Abstract：
Ketamine (KET), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid onset of antidepressant effects in Treatment-Resistant Depression patients and repeated infusions are required to sustain its antidepressant properties. However, KET is an addictive drug, and so more preclinical and clinical research is needed to assess the safety of recurring treatments in both sexes. Thus, the aim of this study was to investigate the reinforcing properties of various doses of KET (0-, 0.125-, 0.25-, 0.5 mg/kg/infusion) and assess KET\'s cue-induced reinstatement and neuronal activation in both sexes of Long Evans rats. Neuronal activation was assessed using the protein expression of the immediate early gene cFos in the nucleus accumbens (Nac), an important brain area implicated in reward, reinforcement and reinstatement to most drug-related cues. Our findings show that KET has reinforcing effects in both male and female rats, albeit exclusively at the highest two doses (0.25 and 0.5 mg/kg/infusion). Furthermore, we noted sex differences, particularly at the highest dose of ketamine, with female rats displaying a higher rate of self-administration. Interestingly, all groups that self-administered KET reinstated to drug-cues. Following drug cue-induced reinstatement test in rats exposed to KET (0.25 mg/kg/infusion) or saline, there was higher cFos protein expression in KET-treated animals compared to saline controls, and higher cFos expression in the core compared to the shell subregions of the Nac. As for reinstatement, there were no notable sex differences reported for cFos expression in the Nac. These findings reveal some sex and dose dependent effects in KET\'s reinforcing properties and that KET at all doses induced similar reinstatement in both sexes. This study also demonstrated that cues associated with ketamine induce comparable neuronal activation in the Nac of both male and female rats. This work warrants further research into the potential addictive properties of KET, especially when administered at lower doses which are now being used in the clinic for treating various psychopathologies.
摘要：
氯胺酮(KET),一种非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，在难治性抑郁症患者中具有迅速的抗抑郁作用，并且需要反复输注以维持其抗抑郁作用。然而,KET是一种上瘾的药物,因此，需要更多的临床前和临床研究来评估男女反复治疗的安全性。因此，本研究的目的是研究各种剂量的KET（0-，0.125-,0.25-，0.5mg/kg/输注），并评估LongEvans大鼠两性的KET提示诱导的恢复和神经元激活。使用伏隔核（Nac）中立即早期基因cfos的蛋白质表达评估神经元激活，一个与奖励有关的重要大脑区域，加强和恢复大多数与毒品有关的线索。我们的发现表明，KET对雄性和雌性大鼠都有增强作用，尽管仅在最高的两个剂量（0.25和0.5mg/kg/输注）。此外，我们注意到性别差异，特别是在最高剂量的氯胺酮，雌性大鼠表现出更高的自我给药率。..有趣的是,自我给药KET的所有组都恢复了药物提示。在暴露于KET（0.25mg/kg/输注）或生理盐水的大鼠中进行药物提示诱导的恢复试验后，与盐水对照相比，在KET处理的动物中cFos蛋白表达更高，与Nac的壳亚区相比，核心中的cFos表达更高。至于复职，在Nac中cFos表达没有明显的性别差异。这些发现揭示了KET的增强特性中的一些性别和剂量依赖性作用，并且所有剂量的KET在两种性别中均诱导了相似的恢复。这项研究还表明，与氯胺酮相关的线索在雄性和雌性大鼠的Nac中诱导可比的神经元激活。这项工作值得进一步研究KET的潜在成瘾特性，特别是在以较低剂量给药时，现在在临床上用于治疗各种精神病理学。
