López-Patiño Marcos A, Yu Lili, Cabral Howard, Zhdanova Irina V
Department of Anatomy and Neurobiology, School of Medicine, Boston University, 715 Albany Street, Boston, MA 02118, USA.
Physiol Behav. 2008 Jan 28;93(1-2):160-71. doi: 10.1016/j.physbeh.2007.08.013. Epub 2007 Aug 25.
Continued usage of cocaine is determined by genetic, conditioned and homeostatic factors, while it is reinforced by drug-induced reward and the emotionally negative state of drug withdrawal, which includes anxiety. The molecular mechanisms of these long-term behavioral and physiological alterations have yet to be fully elucidated. Here we demonstrate that in zebrafish, a wide range of non-anesthetic cocaine doses, 0.015-15 muM, does not result in acute alterations in locomotor activity, in spite of the high brain cocaine levels induced (7-120 pg/microg protein). Conversely, cocaine withdrawal causes hyperactivity associated with stereotypy. The behavioral hyperactivity is progressively increased during the initial period of withdrawal (24-72 h) and is maintained for at least 5 days. Such effect of cocaine withdrawal is aggravated by environmental stimulation and attenuated in the home environment. Administration of cocaine (1.5 microM) or a non-sedative dose of diazepam (5 microM, immersion) acutely counteracts withdrawal-associated hyperactivity and stereotypy in zebrafish, with the magnitude of these effects positively correlating with the degree of prior increase in basal activity. Administration of an anxiogenic benzodiazepine inverse agonist, FG-7142, results in zebrafish behavior similar to that observed during cocaine withdrawal. Together, the results suggest that cocaine withdrawal produces long-lasting behavioral effects in zebrafish which are consistent with an anxiety-like state. Thus, zebrafish, a powerful model for the study of vertebrate genetics, could provide insights into the molecular mechanisms of drug withdrawal.
可卡因的持续使用由遗传、条件和稳态因素决定，而药物诱导的奖赏以及包括焦虑在内的药物戒断时的情绪消极状态会强化这种使用。这些长期行为和生理改变的分子机制尚未完全阐明。在此，我们证明，在斑马鱼中，尽管诱导出了较高的脑可卡因水平（7 - 120 pg/μg蛋白质），但0.015 - 15 μM的多种非麻醉剂量可卡因并不会导致运动活性的急性改变。相反，可卡因戒断会导致与刻板行为相关的多动。在戒断初期（24 - 72小时），行为多动会逐渐增加，并至少持续5天。可卡因戒断的这种效应会因环境刺激而加剧，在家庭环境中则会减弱。给予可卡因（1.5 μM）或非镇静剂量的地西泮（5 μM，浸泡）可急性抵消斑马鱼戒断相关的多动和刻板行为，这些效应的大小与基础活性先前增加的程度呈正相关。给予一种致焦虑的苯二氮䓬反向激动剂FG - 7142，会使斑马鱼产生类似于可卡因戒断时观察到的行为。总之，结果表明可卡因戒断在斑马鱼中产生了与焦虑样状态一致的持久行为效应。因此，斑马鱼作为研究脊椎动物遗传学的有力模型，可为药物戒断的分子机制提供见解。
