The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues
The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues
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DOI：
10.1038/sj.npp.1301509
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发表时间：
2008-05-01
影响因子：
7.6
通讯作者：
Higgins, Guy A.
中科院分区：
文献类型：
--
作者：
Fletcher, Paul J.;Rizos, Zoe;Higgins, Guy A.
之前，我们发现5-HT2受体激动剂Ro60-0175可以减少可卡因的自我给药，以及在药物寻求行为消失后可卡因恢复反应的能力。本实验通过确定Ro60-0175对自我给药的影响是否在重复治疗中持续，以及Ro60-0175是否改变了由育亨宾药理学应激源诱导的恢复，或由自我给药发生的环境，进一步扩展了这些发现。在实验1中，Ro60-0175 （1 mg/kg, s.c）减少了可卡因（0.25 mg/输注）的自我给药，并通过渐进比例计划维持。这种减少持续了每天八次注射。在实验2中，大鼠按照FRI计划，每天2小时自我给药可卡因，持续15天。消退后，育亨宾（1 mg/kg，口服）恢复了应答，并且Ro60-0175 （0.3-3 mg/kg, s.c）剂量依赖性地降低了这种效应。在实验3中，大鼠被训练在不同的环境背景下按照FR1时间表对可卡因作出反应(a)；然后在不同的语境中消失(B)。恢复测试发生在情境A或情境b中。只有当大鼠在最初的自我给药情境(A)中进行测试时，反应才会恢复。Ro60-0175剂量依赖性地减少了这种恢复。Ro60-0175的所有作用均被5-HT2C受体拮抗剂SB242084阻断。因此，Ro60-0175通过5-HT2C受体起作用，减少了由压力源和药物相关线索引发的可卡因自我给药和可卡因寻求。Ro60-0175的效果在8天的试验期内不表现出耐受性。这些结果表明，选择性5-HT2C受体激动剂可能是一种有效的药物滥用治疗策略。
Previously, we showed that the 5-HT2 Creceptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment I, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self- administered cocaine in daily 2 h sessions for 15 days on a FRI chedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B. Responding was reinstated only when rats were tested in the original self- administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT2C receptors, reduces cocaine self- administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.