Leri Francesco, Sorge Robert E, Cummins Erin, Woehrling David, Pfaus James G, Stewart Jane
Department of Psychology, University of Guelph, Guelph, ON, Canada NIG 2WI.
Neuropsychopharmacology. 2007 Nov;32(11):2290-300. doi: 10.1038/sj.npp.1301357. Epub 2007 Feb 21.
It has been demonstrated that high-dose methadone maintenance is efficacious in reducing cocaine abuse in opioid-dependent individuals, but it is not clear whether this is caused by an action of methadone on the direct reinforcing properties of cocaine or on cocaine seeking. Also, it is not clear whether high-dose methadone maintenance may induce behavioral side effects, which could limit its clinical use. Here, we report that high-dose methadone maintenance (20-40 mg/kg/day) does not reduce, and even enhances cocaine (10-30 mg/kg, i.p.)-induced elevation in dopamine concentration in the ventral striatum measured by in vivo microdialysis. In parallel, however, rats maintained on high-dose methadone (30 mg/kg/day) seek and consume significantly less cocaine than controls when tested for intravenous cocaine (0.5 mg/kg/infusion) self-administration on a progressive ratio schedule of reinforcement. This reduction in cocaine self-administration does not result from impaired sensory-motor functioning as rats maintained on high-dose methadone show normal locomotor activity. Furthermore, the reduction in responding for cocaine does not seem to result from general behavioral deficits as male rats maintained on high methadone doses respond normally to palatable food and thermal pain, although their sexual responses to receptive females are greatly suppressed. Taken together, these results from studies in rats support the usefulness of larger doses of methadone to reduce severe cocaine abuse in opioid-dependent individuals and possibly in the management of pure-cocaine addiction.
已证明高剂量美沙酮维持疗法在减少阿片类药物依赖个体的可卡因滥用方面是有效的，但尚不清楚这是由美沙酮对可卡因的直接强化特性的作用还是对觅求可卡因行为的作用所致。此外，高剂量美沙酮维持疗法是否会诱发行为副作用也不清楚，而这可能会限制其临床应用。在此，我们报告高剂量美沙酮维持疗法（20 - 40毫克/千克/天）并不会降低，甚至会增强可卡因（10 - 30毫克/千克，腹腔注射）通过体内微透析测量的腹侧纹状体中多巴胺浓度的升高。然而，与此同时，当在渐进比率强化程序上对大鼠进行静脉注射可卡因（0.5毫克/千克/输注）自我给药测试时，维持高剂量美沙酮（30毫克/千克/天）的大鼠比对照组觅求并消耗的可卡因显著更少。可卡因自我给药的这种减少并非源于感觉运动功能受损，因为维持高剂量美沙酮的大鼠表现出正常的运动活动。此外，对可卡因反应的减少似乎并非源于一般行为缺陷，因为维持高剂量美沙酮的雄性大鼠对美味食物和热痛的反应正常，尽管它们对处于接受状态的雌性的性行为反应受到极大抑制。综上所述，这些在大鼠身上的研究结果支持使用更大剂量的美沙酮来减少阿片类药物依赖个体中严重的可卡因滥用，并且可能用于单纯可卡因成瘾的治疗。
