Randall Patrick A, Lee Christie A, Nunes Eric J, Yohn Samantha E, Nowak Victoria, Khan Bilal, Shah Priya, Pandit Saagar, Vemuri V Kiran, Makriyannis Alex, Baqi Younis, Müller Christa E, Correa Merce, Salamone John D
Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
PLoS One. 2014 Jun 17;9(6):e99320. doi: 10.1371/journal.pone.0099320. eCollection 2014.
Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.
行为激活是动机的一个基本特征，生物体经常根据强化价值和反应成本的评估做出与努力相关的决策。此外，患有重度抑郁症和其他疾病的人通常表现出无活力、精神运动迟缓、疲劳以及与努力相关的决策改变。测量基于努力的决策的任务可作为抑郁症动机症状的动物模型，本研究表征了囊泡单胺转运体（VMAT - 2）抑制剂丁苯那嗪与努力相关的作用。丁苯那嗪可在人类中诱发抑郁症状，并且还优先消耗多巴胺（DA）。使用同时进行的渐进比率（PROG）/常规喂食任务对大鼠进行评估，在该任务中，它们既可以按照PROG程序按压杠杆以获取偏爱的高碳水化合物食物，也可以接近并食用实验箱中随时可得的不太偏爱的实验室常规食物。先前的研究表明，DA拮抗剂氟哌啶醇会降低该任务中PROG的工作输出，但不会降低常规食物摄入量，这些效应与强化物贬值或食欲抑制药物的效应有很大不同。目前的研究表明，丁苯那嗪在PROG/常规程序中产生了与努力相关的反应转变，减少了杠杆按压次数、达到的最高比率以及反应所花费的时间，但没有减少常规食物摄入量。给予亚型选择性DA拮抗剂依考必利（D1）和艾替洛尔（D2）也产生了类似的效果，但大麻素CB1受体中性拮抗剂及假定的食欲抑制剂AM 4413没有产生类似效果，该药物同时抑制了杠杆按压和常规食物摄入量。腺苷A2A拮抗剂MSX - 3、抗抑郁药及儿茶酚胺摄取抑制剂安非他酮以及单胺氧化酶B抑制剂司来吉兰，均逆转了丁苯那嗪所诱发的损伤。这项研究证明了PROG/常规程序作为抑郁症患者中观察到的与努力相关缺陷的啮齿动物模型的潜在效用。
