Howell Leonard L, Wilcox Kristin M, Lindsey Kimberly P, Kimmel Heather L
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Neuropsychopharmacology. 2006 Mar;31(3):585-93. doi: 10.1038/sj.npp.1300828.
The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.
非典型抗精神病药物奥氮平的神经药理学特性表明它可能是一种治疗可卡因成瘾的有效药物。本研究采用静脉注射药物自身给药范式，在非人灵长类动物中获取关于奥氮平调节可卡因强化作用有效性的确切证据。将奥氮平的作用与抗精神病药物氟哌啶醇的作用进行直接比较。恒河猴（n = 7）接受训练，在二阶固定间隔600秒、固定比率20的给药方案下自身注射可卡因（0.03 - 0.3毫克/千克/注射）。实验时段包括五个连续的固定间隔，每个间隔后有1分钟的超时。在药物相互作用实验中，在每次实验前15分钟静脉注射单剂量的奥氮平（0.03 - 0.3毫克/千克）或氟哌啶醇（0.01 - 0.03毫克/千克），连续至少进行三次实验。在药物替代实验中，用不同剂量的奥氮平（0.01 - 0.1毫克/千克/注射）替代可卡因，直到反应稳定。奥氮平在预处理剂量下导致可卡因自身给药量呈剂量相关下降，这些剂量没有明显的行为效应表明有镇静作用。0.1毫克/千克的剂量使所有受试者的可卡因自身给药行为消失。相比之下，抑制可卡因自身给药的氟哌啶醇剂量会引起明显的镇静和僵住症。在一系列单位剂量范围内，奥氮平未能使自身给药行为维持在高于生理盐水消退水平之上。在另一组清醒恒河猴（n = 3）中进行的体内微透析实验证实了先前在啮齿动物中的报道，即奥氮平能有效增加腹侧纹状体中的细胞外多巴胺。显著抑制可卡因自身给药行为的奥氮平剂量使多巴胺增加至对照值的约190%。最后，用氟西汀预处理对奥氮平诱导的纹状体多巴胺增加没有系统性影响。结果表明，奥氮平在增强多巴胺释放但不维持药物自身给药的剂量下，能有效抑制非人灵长类动物的可卡因自身给药行为。
