Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, 13902, USA.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA.
Neuropsychopharmacology. 2019 Oct;44(11):1886-1895. doi: 10.1038/s41386-019-0415-7. Epub 2019 May 16.
Alcohol use typically begins in adolescence, increasing the likelihood of adult mental disorders such as anxiety. However, the cellular mechanisms underlying the consequences of adolescent alcohol exposure as well as the behavioral consequences remain poorly understood. We examined the effects of adolescent or adult chronic intermittent ethanol (CIE) exposure on intrinsic excitability of striatal medium-sized spiny neurons (MSNs) and anxiety levels. Rats underwent one of the following procedures: (1) light-dark transition (LDT) and open-field (OF) tests to evaluate anxiety levels and general locomotion; (2) whole-cell patch clamp recordings and biocytin labeling to assess excitability of striatal MSNs, as well as morphological properties; and (3) western blot immunostaining to determine small conductance (SK) calcium-activated potassium channel protein levels. Three weeks, but not 2 days, after CIE treatment, adolescent CIE-treated rats showed shorter crossover latency from the light to dark side in the LDT test and higher MSN excitability in the nucleus accumbens shell (NAcS). Furthermore, the amplitude of the medium afterhyperpolarization (mAHP), mediated by SK channels, and SK3 protein levels in the NAcS decreased concomitantly. Finally, increased anxiety levels, increased excitability, and decreased amplitude of mAHP of NAcS MSNs were reversed by SK channel activator 1-EBIO and mimicked by the SK channel blocker apamin. Thus, adolescent ethanol exposure increases adult anxiety-like behavior by downregulating SK channel function and protein expression, which leads to an increase of intrinsic excitability in NAcS MSNs. SK channels in the NAcS may serve as a target to treat adolescent alcohol binge exposure-induced mental disorders, such as anxiety in adulthood.
酒精使用通常始于青少年时期，增加了成年后出现焦虑等精神障碍的可能性。然而，青少年期酒精暴露的后果以及行为后果的细胞机制仍知之甚少。我们研究了青少年或成年慢性间歇性乙醇（CIE）暴露对纹状体中型多棘神经元（MSN）固有兴奋性和焦虑水平的影响。大鼠接受以下程序之一：（1）明暗过渡（LDT）和旷场（OF）测试，以评估焦虑水平和一般运动；（2）全细胞膜片钳记录和生物胞素标记，以评估纹状体 MSN 的兴奋性和形态特性；（3）western blot 免疫染色，以确定小电导（SK）钙激活钾通道蛋白水平。在 CIE 治疗后 3 周而不是 2 天，青少年 CIE 处理组大鼠在 LDT 测试中从亮侧到暗侧的交叉潜伏期更短，伏隔核壳（NAcS）中的 MSN 兴奋性更高。此外，由 SK 通道介导的中后超极化（mAHP）的幅度以及 NAcS 中的 SK3 蛋白水平同时降低。最后，通过 SK 通道激活剂 1-EBIO 逆转了 NAcS MSN 的焦虑水平升高、兴奋性升高和 mAHP 幅度降低，而 SK 通道阻断剂 apamin 则模拟了这种现象。因此，青少年期乙醇暴露通过下调 SK 通道功能和蛋白表达增加成年期焦虑样行为，从而导致 NAcS MSN 固有兴奋性增加。NAcS 中的 SK 通道可能作为治疗青少年酒精 binge 暴露引起的精神障碍（如成年期焦虑）的靶点。
