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首页> 外文期刊>Neuropsychopharmacology >Is Slow-Onset Long-Acting Monoamine Transport Blockade to Cocaine as Methadone is to Heroin|[quest]| Implication for Anti-Addiction Medications
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Is Slow-Onset Long-Acting Monoamine Transport Blockade to Cocaine as Methadone is to Heroin|[quest]| Implication for Anti-Addiction Medications

机译：美沙酮对海洛因的影响是对可卡因的慢效长效单胺转运封锁吗[[quest] |反成瘾药物的含义

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The success of methadone in treating opiate addiction has suggested that long-acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadone's effects on heroin's actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48?h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroin's actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadone's actions, that is, functionally antagonizing cocaine's action while blocking monoamine transporters to augment synaptic DA.
机译：美沙酮在治疗鸦片成瘾方面的成功表明，长效激动剂疗法可能对治疗可卡因成瘾同样有用。在这里，我们使用慢效长效单胺再摄取抑制剂31,345（一种反氨基四氢萘类似物）在各种成瘾相关的动物模型中检验了这一假设，并将其与美沙酮在同一动物模型中对美沙酮对海洛因作用的影响进行了比较。 。全身给药31,345可以长期增强脑电刺激奖励（BSR）和伏隔核（NAc）多巴胺（DA）。用31,345增强的可卡因增强的BSR预处理，延长的可卡因增强的NAc DA预处理，可卡因的自我给药速率长期降低（24-48？h），而没有明显的灭绝模式，表明31,345与可卡因具有相加作用。相反，美沙酮预处理不仅剂量依赖性地以消灭方式抑制海洛因的自我给药，而且剂量依赖性地抑制海洛因增强的BSR和NAc DA，表明海洛因作用的美沙酮具有功能拮抗作用。此外，31,345剂似乎具有重大的滥用责任，因为它可产生剂量依赖性的BSR和NAc DA增强，维持较低的自我给药行为速率，并具有剂量依赖性地恢复药物寻找行为。相反，美沙酮仅以灭绝模式部分维持自我给药，而不能诱导恢复寻药行为。这些发现表明31,345是一种可卡因样缓慢发作的长效单胺转运蛋白抑制剂，可作为可卡因成瘾的激动剂疗法。但是，其作用方式似乎与美沙酮明显不同。理想的可卡因激动剂替代品应充分模拟美沙酮的作用，即在功能上拮抗可卡因的作用，同时阻断单胺转运蛋白以增强突触DA。

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