent phenotypes seen in Girk2−/− mice could reflect increased intrinsic excitability of or diminished inhibitory feedback to midbrain dopamine neurons, or secondary adaptations triggered by Girk2 ablation. We addressed these possibilities by evaluating Girk−/− mice in behavioral, electrophysiological, and cell biological assays centered on the mesolimbic dopamine system. Despite differences in the contribution of Girk1 and Girk2 subunits to Girk signaling in midbrain dopamine neurons, Girk1−/− and Girk2−/− mice exhibited comparable baseline hyperactivities and enhanced responses to cocaine. Girk ablation also correlated with altered afferent input to dopamine neurons in the ventral tegmental area. Dopamine neurons from Girk1−/− and Girk2−/− mice exhibited elevated glutamatergic neurotransmission, paralleled by increased synaptic levels of α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate glutamate receptors. In addition, synapse density, α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor levels, and glutamatergic neurotransmission were elevated in medium spiny neurons of the nucleus accumbens from Girk1−/− and Girk2−/− mice. We conclude that dopamine‐dependent phenotypes in Girk2−/− mice are not solely attributable to a loss of Girk signaling in dopamine neurons, and likely involve secondary adaptations facilitating glutamatergic signaling in the mesolimbic reward system.

Operant conditioning paradigms are useful for studying factors involved in reward, particularly when combined with the tools of genetic manipulation in mice. Published operant studies involving mice vary widely with respect to design, and insight into the consequences of design choices on performance in mice is limited. Here, we evaluated the impact of five design variables on the performance of inbred male mice in operant tasks involving solid food pellets as reinforcing agents. We found that the use of lever-press or nose-poke during FR1 sessions did not impact the performance of C57BL/6 mice, but that the lever-press approach correlated with enhanced performance during PR testing. While FR1 session duration had a notable impact on the rate of acquisition of foodmaintained responding, performance during FR1 and PR sessions was largely unaffected. Higher order schedules of reinforcement (FR3 and FR5) led to elevated responding during both FR and PR sessions, and improved the correspondence between rewards earned and consumed. Single and group-housed mice performed indistinguishably during FR1 and PR sessions, while environmental enrichment combined with group housing accelerated the rate of acquisition of food-maintained responding while decreasing responding during PR testing. Finally, while C57BL/6 and 129/Sv mice exhibited comparable behavior during FR1 sessions, C57BL/6 mice tended to acquire foodmaintained responding faster than 129/Sv counterparts, and exhibited elevated responding during PR testing. Altogether, our findings indicate that while operant performance for food in mice is relatively insensitive to many study parameters, experimental outcomes can be shaped predictably with proper design decisions.