YQA-14

Accumulating preclinical evidence suggests that selective antagonists of dopamine receptor D3 (Drd3) affects opioid-induced addictive behaviors across various animal models, highlighting Drd3 as a potential therapeutic target for opioid use disorders. However, the cellular type and neural circuit mechanisms by which Drd3 mediates these effects remains unclear. We employed YQA14, a selective antagonist and knock-out to selectively block or delete Drd3 in the nucleus accumbens (NAc) or ventral tegmental area (VTA). We utilized a battery of morphine-induced self-administration assays, fiber photometry, RNAscope in situ hybridization and RT-PCR to functionally characterize the roles of antagonists of Drd3s in the morphine actions. Our results revealed Drd3 mRNA expression in approximately 80 % of vesicular GABA transporter 1 (VGAT1)-positive GABA neurons in the NAc and approximately 50 % of tyrosine hydroxylase (TH)-positive dopamine neurons in the VTA. Strikingly, microinjections of YQA14 into the NAc, rather than the VTA, inhibited morphine taking and cue-induced drug-seeking. Transgenic down-regulation of Drd3 gene expression in the NAc yielded similar results. To explore the dopamine-dependent mechanism underlying Drd3's action, we found that intra-NAc microinjections of YQA14 significantly reduced morphine- or cue-induced activation of dopamine neurons in the VTA during morphine self-administration or cue-induced drug-seeking tests. These results suggest that YQA14 effectively reduces opioid taking and seeking, mainly by blocking Drd3 in the NAc, which subsequently inhibits VTA dopamine neuron activity and opioid action in dopamine transmission.