Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
J Pharmacol Exp Ther. 2012 Sep;342(3):761-9. doi: 10.1124/jpet.112.195156. Epub 2012 Jun 8.
Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT(2C)R) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT(2C)R antagonists have not been evaluated in nonhuman primates. The present studies used operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT(2C)R antagonism on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT(2C)R antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (vehicle, 0.01-0.1 mg/kg) produced behavioral-stimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to self-administer intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (vehicle, 0.03-0.1 mg/kg) modulated cocaine-induced reinstatement of previously extinguished responding and maintained self-administration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT(2C)R-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile that is qualitatively similar to other psychostimulants, although its efficacy is modest compared with cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of some degree of abuse potential in humans.
5-羟色胺（5-HT）2C 受体（5-HT(2C)R）拮抗剂被认为是治疗各种情感障碍的潜在药物，但有证据表明，这些化合物会增强老鼠体内可卡因和相关精神兴奋剂的作用。然而，选择性 5-HT(2C)R 拮抗剂在非人类灵长类动物中的作用尚未得到评估。本研究使用操作性行为和体内微透析技术，评估 5-HT(2C)R 拮抗剂对松鼠猴可卡因行为和神经化学效应的影响。在接受刺激终止固定间隔训练的实验动物中，用高度选择性 5-HT(2C)R 拮抗剂 6-氯-2,3-二氢-5-甲基-N-[6-[(2-甲基-3-吡啶基)氧基]-3-吡啶基]-1H-吲哚-1-羧酸酰胺二盐酸盐（SB 242084）（载体，0.01-0.1mg/kg）预处理会产生单独的行为刺激作用，并以明显相加的方式与可卡因相互作用。在接受第二阶药物输送程序训练以自行静脉注射可卡因的猴子中，SB 242084（载体，0.03-0.1mg/kg）调节可卡因诱发的先前已消除反应的复燃，并在可卡因可用性被取代时维持自我给药行为。这些研究是首次在任何物种中评估 5-HT(2C)R 选择性拮抗剂的直接强化作用。最后，体内微透析研究显示，SB 242084（0.1mg/kg）预处理调节了清醒动物伏隔核而非尾状核内可卡因引起的多巴胺增加。总之，这些结果表明，SB 242084 表现出与其他精神兴奋剂相似的行为特征，尽管与可卡因相比，其疗效较为温和。与可卡因的相互作用以及可卡因替代物的自我给药表明，在人类中可能存在一定程度的滥用潜力。
