Department of Biomedical Sciences, College of Medicine, Program in Neuroscience, Florida State University, Tallahassee, FL, USA.
Department of Biomedical Sciences, College of Medicine, Program in Neuroscience, Florida State University, Tallahassee, FL, USA.
Neuropharmacology. 2024 Sep 1;255:110008. doi: 10.1016/j.neuropharm.2024.110008. Epub 2024 May 24.
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.
氯胺酮（KET）是非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，在治疗抵抗性抑郁症患者中具有快速抗抑郁作用，需要重复输注以维持其抗抑郁特性。然而，KET 是一种成瘾性药物，因此需要更多的临床前和临床研究来评估两性中反复治疗的安全性。因此，本研究旨在研究不同剂量 KET（0-、0.125-、0.25-、0.5mg/kg/输注）的强化作用，并评估 KET 在长爪沙鼠两性中的线索诱导复吸和神经元激活。通过核 Accumbens（Nac）中即时早期基因 cFos 的蛋白表达评估神经元激活，Nac 是与大多数与药物相关线索的奖赏、强化和复吸有关的重要脑区。我们的研究结果表明，KET 在雄性和雌性大鼠中均具有强化作用，尽管仅在最高两种剂量（0.25 和 0.5mg/kg/输注）时才有作用。此外，我们还注意到性别差异，尤其是在最高剂量的氯胺酮时，雌性大鼠表现出自发性更高。有趣的是，所有自我管理 KET 的群体都对药物线索进行了复吸。在暴露于 KET（0.25mg/kg/输注）或生理盐水的大鼠进行药物线索诱导复吸试验后，与生理盐水对照组相比，KET 治疗动物的 cFos 蛋白表达更高，而 Nac 的核心区域比壳区的 cFos 表达更高。至于复吸，Nac 中的 cFos 表达在两性之间没有明显的性别差异。这些发现揭示了 KET 的强化特性中的一些性别和剂量依赖性影响，并且所有剂量的 KET 在两性中均引起相似的复吸。本研究还表明，与 KET 相关的线索在雄性和雌性大鼠的 Nac 中诱导相似的神经元激活。这项工作需要进一步研究 KET 的潜在成瘾性，特别是在现在用于治疗各种精神病理学的较低剂量下使用时。
