Burbassi Silvia, Cervo Luigi
Experimental Psychopharmacology, Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
Psychopharmacology (Berl). 2008 Jan;196(1):15-27. doi: 10.1007/s00213-007-0916-7. Epub 2007 Sep 27.
It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT2C receptor-dependent mechanism.
We investigated whether Ro 60-0175, a nonselective 5-HT2B-2C agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT2C receptor's role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT2C antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer.
Different groups of free-feeding rats were trained to associate discriminative stimuli (SDs) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld.
Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior.
These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT2C agonist in preventing cue-controlled cocaine-seeking and relapse.
有研究表明，芬氟拉明和氟西汀等间接激动剂诱导的5-羟色胺传递增加，通过5-HT2C受体依赖性机制减弱了线索诱发的大鼠可卡因觅求行为的恢复。
我们研究了非选择性5-HT2B-2C激动剂Ro 60-0175是否会影响线索诱发的可卡因觅求行为的恢复。我们通过研究其与选择性5-HT2C拮抗剂SB-242,084的相互作用，评估了5-HT2C受体在Ro 60-0175中的作用。该研究还探讨了Ro 60-0175是否会影响与蔗糖（一种高度可口的营养强化剂）相关的线索诱发的觅求行为。
将不同组的自由进食大鼠训练，使其在双杠杆操作箱中将辨别性刺激（SDs）与可卡因、蔗糖颗粒的可得性或无奖励联系起来。可卡因和蔗糖颗粒按照FR1强化程序可得，每次强化后会有20秒的超时，由活动杠杆上方的提示灯发出信号。在没有线索的情况下强化反应消退后，在恢复实验中重新引入与强化物相关的刺激，此时不给予强化物。
腹腔注射剂量为0.1至1mg/kg的Ro 60-0175剂量依赖性地减少了可卡因觅求行为，而1mg/kg对蔗糖颗粒没有这种作用。皮下注射1mg/kg的SB-242,084预处理完全阻止了对可卡因觅求行为的影响。
这些发现（前提是可以外推至戒除毒瘾的人类成瘾者）表明，选择性5-HT2C激动剂在预防线索控制的可卡因觅求及复发方面具有治疗潜力。
