Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain
Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain
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DOI：
10.1038/sj.npp.1300927
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发表时间：
2006-07-01
影响因子：
7.6
通讯作者：
Kreek, Mary Jeanne
中科院分区：
文献类型：
--
作者：
Leri, Francesco;Zhou, Yan;Kreek, Mary Jeanne
适当剂量的美沙酮维持治疗可有效减少海洛因依赖者可卡因滥用。在本研究中，我们研究了大剂量美沙酮维持可卡因条件性位置偏爱（CPP）和可卡因静脉自我给药的效果。植入美沙酮填充的渗透微型泵（20和55 mg/kg/天，SC）并以可卡因（1、5和20 mg/kg，i. p.）不表达可卡因CPP。类似地，在可卡因预处理（20 mg/kg）后植入美沙酮泵（55 mg/kg/天）的大鼠既没有表现出自发性也没有表现出可卡因沉淀（20 mg/ kg，i. p.）CPP。相比之下，美沙酮维持（30和55 mg/kg/天，SC）未改变不同剂量可卡因（0.1、0.5和2.0 mg/kg/inf）的静脉自我给药（连续强化时间表）。为了探索美沙酮维持和可卡因调节之间的神经药理学相互作用，我们定量测量美沙酮维持后10天μ阿片受体（莫尔）和前阿黑皮素基因的mRNA水平。在CPP条件化过程中，暴露于可卡因的大鼠中脑中央核和额叶皮质的莫尔mRNA水平显著升高。然而，上调莫尔mRNA水平的核心细胞核美沙酮维持剂量依赖性的方式减少。总之，我们的研究结果表明，高剂量美沙酮维持不会改变可卡因的直接增强作用，但可能通过阻止可卡因条件反射诱导的丘脑核核心中的莫尔改变来阻断自发和可卡因沉淀的可卡因寻求。
Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/ kg,i.p.) CPP. In contrast, methadone maintenance ( 30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.