Enduring effects of adolescent ketamine exposure on cocaine- and sucrose-induced reward in male and female C57BL/6 mice
Enduring effects of adolescent ketamine exposure on cocaine- and sucrose-induced reward in male and female C57BL/6 mice
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DOI：
10.1038/s41386-020-0654-7
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发表时间：
2020-03-12
影响因子：
7.6
通讯作者：
Iniguez, Sergio D.
中科院分区：
文献类型：
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作者：
Garcia-Carachure, Israel;Flores-Ramirez, Francisco J.;Iniguez, Sergio D.
氯胺酮对青少年难治性抑郁症显示出良好的抗抑郁功效。然而，接触氯胺酮的潜在持久后果尚未得到彻底评估。因此，我们通过三个独立的实验检查了青少年氯胺酮治疗是否会导致成年后蔗糖和可卡因的有益特性发生长期变化。在实验 1 中，青春期雄性和雌性 C57BL/6 小鼠连续 15 天（产后天 [PD] 35-49）接受氯胺酮 (20 mg/kg)。二十一天后（PD70；成年），我们通过两瓶选择设计检查了他们对蔗糖（1%）的行为反应，或使用条件位置偏好（CPP）测试检查了可卡因（0、5、10 mg/kg）的行为反应。我们发现，幼年氯胺酮预处理增加了雄性而非雌性成年小鼠对蔗糖和与可卡因配对的环境的偏好。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，没有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）时，即社交失败或替代失败压力范式——介导抑郁相关表型（以及氯胺酮抗抑郁药样反应）的程序，没有观察到这些措施的长期差异。总的来说，我们证明，在没有身体或心理压力的情况下，青少年接触氯胺酮会增加以后生活中对蔗糖和可卡因有益特性的偏好，并以性别和年龄特定的方式进行。因此，这项临床前工作使人们认识到与青少年接触氯胺酮相关的潜在长期行为后果。
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.