Ketamine has shown promising antidepressant efficacy for adolescent treatment-resistant depression. However, the potential enduring consequences of ketamine exposure have not been thoroughly evaluated. Thus, we examined if juvenile ketamine treatment results in long-lasting changes for the rewarding properties of sucrose and cocaine in adulthood, across three separate experiments. In Experiment 1, adolescent male and female C57BL/6 mice received ketamine (20 mg/kg) for 15 consecutive days (Postnatal Day [PD] 35-49). Twenty-one days later (PD70; adulthood) we examined their behavioral responsivity to sucrose (1%) on a two-bottle choice design, or cocaine (0, 5, 10 mg/kg) using the conditioned place preference (CPP) test. We found that juvenile ketamine-pretreatment increased preference for sucrose and environments paired with cocaine in male, but not female, adult mice. This long-term outcome was not observed when male and female mice received ketamine as adults (PD70-84) and tested for sucrose and cocaine preference 21-days later (Experiment 2). Similarly, in Experiment 3, no long-lasting differences in these measures were observed when adolescent male mice were exposed to concomitant ketamine and social stressors (PD35-44), namely the social defeat or vicarious defeat stress paradigms-procedures that mediated a depression-related phenotype (along with a ketamine antidepressant-like response). Collectively, we demonstrate that in the absence of physical or psychological stress, adolescent ketamine exposure increases later life preference for the rewarding properties of sucrose and cocaine in a sex- and age-specific manner. As such, this preclinical work provides awareness for the potential long-term behavioral consequences associated with juvenile ketamine exposure.

中文翻译：

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青少年氯胺酮暴露对雄性和雌性 C57BL/6 小鼠可卡因和蔗糖诱导的奖励的持久影响。

氯胺酮已显示出对青少年难治性抑郁症的抗抑郁疗效。然而，尚未对氯胺酮暴露的潜在持久后果进行彻底评估。因此，我们在三个独立的实验中检查了青少年氯胺酮治疗是否会导致成年期蔗糖和可卡因有益特性的长期变化。在实验 1 中，青春期雄性和雌性 C57BL/6 小鼠连续 15 天（产后日 [PD] 35-49）接受氯胺酮 (20 毫克/千克)。21 天后（PD70；成年），我们使用条件位置偏好 (CPP) 测试检查了他们在两瓶选择设计中对蔗糖 (1%) 或可卡因 (0、5、10 毫克/公斤) 的行为反应性. 我们发现幼年氯胺酮预处理增加了雄性对蔗糖和环境与可卡因配对的偏好，但不是雌性成年小鼠。当雄性和雌性小鼠成年后接受氯胺酮 (PD70-84) 并在 21 天后测试蔗糖和可卡因偏好时，未观察到这种长期结果（实验 2）。同样，在实验 3 中，当青春期雄性小鼠同时暴露于氯胺酮和社会压力源 (PD35-44)，即社会失败或替代失败压力范式 - 介导抑郁症的程序时，未观察到这些措施的长期差异 -相关表型（以及氯胺酮抗抑郁样反应）。总的来说，我们证明，在没有身体或心理压力的情况下，青少年氯胺酮暴露会以性别和年龄特定的方式增加晚年对蔗糖和可卡因有益特性的偏好。像这样，