The effects of dopamine D4 receptor ligands on operant alcohol self-administration and cue- and stress-induced reinstatement in rats.

Dopamine, a neurotransmitter with 5 receptor subtypes, is critical to the dependence-forming properties of drugs of abuse. The role of the dopamine D receptor subtype in substance use disorders has remained somewhat elusive but the recent development of selective ligands holds promise for future investigations of this receptor subtype in substance use disorders, including alcohol use disorder. The purpose of the present study was to further elucidate the effects of a selective antagonist (L-745,870) and agonist (PD 168,077) on alcohol self-administration and reinstatement induced either by cues or stress. It was found that the D antagonist, but not agonist, reduced alcohol intake at the highest doses. Further, the D antagonist reduced stress-induced reinstatement, with no effects on cue-induced reinstatement; the agonist was without effect on either form of reinstatement. The dopamine D receptor antagonist was without effect on food reinforcement. This work deepens existing lines of evidence that the dopamine D receptor is involved in substance use disorders and suggests that dopamine D receptor blockade diminishes motivation for alcohol-taking without influencing natural food rewards. Furthermore, there appears to be a plausible effect of dopamine D receptor blockade interfering with stress- but not cue-induced alcohol-seeking.