Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Neuroscience Research Building, 320 W. 15th Street, Suite 300B, Indianapolis, IN, 46202-2266, USA.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
Psychopharmacology (Berl). 2020 Sep;237(9):2601-2611. doi: 10.1007/s00213-020-05557-1. Epub 2020 Jun 30.
Binge-like alcohol consumption during adolescence associates with several deleterious consequences during adulthood including an increased risk for developing alcohol use disorder (AUD) and other addictions. Replicated preclinical data has indicated that adolescent exposure to binge-like levels of alcohol results in a reduction of choline acetyltransferase (ChAT) and an upregulation in the α7 nicotinic receptor (α7). From this information, we hypothesized that the α7 plays a critical role in mediating the effects of adolescent alcohol exposure.
Male and female P rats were injected with the α7 agonist AR-R17779 (AR) once during 6 time points between post-natal days (PND) 29-37. Separate groups were injected with the α7 negative allosteric modulator (NAM) dehydronorketamine (DHNK) 2 h before administration of 4 g/kg EtOH (14 total exposures) during PND 28-48. On PND 75, all rats were given access to water and ethanol (15 and 30%) for 6 consecutive weeks (acquisition). All rats were then deprived of EtOH for 2 weeks and then, alcohol was returned (relapse).
Administration of AR during adolescence significantly increased acquisition of alcohol consumption during adulthood and prolonged relapse drinking in P rats. In contrast, administration of DHNK prior to binge-like EtOH exposure during adolescence prevented the increase in alcohol consumption observed during acquisition of alcohol consumption and the enhancement of relapse drinking observed during adulthood.
The data indicate that α7 mediates the effects of alcohol during adolescence. The data also indicate that α7 NAMs are potential prophylactic agents to reduce the deleterious effects of adolescent alcohol abuse.
青春期的 binge-like 饮酒与成年后多种有害后果相关联，包括增加发展为酒精使用障碍（AUD）和其他成瘾的风险。经过复制的临床前数据表明，青春期暴露于 binge-like 水平的酒精会导致胆碱乙酰转移酶（ChAT）减少和α7 烟碱型乙酰胆碱受体（α7）上调。根据这些信息，我们假设α7 在介导青春期酒精暴露的影响中起关键作用。
雄性和雌性 P 大鼠在 PND 29-37 之间的 6 个时间点接受一次 α7 激动剂 AR-R17779（AR）注射。单独的组在 PND 28-48 期间接受 4 g/kg EtOH（共 14 次暴露）之前 2 小时接受 α7 负变构调节剂（NAM）脱氢去甲氯胺酮（DHNK）注射。在 PND 75 时，所有大鼠都有 6 周的时间接触水和乙醇（15%和 30%）（获得）。所有大鼠都被剥夺乙醇 2 周，然后再恢复乙醇（复发）。
青春期给予 AR 显著增加了成年期酒精摄入的获得，延长了 P 大鼠的复发饮酒。相比之下，在青春期 binge-like EtOH 暴露之前给予 DHNK 会防止在获得酒精摄入期间观察到的酒精摄入增加和在成年期间观察到的复发饮酒增强。
数据表明，α7 在青春期调节酒精的作用。数据还表明，α7 NAMs 是潜在的预防剂，可减少青春期酒精滥用的有害影响。
