Nadia Henkous, Fabienne Martins, Pierard Christophe, Nicole Mons, Daniel Beracochea
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA), Université de Bordeaux, CNRS UMR 5287, Pessac, France.
Institut de Recherche Biomédicale des Armées (IRBA), Place Général Valérie André, Brétigny-sur-Orge, France.
Front Psychiatry. 2022 May 24;13:799225. doi: 10.3389/fpsyt.2022.799225. eCollection 2022.
Our study aims at comparing in C57/Bl male mice, the impact of repeated injections of baclofen (an agonist of GABAB receptor) or diazepam (a benzodiazepine acting through a positive allosteric modulation of GABAA receptor) administered during the alcohol-withdrawal period on hippocampus-dependent memory impairments and brain regional glucocorticoid dysfunction after a short (1-week) or a long (4-week) abstinence. Hence, mice were submitted to a 6-month alcohol consumption (12%v/v) and were progressively withdrawn to water. Then, after a 1- or 4-weeks abstinence, they were submitted to a contextual memory task followed by measurements of corticosterone concentrations in the dorsal hippocampus (dHPC), the ventral hippocampus (vHPC) and the prefrontal cortex (PFC). Results showed that 1- and 4-week withdrawn mice exhibited a severe memory deficit and a significant abnormal rise of the test-induced increase of corticosterone (TICC) in the dHPC, as compared to water-controls or to mice still under alcohol consumption. Repeated daily systemic administrations of decreasing doses of diazepam (ranged from 0.5 to 0.12 mg/kg) or baclofen (ranged from 1.5 to 0.37 mg/kg) during the last 15 days of the withdrawal period, normalized both memory and TICC scores in the dHPC in 1-week withdrawn animals; in contrast, only baclofen-withdrawn mice showed both normal memory performance and TICC scores in the dHPC after a 4-week withdrawal period. In conclusion, the memory improvement observed in 4-week withdrawn mice administered with baclofen stem from the protracted normalization of glucocorticoid activity in the dHPC, a phenomenon encountered only transitorily in diazepam-treated withdrawn mice.
我们的研究旨在比较在C57/Bl雄性小鼠中，在戒酒期重复注射巴氯芬（一种GABAB受体激动剂）或地西泮（一种通过对GABAA受体进行正变构调节起作用的苯二氮䓬类药物），对短期（1周）或长期（4周）戒酒后脑海马体依赖性记忆障碍和脑区糖皮质激素功能障碍的影响。因此，将小鼠进行为期6个月的酒精摄入（12%v/v），并逐渐戒断至饮水。然后，在戒断1周或4周后，让它们接受情境记忆任务，随后测量背侧海马体（dHPC）、腹侧海马体（vHPC）和前额叶皮层（PFC）中的皮质酮浓度。结果显示，与饮水对照小鼠或仍在摄入酒精的小鼠相比，戒断1周和4周的小鼠表现出严重的记忆缺陷，且dHPC中应激诱导的皮质酮增加（TICC）显著异常升高。在戒断期的最后15天，每天重复对小鼠进行递减剂量的地西泮（范围为0.5至0.12 mg/kg）或巴氯芬（范围为1.5至0.37 mg/kg）的全身给药，可使戒断1周的动物dHPC中的记忆和TICC评分恢复正常；相比之下，在4周戒断期后，只有接受巴氯芬治疗的小鼠在dHPC中表现出正常的记忆表现和TICC评分。总之，在接受巴氯芬治疗的4周戒断小鼠中观察到的记忆改善源于dHPC中糖皮质激素活性的长期正常化，这一现象在地西泮治疗的戒断小鼠中只是短暂出现。
