Cocaine use disorder (CUD) is associated with neurobehavioral deficits that are resistant to current treatments. While craving and high rates of relapse are prominent features of CUD, persistent cognitive impairments are common and linked to poorer treatment outcomes. Here we sought to develop an animal model to study post-cocaine changes in drug seeking and working memory, and to evaluate ‘therapeutic’ effects of combined glutamate mGlu5 and adenosine A2a receptor blockade. As mGlu5 antagonists reduce drug seeking, and A2a blockade ameliorates working memory impairment, we hypothesized that mGlu5 + A2a antagonist cocktail would reduce both cocaine relapse and post-cocaine working memory deficits. Adult male Sprague-Dawley rats were first trained and tested in an operant delayed match-to-sample (DMS) task to establish the working memory baseline, followed by 6 days of limited and 12 days of extended access cocaine self-administration. Chronic cocaine reduced working memory performance (abstinence day 30–40) and produced robust time-dependent cocaine seeking at 45-, but not 120-days of abstinence. Systemic administration of A2a antagonist KW-6002 (0.125 and 1 mg/kg) failed to rescue post-cocaine working memory deficit. It also failed to reverse working memory impairment produced by mGlu5 NAM MTEP (1 mg/kg). Finally, KW-6002 prevented the ability of MTEP to reduce cocaine seeking and increased locomotor behavior. Thus, despite mGlu5 and A2a being exclusively co-localized in the striatum and showing behavioral synergism towards reducing cocaine effects in some studies, our findings advocate against the use of mGlu5 + A2a antagonist cocktail as it may further compromise cognitive deficits and augment drug craving in CUD.

可卡因使用障碍 (CUD) 与对当前治疗有抵抗力的神经行为缺陷有关。虽然渴望和高复发率是 CUD 的突出特征，但持续的认知障碍很常见，并且与较差的治疗结果有关。在这里，我们试图开发一种动物模型来研究可卡因后药物寻求和工作记忆的变化，并评估联合谷氨酸 mGlu5 和腺苷 A2a 受体阻断剂的“治疗”效果。由于 mGlu5 拮抗剂减少了药物寻求，而 A2a 阻断剂可改善工作记忆障碍，我们假设 mGlu5 + A2a 拮抗剂鸡尾酒会减少可卡因复发和可卡因后工作记忆缺陷。成年雄性 Sprague-Dawley 大鼠首先在操作性延迟匹配样本 (DMS) 任务中接受训练和测试，以建立工作记忆基线，随后是 6 天的有限可卡因自我管理和 12 天的延长可卡因自我管理。慢性可卡因会降低工作记忆表现（禁欲 30-40 天），并在 45 天而非 120 天的禁欲时产生强大的时间依赖性可卡因寻求。A2a 拮抗剂 KW-6002（0.125 和 1 mg/kg）的全身给药未能挽救可卡因后工作记忆缺陷。它还未能逆转 mGlu5 NAM MTEP (1 mg/kg) 产生的工作记忆障碍。最后，KW-6002 阻止了 MTEP 减少可卡因寻找和增加运动行为的能力。因此，尽管 mGlu5 和 A2a 完全共定位于纹状体中，并且在一些研究中显示出对减少可卡因影响的行为协同作用，