Banks Matthew L, Blough Bruce E
1] Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA [2] Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA.
Neuropsychopharmacology. 2015 Aug;40(9):2198-206. doi: 10.1038/npp.2015.63. Epub 2015 Mar 6.
Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.
临床前和人体实验室选择程序在增进我们对药物强化的神经生物学机制的了解以及治疗药物成瘾候选药物的研发过程中具有不可估量的价值。然而，关于甲基苯丙胺与食物选择的神经药理学机制却知之甚少。本研究的目的是建立一种甲基苯丙胺与食物选择程序，并确定两种具有临床相关性的化合物的治疗效果：单胺摄取抑制剂安非他酮和多巴胺拮抗剂利培酮。恒河猴（n = 6）在7天的安非他酮（0.32 - 1.8毫克/千克/小时）和利培酮（0.001 - 0.0056毫克/千克/小时）治疗期间，按照食物递送（1克颗粒，固定比率（FR）100程序）和静脉注射甲基苯丙胺（0 - 0.32毫克/千克/注射，FR10程序）的并发程序做出反应。为了进行比较，还研究了移除食物颗粒或甲基苯丙胺注射以及改变FR反应要求的影响。在生理盐水治疗条件下，与不给予甲基苯丙胺或小剂量甲基苯丙胺（0.01 - 0.032毫克/千克/注射）相比，食物更受偏爱。较大剂量的甲基苯丙胺导致对甲基苯丙胺的偏爱增加，而0.32毫克/千克/注射的甲基苯丙胺维持了几乎排他性的偏爱。移除食物供应增加了对甲基苯丙胺的选择，而移除甲基苯丙胺供应则降低了对甲基苯丙胺的选择。当食物和药物的FR反应要求相同时（FR100:FR100或FR10:FR10），甲基苯丙胺的选择没有显著改变。利培酮治疗增加了对甲基苯丙胺的选择，而安非他酮治疗在降低操作性行为速率的剂量范围内没有改变对甲基苯丙胺的选择。总体而言，安非他酮和利培酮的这些阴性结果与先前的人体实验室和临床试验一致，并支持这种临床前甲基苯丙胺与食物选择模型的潜在有效性。
