School of Life Sciences (Mr Garcia, Mr Cotter, Mr Leslie, and Dr Neisewander), and Psychology Department (Dr Olive), Arizona State University, Tempe, Arizona.
Int J Neuropsychopharmacol. 2017 Aug 1;20(8):644-653. doi: 10.1093/ijnp/pyx025.
5-HT1B receptor agonists enhance cocaine intake during daily self-administration sessions but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1B receptor agonists produce similar abstinence-dependent effects on methamphetamine intake.
Male rats were trained to self-administer methamphetamine (0.1 mg/kg, i.v.) on low (fixed ratio 5 and variable ratio 5) and high (progressive ratio) effort schedules of reinforcement until intake was stable. Rats were then tested for the effects of the selective 5-HT1B receptor agonist, CP 94,253 (5.6 or 10 mg/kg), or the less selective but clinically available 5-HT1B/1D receptor agonist, zolmitriptan (10 mg/kg), on methamphetamine self-administration both before and after a 21-day forced abstinence period during which the rats remained in their home cages.
The inverted U-shaped, methamphetamine dose-response function for intake on the fixed ratio 5 schedule was shifted downward by CP 94,253 both before and after abstinence. The CP 94,253-induced decrease in methamphetamine intake was replicated in rats tested on a variable ratio 5 schedule, and the 5-HT1B receptor antagonist SB 224,289 (10 mg/kg) reversed this effect. CP 94,253 also attenuated methamphetamine intake on a progressive ratio schedule both pre- and postabstinence. Similarly, zolmitriptan attenuated methamphetamine intake on a variable ratio 5 schedule both pre- and postabstinence, and the latter effect was sustained after each of 2 more treatments given every 2 to 3 days prior to daily sessions.
Unlike the abstinence-dependent effect of 5-HT1B receptor agonists on cocaine intake reported previously, both CP 94,253 and zolmitriptan decreased methamphetamine intake regardless of abstinence. These findings suggest that 5-HT1B receptor agonists may have clinical efficacy for psychostimulant use disorders.
5-HT1B 受体激动剂可增强可卡因在每日自我给药期间的摄入量，但在长时间戒断后检测时会降低可卡因的摄入量。我们研究了 5-HT1B 受体激动剂是否对甲基苯丙胺的摄入量产生类似的戒断依赖性影响。
雄性大鼠接受训练，通过静脉注射（0.1mg/kg）自我给药甲基苯丙胺（低努力水平：固定比率 5 和可变比率 5；高努力水平：递增比率），直到摄入量稳定。然后，在为期 21 天的强制戒断期间，大鼠被置于其家中的笼子里，在此期间，检测选择性 5-HT1B 受体激动剂 CP 94,253（5.6 或 10mg/kg）或选择性较低但临床可用的 5-HT1B/1D 受体激动剂佐米曲坦（10mg/kg）对甲基苯丙胺自我给药的影响，分别在戒断前和戒断后进行。
CP 94,253 不仅在戒断前，而且在戒断后，都使甲基苯丙胺在固定比率 5 时间表上的摄入量呈倒 U 形、剂量依赖性下降。在接受可变比率 5 时间表测试的大鼠中，CP 94,253 引起的甲基苯丙胺摄入量减少得到了复制，而 5-HT1B 受体拮抗剂 SB 224,289（10mg/kg）则逆转了这一效应。CP 94,253 还在递增比率时间表上减轻了甲基苯丙胺的摄入量，无论是在戒断前还是戒断后。同样，佐米曲坦在可变比率 5 时间表上减轻了甲基苯丙胺的摄入量，无论是在戒断前还是戒断后，并且在每天一次的治疗前每 2 到 3 天给予 2 次以上的治疗后，这种效果仍持续存在。
与之前报道的 5-HT1B 受体激动剂对可卡因摄入量的戒断依赖性效应不同，CP 94,253 和佐米曲坦都降低了甲基苯丙胺的摄入量，无论是否戒断。这些发现表明，5-HT1B 受体激动剂可能对精神兴奋剂使用障碍具有临床疗效。
Zotero 插件
