Effects of exposure to chronic uncertainty and a sensitizing regimen of amphetamine injections on locomotion, decision-making, and dopamine receptors in rats.

Gambling disorder (GD) is a behavioral addiction that may be linked to alterations in dopamine (DA) systems. Gambling involves chronic exposure to uncertain reward, which can sensitize the activity of DA systems. Here we explored how combinations of Pavlovian and instrumental uncertainty impact DA sensitization and risky decision-making. Experiment 1: 40 rats underwent 66 uncertainty exposure (UE) sessions during which they responded for saccharin. Animal responding was reinforced according to a fixed or variable (FR/VR) ratio schedule that turned on a conditioned stimulus (CS; light), which predicted saccharin on 50% or 100% of trials. Animals responded under one of the four conditions: FR-CS100% (no uncertainty), VR-CS100%, FR-CS50%, and VR-CS50% (maximal uncertainty). DA sensitization was inferred from an enhanced locomotor response to d-amphetamine (d-AMPH; 0.5 mg/kg) challenge. The rat gambling task (rGT) was used to assess decision-making. Experiment 2: 24 rats received 5 weeks of sensitizing d-AMPH or saline doses, followed by locomotor activity and rGT testing. Experiment 3: Effects of UE and a sensitizing d-AMPH regimen on DA D1, D2, and D3 receptor binding were assessed in 44 rats using autoradiography. Compared to FR-CS100%, VR-CS100% and VR-CS50% rats displayed a greater locomotor response to d-AMPH, and VR-CS50% rats demonstrated riskier decision-making. Chronic d-AMPH-treated rats mirrored the effects of VR-CS50% groups on these two indices. Both VR-CS50% and d-AMPH-treated groups had increased striatal DA D2 receptor binding. These results suggest that chronic uncertainty exposure, similar to exposure to a sensitizing d-AMPH regimen, sensitized the function of DA systems and increased risky decision-making.

Dissociable roles of the nucleus accumbens D1 and D2 receptors in regulating cue-elicited approach-avoidance conflict decision-making.

RATIONALE: Approach and avoidance decisions are made when an animal experiences a state of motivational conflict inflicted by stimuli imbued with both positive and negative valences. The nucleus accumbens (NAc), a site where valenced information and action selection converge, has recently been found to be critically involved in the resolution of approach-avoidance conflict. However, the individual roles of the region's dopamine receptor D1 (D1R)- and D2 (D2R)-expressing medium spiny neurons (MSNs) in regulating conflict resolution have not been well established. OBJECTIVES: Here, we examined the roles of NAc D1R and D2R in cue-elicited approach-avoidance decision-making. METHODS: Using a conditioned mixed-valence conflict paradigm, rats were initially trained in a radial maze to associate separate visuotactile cues with sucrose reward, foot shock punishment, and no outcome. Following acquisition of the cue-outcome associations, rats were subjected to a conditioned approach-avoidance conflict scenario, in which they were presented with a maze arm containing a superimposition of the reward and punishment cues, and another arm containing neutral cues. RESULTS: Post-training intra-NAc D1R antagonism (SCH23390) led to an avoidance of the arm containing the mixed-valence cue over the neutral arm, whereas intra-NAc D2R antagonism (sulpiride) resulted in rats exhibiting a preference for the mixed-valence arm. CONCLUSION: Our results suggest that NAc D1R and D2R exert differential control over decision-making involving cue-elicited approach-avoidance conflict resolution.