Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts.
Eur J Neurosci. 2019 Aug;50(4):2740-2749. doi: 10.1111/ejn.14437. Epub 2019 Jun 1.
Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self-administration and returned to pre-cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self-administration (1.5 mg kg inj , 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast-scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate-putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self-administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate-putamen, neither cocaine self-administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self-administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.
尽管对可卡因滥用的神经生物学基础进行了几十年的研究，但治疗可卡因成瘾的药物治疗方法在很大程度上并不有效。来自临床前研究和门诊临床试验的综合证据表明，使用安非他命治疗可有效减少可卡因的摄入量。尽管有人认为安非他命治疗通过替代激动剂治疗减少可卡因的摄入量，但我们最近表明，可卡因自我给药会改变多巴胺信号的多个方面，而安非他命治疗会使伏隔核中的多巴胺信号恢复到可卡因给药前的功能。在这里，我们试图确定这些影响是否在女性受试者中也明显，以及在纹状体的不同区域中是否明显。雌性大鼠进行了 5 天的可卡因自我给药（1.5mg/kg 注射，每天 40 次），并在处死前 1 小时接受单次安非他命（0.56mg/kg）或生理盐水输注治疗。然后，我们使用在伏隔核核心或外侧尾壳核-苍白球进行的离体快速扫描循环伏安法，检查多巴胺信号和可卡因效力。我们发现，在伏隔核核心，可卡因自我给药会降低多巴胺摄取率和可卡因效力，而这两种改变都可以通过安非他命治疗来恢复。在外侧尾壳核-苍白球中，可卡因自我给药或安非他命治疗都不会改变多巴胺摄取；然而，可卡因效力会因自我给药而降低，并通过安非他命治疗恢复到对照水平。这些发现共同支持了安非他命治疗可卡因成瘾的作用超出了替代激动剂治疗的范围，并表明可卡因耐受的发展在两性中是相似的。
