Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine's subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine's behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.

中文翻译：

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L 型钙通道阻滞剂伊拉地平通过增强腹侧被盖区到伏隔核通路的多巴胺能活性来减弱提示诱导的可卡因寻求。


之前的临床前和临床研究主要集中在 L 型钙通道 (LTCC) 作为药物滥用的潜在治疗靶点。虽然一些临床研究已经检验了 LTCC 阻滞剂改变可卡因主观效应的能力，但很少有 LTCC 研究检验了可卡因复发。在这里，我们检查了 LTCC 抑制剂伊拉地平的腹侧被盖区 (VTA) 特异性或全身给药是否改变了大鼠模型中的可卡因寻求行为。雄性 Sprague-Dawley 大鼠首先接受 10 天的可卡因自我给药训练（2 小时训练），其中主动压低杠杆导致输注约 0.5 mg/kg 可卡因，并伴有音调 + 灯光提示。然后，老鼠经历了 10 天的强制戒酒，不得接触可卡因或可卡因线索。然后将大鼠送回操作室进行提示诱导的可卡因寻求测试，其中在原始训练环境中主动压低杠杆导致音调+光提示呈现。我们发现 VTA 特异性或全身性伊拉地平给药可显着减弱可卡因寻求，而不会改变可卡因服用或自然奖赏寻求。伏核 (NAc) 核心中的多巴胺 (DA) 信号传导对于线索诱导的药物寻找是必要且充分的。令人惊讶的是，在我们的研究中，伊拉地平增强了可卡因戒断大鼠的强直和阶段性 DA 信号传导，而在蔗糖戒断或未接触过蔗糖的大鼠中没有变化。引人注目的是，伊拉地平的行为效应依赖于 NAc 核心 DA 受体的激活。总之，我们的研究结果揭示了 FDA 批准的药物伊拉地平可以减少可卡因复发的新机制。