Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances. In parallel, we examined the impact of ketamine administration on long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST), a region implicated in affective disturbances. We administered ketamine (3 mg/kg i.p.) to female C57BL/6J mice with a history of chronic ethanol drinking at either the onset, two, or 6 days- post-abstinence and observed its impact on affective behavior in the elevated plus maze (EPM), the Novelty Suppressed Feeding Test (NSFT), and the Forced Swim Test (FST). In addition, we assessed BNST synaptic plasticity with field potential electrophysiology two to 3 weeks into abstinence. We found that early abstinence was associated with disrupted behavior on the EPM. Ketamine administered at the onset of forced abstinence prevented both the deficit in early EPM behavior, and the delayed deficits in NSFT and FST. However, ketamine administered either two or 6 days post-abstinence failed to prevent the abstinence-induced affective disturbances. To begin to explore potential alterations in neural circuit activity that accompanies these actions of ketamine, we assessed the impact of ketamine administration at the onset of forced abstinence and measured LTP induction in the BNST. We find that early ketamine administration persistently increased the capacity for LTP within the BNST. These findings suggest a critical period at the onset of forced abstinence in which ketamine inoculation can prevent the development of affective disturbances, in part by enhancing plasticity within the BNST.

中文翻译：

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在强制戒酒后的关键时期服用氯胺酮可抑制时间依赖性情感障碍的发展。

长期禁饮两次选择乙醇的禁欲在雌性C57BL / 6J小鼠中产生了负面的情感状态。我们以前曾报道过，在测试前30分钟给予氯胺酮可迅速逆转这种破坏行为。在这里，我们评估了氯胺酮是否可以用作对抗依赖欲的情感障碍发展的孕育剂。同时，我们研究了氯胺酮给药对终末纹状体床核（BNST）（涉及情感障碍的区域）中长期增强作用（LTP）的影响。我们向雌性C57BL / 6J小鼠（在禁欲发作的开始，两天或六天后有慢性乙醇饮酒史）给予氯胺酮（3 mg / kg ip），并观察其对高架迷宫中情感行为的影响（ EPM），新奇抑制喂食测试（NSFT）和强迫游泳测试（FST）。此外，我们在禁欲期2至3周时用场电位电生理学评估了BNST突触可塑性。我们发现，早期节制与EPM行为受阻有关。在强迫戒断发作时服用氯胺酮既可以预防早期EPM行为的缺陷，也可以预防NSFT和FST的延迟缺陷。但是，戒酒后两天或六天服用氯胺酮无法阻止戒酒所致的情感障碍。为了开始探索氯胺酮伴随这些作用的神经回路活动的潜在变化，我们评估了强迫戒断开始时氯胺酮给药的影响，并测量了BNST中的LTP诱导。我们发现，早期的氯胺酮管理持续增加了BNST内LTP的能力。这些发现表明在强迫戒断发作的关键时期，氯胺酮的接种可以防止情感障碍的发展，部分是通过增强BNST内的可塑性来实现的。