The Impact of Selective Dopamine D2, D3 and D4 Ligands on the Rat Gambling Task.

Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no approved pharmacological treatments for gambling disorder. Evidence suggests a role for dopamine in gambling disorder and thus may provide a therapeutic target. The present study therefore aimed to investigate the effects of selective antagonists and agonists of D2, D3 and D4 receptors in a rodent analogue of the Iowa gambling task used clinically. In this rat gambling task (rGT), animals are trained to associate different response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. As in the Iowa gambling task, the optimal strategy is to avoid the tempting high-risk high-reward options, and instead favor those linked to smaller per-trial rewards but also lower punishments, thereby maximizing the amount of reward earned over time. Administration of those selective ligands did not affect decision making under the rGT. Only the D4 drug had modest effects on latency measures suggesting that D4 may contribute in some ways to decision making under this task.

Dopamine D3 receptors in the basolateral amygdala and the lateral habenula modulate cue-induced reinstatement of nicotine seeking.

Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 µg/0.5 µl/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 µg/0.5 µl/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [(125)I]7-OH-PIPAT to D3 receptors in the lateral habenula and in the basolateral amygdala is consistent with an important role of D3 receptors in these areas in nicotine seeking. It was also found that systemic administration of the selective D2 antagonist L741626 decreased cue-induced reinstatement, consistent with a role of D2 and D3 receptors in modulating this behavior. The current study supports an important role for D3 receptors in the basolateral amygdala and lateral habenula in cue-induced reinstatement.

The selective dopamine D3 receptor antagonist SB 277011-A, but not the partial agonist BP 897, blocks cue-induced reinstatement of nicotine-seeking.

The dopamine D3 receptor (DRD3) has been suggested to be involved in the mechanisms underlying stimulus-controlled drug-seeking behaviour. Ligands acting as DRD3 antagonists (SB 277011-A) or DRD3 partial agonists (BP 897) have shown some promise for reducing the influence of drug-associated cues on motivational behaviour. Here, effects of SB 277011-A and BP 897 were evaluated on cue-induced reinstatement of nicotine-seeking in rats. The effects of BP 897 on nicotine self-administration under a fixed-ratio 5 (FR5) schedule of reinforcement were also evaluated. SB 277011-A (1-10 mg/kg) was able to block cue-induced reinstatement of nicotine-seeking, indicating that DRD3 selective antagonism may be an effective approach to prevent relapse for nicotine. In contrast, BP 897 did not block the cue-induced reinstatement of nicotine-seeking or nicotine-taking under the FR5 schedule. In a control study, rats did not respond to the light stimuli without nicotine delivery, indicating that the responding for the drug-associated cues was induced by the previous pairing of light stimuli with nicotine's effects. These findings validate the role of DRD3 on reactivity to drug-associated stimuli and suggest that the DRD3 antagonist, but perhaps not the DRD3 partial agonist, could be used to prevent relapse in tobacco smokers.