Roni Monzurul Amin, Rahman Shafiqur
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
Alcohol. 2017 Jun;61:63-70. doi: 10.1016/j.alcohol.2017.01.015. Epub 2017 May 26.
Evidence indicates that the brain nicotinic acetylcholine receptor (nAChRs) ligand lobeline reduces depression-like behaviors, ethanol drinking, and nicotine withdrawal-induced depression-like behaviors. The purpose of the present study was to determine the effects of lobeline on ethanol abstinence-induced depression-like behavior and associated neuroadaptive changes in mice. Adult C57BL/6J male mice were allowed to drink 10% ethanol for 4 weeks using a two-bottle choice procedure. Mice were tested after 24 h and 14 days of ethanol abstinence in a forced swim test (FST), a measure for depression-like behavior. Acute lobeline treatment (1 mg/kg) significantly reduced immobility time compared to controls after 24 h and 14 days of abstinence. In addition, abstinence from chronic ethanol exposure reduced serotonin levels in the hippocampus, which was reversed by acute lobeline treatment. Repeated lobeline treatment (1 mg/kg, once daily) for 14 days during ethanol abstinence also significantly reduced FST immobility in mice exposed to ethanol. Chronic ethanol exposure significantly reduced the number of 5-bromo 2'-deoxyuridine (BrdU)-positive cells in the dentate gyrus of the hippocampus, indicating decreased hippocampal cell proliferation. Abstinence from chronic ethanol exposure also decreased brain-derived neurotrophic factor (BDNF) in the dentate gyrus and CA3 region of the hippocampus. In contrast, repeated lobeline treatment significantly increased both BrdU- and BDNF-positive cells. Taken together, our results indicate that lobeline produced antidepressant-like effects, likely by targeting brain β2-containing nAChRs, serotonergic neurotransmission, and/or hippocampal cell proliferation. Therefore, lobeline may have therapeutic utility to treat alcohol abstinence-induced depression.
有证据表明，脑烟碱型乙酰胆碱受体（nAChRs）配体洛贝林可减轻抑郁样行为、乙醇摄入以及尼古丁戒断诱导的抑郁样行为。本研究的目的是确定洛贝林对小鼠乙醇戒断诱导的抑郁样行为及相关神经适应性变化的影响。成年C57BL/6J雄性小鼠通过双瓶选择程序饮用10%乙醇4周。在乙醇戒断24小时和14天后，通过强迫游泳试验（FST）对小鼠进行测试，该试验是一种抑郁样行为的测量方法。急性洛贝林治疗（1毫克/千克）与对照组相比，在戒断24小时和14天后显著减少了不动时间。此外，长期乙醇暴露后的戒断降低了海马体中的血清素水平，而急性洛贝林治疗可使其恢复。在乙醇戒断期间重复给予洛贝林治疗（1毫克/千克，每日一次）14天，也显著降低了暴露于乙醇的小鼠的FST不动时间。长期乙醇暴露显著减少了海马齿状回中5-溴-2'-脱氧尿苷（BrdU）阳性细胞的数量，表明海马细胞增殖减少。长期乙醇暴露后的戒断也降低了海马齿状回和CA3区域的脑源性神经营养因子（BDNF）。相反，重复给予洛贝林治疗显著增加了BrdU和BDNF阳性细胞。综上所述，我们的结果表明，洛贝林可能通过靶向含脑β2的nAChRs、血清素能神经传递和/或海马细胞增殖产生抗抑郁样作用。因此，洛贝林可能对治疗酒精戒断诱导的抑郁具有治疗作用。
