Getachew Bruk, Tizabi Yousef
Department of Pharmacology, Howard University College of Medicine, Washington, DC, USA.
J Drug Alcohol Res. 2019;8. doi: 10.4303/jdar/236069.
The co-morbidity between heavy drinking and depression can negatively influence successful cessation of alcohol use. Since ketamine, a glutamatergic NMDA receptor antagonist, has shown promise as a quick-acting antidepressant, we studied its effects specifically on alcohol withdrawal-induced depression. We also evaluated the effects of NBQX an AMPA/kainate receptor antagonist, because some of the effects of ketamine are proposed to be indirectly mediated through these receptors. Adult male Wistar rats were exposed daily to ethanol via inhalation chambers 4 h/day for 7 days (blood alcohol concentration=160 mg%), followed by daily intraperitoneal injections of ketamine (2.5 mg/kg), NBQX (5mg/kg), alone or in combination. Eighteen hours later, open field locomotor activity (OFLA) followed by forced swim test (FST) were performed. The animals were sacrificed 2 h later for evaluation of brain-derived neurotrophic factor (BDNF) in the hippocampus. Alcohol withdrawal did not affect OFLA, but caused an increase in immobility in FST, suggesting induction of "depressive-like" helplessness. Both ketamine and NBQX normalized the swimming score in FST. The combination of the two drugs, however, cancelled each other's effect. Parallel to these behavioral observations, both ketamine and NBQX normalized the reduction in hippocampal BDNF caused by alcohol withdrawal. Here also, the combination of the two drugs cancelled each other's effect. These results suggest that either NMDA or AMPA/kainate receptor antagonists, acting at least partially through hippocampal BDNF, may be of therapeutic potential in alcohol use disorder.
重度饮酒与抑郁症之间的共病情况会对成功戒酒产生负面影响。由于氯胺酮（一种谷氨酸能N-甲基-D-天冬氨酸受体拮抗剂）已显示出作为速效抗抑郁药的前景，我们专门研究了其对酒精戒断所致抑郁症的影响。我们还评估了AMPA/海人酸受体拮抗剂NBQX的作用，因为有人提出氯胺酮的某些作用是通过这些受体间接介导的。成年雄性Wistar大鼠每天通过吸入室暴露于乙醇中，每天4小时，持续7天（血液酒精浓度 = 160毫克%），随后每天腹腔注射氯胺酮（2.5毫克/千克）、NBQX（5毫克/千克），单独使用或联合使用。18小时后，进行旷场运动活动（OFLA），然后进行强迫游泳试验（FST）。2小时后处死动物，以评估海马体中的脑源性神经营养因子（BDNF）。酒精戒断不影响OFLA，但导致FST中不动时间增加，提示诱导出“抑郁样”无助状态。氯胺酮和NBQX均使FST中的游泳评分恢复正常。然而，两种药物联合使用时相互抵消了对方的作用。与这些行为观察结果平行的是，氯胺酮和NBQX均使酒精戒断引起的海马体BDNF减少恢复正常。同样，两种药物联合使用时也相互抵消了对方的作用。这些结果表明，NMDA或AMPA/海人酸受体拮抗剂，至少部分通过海马体BDNF起作用，可能对酒精使用障碍具有治疗潜力。
