Psychology Department, Queens College of the City University of New York, Flushing, New York, USA.
Addict Biol. 2021 Jul;26(4):e12988. doi: 10.1111/adb.12988. Epub 2021 Jan 25.
Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new compounds in preclinical studies when administered as independent treatments. In this series of experiments, we explored the effects of coadministration of a D1-receptor partial agonist (SKF 77434) and a D3-receptor antagonist (NGB 2904) in heroin-seeking rats within a "conflict" model of abstinence and cue-induced relapse. Rats were first trained to press a lever to self-administer heroin, and drug delivery was paired contingently with cues (e.g., light and pump noise). Self-initiated abstinence was facilitated by applying electrical current to the flooring in front of the levers. Lastly, a relapse response was provoked by noncontingent presentation of conditioned cues. Prior to provocation, rats received a systemic injection of SKF 77434, NGB 2904, or a combination of both compounds to assess treatment effects on lever pressing. Results indicated that the coadministration of low (i.e., independently ineffective) doses of both compounds was more effective in reducing cue-induced relapse to heroin seeking than either compound alone, with some evidence of drug synergism. Follow-up studies indicated that this reduction was not due to motoric impairment nor enhanced sensitivity to the electrified flooring and that this treatment did not significantly affect motivation for food. Implications for the treatment of opiate use disorder and recommendations for further research are discussed.
靶向多巴胺（DA）D1 或 D3 受体的化合物已显示出作为潜在干预措施在动物模型中的线索诱导复吸的前景。然而，当作为独立治疗药物使用时，不理想的副作用或药效学特征限制了新化合物在临床前研究中的进展。在这一系列实验中，我们在戒断和线索诱导复吸的“冲突”模型中，探讨了 D1 受体部分激动剂（SKF 77434）和 D3 受体拮抗剂（NGB 2904）联合给药对海洛因觅药大鼠的影响。大鼠首先接受训练，按压杠杆自行注射海洛因，药物输送与线索（例如灯光和泵噪声）有条件地配对。通过对杠杆前的地板施加电流，促进了自我发起的禁欲。最后，通过非条件呈现条件线索引发复吸反应。在挑衅之前，大鼠接受系统注射 SKF 77434、NGB 2904 或两种化合物的组合，以评估治疗对杠杆按压的影响。结果表明，联合使用两种低剂量（即单独无效）的化合物更有效地减少线索诱导的海洛因觅药复吸，比单独使用任何一种化合物都更有效，并且有一些药物协同作用的证据。后续研究表明，这种减少不是由于运动障碍，也不是由于对通电地板的敏感性增强，而且这种治疗对食物的动机没有显著影响。讨论了该治疗方法对阿片类药物使用障碍的影响，并提出了进一步研究的建议。
