Behavioral Pharmacology Group, Laboratory of Animal Morphology and Pathology, State University of North Fluminense Darcy Ribeiro, Avenida Alberto Lamego, 2000, Campos dos Goytacazes, 28013-602 RJ, Brazil.
Department of Entomology and Plant Pathology, State University of North Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ, Brazil.
Behav Brain Res. 2020 Feb 17;380:112398. doi: 10.1016/j.bbr.2019.112398. Epub 2019 Nov 29.
The development of sensitization is one of the hallmarks of addictive drugs. Consistent with this relationship many studies have demonstrated that the highly addictive opioid agonist morphine induces sensitization effects. In this study, we administered morphine (10 mg/kg) (MOR) to induce sensitization. In that sensitization is considered to involve associative processes and that dopamine activity is an important contributor to learning and memory processes, we administered a dopamine inhibitory treatment using apomorphine (0.05 mg/kg) (APO) during memory consolidation following a morphine sensitization treatment protocol. Seemingly, a decrease in dopamine activity during consolidation would impair the salience of the association of the morphine response with the contextual cues during consolidation and interfere with the development of morphine sensitization. In two separate experiments, MOR or vehicle (VEH) were administered pre-trial and either VEH or APO were administered post-trial over 5 and 10 days of treatment, respectively. In both the 5 and 10 drug treatment sessions post-trial experiments, MOR groups given VEH immediately post-trial exhibited strong sensitization effects. These sensitization effects were substantially attenuated in the MOR groups given APO immediately post-trial but not in the MOR groups given APO after a 15 min. post-trial delay. In subsequent conditioning and sensitization challenge tests, the MOR groups that had been given APO immediately post-trial exhibited diminished sensitization and conditioned responses relative to MOR groups that had received VEH or APO delayed post-trial. This MOR-APO interaction effect was unique in that it occurred post-trial so that it was only expressed in a pre-trial test in which only MOR was administered. Seemingly, the inhibitory dopamine effect of APO was incorporated into memory during the post-trial consolidation process suggesting that drug/drug interactions can occur during consolidation.
敏化的发展是成瘾药物的特征之一。许多研究一致表明，高度成瘾的阿片类激动剂吗啡会诱导敏化效应。在这项研究中，我们给予吗啡（10mg/kg）（MOR）以诱导敏化。由于敏化被认为涉及联想过程，并且多巴胺活动是学习和记忆过程的重要贡献者，我们在吗啡敏化治疗方案后使用阿扑吗啡（0.05mg/kg）（APO）进行记忆巩固时给予多巴胺抑制治疗。似乎在巩固过程中降低多巴胺活性会降低吗啡反应与巩固过程中上下文线索的关联的显著性，并干扰吗啡敏化的发展。在两个单独的实验中，MOR 或载体（VEH）在试验前给予，并且在试验后分别在 5 天和 10 天的治疗中给予 VEH 或 APO。在试验后 5 天和 10 天的药物治疗中，MOR 组在试验后立即给予 VEH 表现出强烈的敏化效应。这些敏化效应在 MOR 组在试验后立即给予 APO 时大大减弱，但在 MOR 组在试验后 15 分钟给予 APO 时没有减弱。在随后的条件反射和敏化挑战测试中，与接受 VEH 或 APO 延迟试验后接受 MOR 组相比，在试验后立即给予 APO 的 MOR 组表现出减弱的敏化和条件反射。这种 MOR-APO 相互作用效应是独特的，因为它发生在试验后，因此仅在仅给予 MOR 的预试验中表达。似乎 APO 的抑制性多巴胺效应在试验后巩固过程中被纳入记忆中，这表明药物/药物相互作用可能发生在巩固过程中。
