VTA GABA Neuron Activation Disrupts Reward Seeking by Altering Temporal Processing
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The ventral tegmental area (VTA) plays a critical role in reward-seeking, and is composed primarily of dopamine (~75%) and GABA (~25%) neurons. However, few studies have functionally evaluated the role of VTA GABA neurons in behavior. Recently we used a new viral approach to target activating DREADDs (Designer Receptor Exclusively Activated by Designer Drugs, hM3D) to GAD1+ VTA GABA neurons in wildtype rats. We first sought to determine how VTA GABA neurons regulate ethanol seeking behaviors in an operant self-administration task. While the DREADD ligand, clozapine n-oxide (CNO, 0.3 mg/kg, i.p.) did not change either the reinforcers obtained under a fixed ratio 1 schedule, or the breakpoints in a progressive ratio schedule, we observed a profound change in the pattern of responding for ethanol. Specifically, across ethanol doses the number of bouts and the inter-bout intervals decreased, while bout length increased. The rats responded more slowly, yet consistently throughout the six-hour session. We next explored the effect of VTA GABA activation on the perception of time in two fixed interval (FI) tasks, one in which there were no reward predictive cues (non-cued FI), and another where the start of the FI was signaled by a constant cue that played until the animal obtained a reward (cued FI). Under saline conditions in both tasks, responding was characterized by "scalloping", with an acceleration of responding towards the end of the 30s FI. In the non-cued FI task, VTA GABA activation decreased the overall rate and number of responses, and the time between the end of the 30s interval and when the rats made a rewarded response increased. Yet responding still conformed to the scalloped pattern during the FI. However, in the cued FI task, after VTA GABA activation the distribution of responses during the FI was completely flat (i.e. no scalloping), and responding was more erratic, even though total responses and earned rewards earned did not change. The cued FI30 schedule of reinforcement was therefore more sensitive to disruption by VTA GABA activation, likely due to the convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activation disrupts operant responding for rewards by altering interval timing.