Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.
Institute of Neuroscience-Cagliari, National Research Council (CNR), Italy.
Addict Biol. 2018 Mar;23(2):556-568. doi: 10.1111/adb.12509. Epub 2017 Apr 21.
Dopamine agonists have been proposed as therapeutic tools for cocaine addiction. We have recently demonstrated that indirect dopamine agonists, including levodopa (L-DOPA), markedly increase cocaine-induced dopamine release in the medial prefrontal cortex (mPFC) of rats leading to the suppression of cocaine-seeking behavior. This study was aimed to understand the behavioral and neurochemical effects of L-DOPA on cocaine-taking and cocaine-seeking in rats. After reaching a stable pattern of intravenous cocaine self-administration under a continuous fixed ratio (FR-1) schedule of reinforcement, male rats were treated with L-DOPA at different steps of the self-administration protocol. We found that L-DOPA reduced cocaine self-administration under FR-1 schedule of reinforcement and decreased the breaking points and the amount of cocaine self-administered under the progressive ratio schedule of reinforcement. Levodopa also decreased cocaine-seeking behavior both in a saline substitution test and in the cue priming-induced reinstatement test, without affecting general motor activity. Importantly, L-DOPA greatly potentiated cocaine-induced dopamine release in the mPFC of self-administering rats while reducing their cocaine intake. In the same brain area, L-DOPA also increased dopamine levels during cue priming-induced reinstatement of cocaine-seeking behavior. The potentiating effect was also evident in the mPFC but not nucleus accumbens core of drug-naïve rats passively administered with cocaine. Altogether, these findings demonstrate that L-DOPA efficaciously reduces the reinforcing and motivational effects of cocaine likely potentiating dopamine transmission in the mPFC. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.
多巴胺激动剂被提议作为治疗可卡因成瘾的治疗工具。我们最近证明，间接多巴胺激动剂，包括左旋多巴（L-DOPA），显著增加了内侧前额叶皮层（mPFC）中可卡因诱导的多巴胺释放，从而抑制了可卡因寻求行为。这项研究旨在了解 L-DOPA 对大鼠可卡因摄取和可卡因寻求的行为和神经化学影响。在达到静脉内可卡因自我给药的稳定模式后，根据连续固定比率（FR-1）强化方案进行强化，雄性大鼠在自我给药方案的不同步骤中接受 L-DOPA 治疗。我们发现 L-DOPA 减少了 FR-1 强化方案下的可卡因自我给药，并减少了递增比率强化方案下的突破点和可卡因自我给药量。左旋多巴还减少了盐水替代测试和线索启动诱导复吸测试中的可卡因寻求行为，而不影响一般运动活动。重要的是，L-DOPA 大大增强了自我给药大鼠 mPFC 中可卡因诱导的多巴胺释放，同时减少了可卡因的摄入。在同一脑区，L-DOPA 还增加了线索启动诱导可卡因寻求行为复吸期间的多巴胺水平。这种增强作用在 mPFC 中也很明显，但在药物-naïve 大鼠的伏隔核核心中则不明显，这些大鼠被动给予可卡因。总之，这些发现表明，L-DOPA 有效地减少了可卡因的强化和动机作用，可能增强了 mPFC 中的多巴胺传递。它预防线索启动诱导可卡因寻求复吸的能力表明，它可能有效降低戒断患者复吸可卡因的风险。
