The effects of postnatal alcohol exposure and galantamine on the context pre-exposure facilitation effect and acetylcholine efflux using in vivo microdialysis.
The effects of postnatal alcohol exposure and galantamine on the context pre-exposure facilitation effect and acetylcholine efflux using in vivo microdialysis.
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DOI：
10.1016/j.alcohol.2015.01.010
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发表时间：
2015-05
期刊：
影响因子：
2.3
通讯作者：
Kelly, Sandra J.
中科院分区：
文献类型：
--
作者：
Perkins, Amy E.;Fadel, Jim R.;Kelly, Sandra J.
关键词：
胎儿酒精谱系障碍(FASD)影响2-5%的儿童。FASD已被证明会对大脑的多个区域造成损害，但对海马体的损害可能特别可以解释学习和记忆方面的缺陷，这是FASD的特征症状。乙酰胆碱神经递质系统是海马体的主要输入，也可能是发育中酒精暴露的目标。酒精(3.0g/kg/d)灌胃给发育期雄性大鼠仔鼠(出生后第2~10天；乙醇处理组[ET])，对照组给予假插管(IC)或不给予任何处理(NC)。实验1采用体内微透析法测定青少年(PD 32~35)的乙酰胆碱外流。在微透析过程中，检测高K+/Ca~(2+)ACSF溶液(PD 32-33)和急性加兰他明(乙酰胆碱酯酶[AChE]抑制剂)(2.0 mg/kg；PD 34-35)对乙酰胆碱外流的影响。酒精暴露的动物在基线时的乙酰胆碱外排没有差别。然而，与未治疗的对照组相比，酒精暴露的动物K+/Ca~(2+)诱导的乙酰胆碱外流减少，而与两个对照组相比，加兰他明的乙酰胆碱反应增强。实验2测试了慢性给予加兰他明(2.0 mg/kg；PD 11-30)是否可以在暴露前促进效应(CPFE；PD 30-32)的背景下减轻酒精诱导的学习障碍。慢性加兰他明和出生后酒精暴露都不会影响CPFE任务的表现。免疫组织化学方法检测胆碱乙酰转移酶(ChAT；内侧隔)、囊泡型乙酰胆碱转运体(VAChT；腹侧CA1)和α7烟碱型乙酰胆碱受体(α7nAChR；腹侧CA1)的表达。1)或慢性加兰他明和行为测试(Exp.2)。无论是酒精暴露还是行为测试都没有显著改变海马腹侧CA1区Vacht或α7nAChRs的密度。在表现出情境-休克关联的ET动物中，ChAT+细胞的平均数量增加；在学习了情境-休克关联的IC和NC动物中，或者在不需要学习的对照任务中的任何动物中，都没有变化。综上所述，这些结果表明，在酒精暴露的动物中，在药物操作(如加兰他明)的条件下，海马乙酰胆碱系统受到显著破坏。此外，在酒精暴露的动物中，Chat被上调，这些动物学会了将上下文和震惊联系起来，这可能解释了它们执行这一任务的能力。发育期酒精暴露可能通过胆碱能机制扰乱青春期的学习和记忆。
Fetal alcohol spectrum disorders (FASD) affect 2–5% of children. FASD have been shown to cause damage to multiple brain regions, but damage to the hippocampus specifically may explain deficits in learning and memory that are hallmark symptoms of FASD. The acetylcholine neurotransmitter system is a major input to the hippocampus and is a possible target of developmental alcohol exposure. Alcohol (3.0 g/kg/day) was administered via intragastric intubation to developing male rat pups (postnatal day [PD] 2–10; ethanol-treated [ET]), with controls receiving a sham intubation (IC) or no treatment (NC). In Experiment 1, in vivo microdialysis was used to measure acetylcholine efflux in adolescents (PD 32–35). During microdialysis, the effects of a high K+/Ca2+ aCSF solution (PD 32–33) and an acute galantamine (acetylcholinesterase [AChE] inhibitor) injection (2.0 mg/kg; PD 34–35) on acetylcholine efflux were measured. Alcohol-exposed animals did not differ in acetylcholine efflux at baseline. However, alcohol-exposed animals had a decrease in K+/Ca2+-induced acetylcholine efflux compared to non-treated controls, and an enhanced acetylcholine response to galantamine compared to both control groups. Experiment 2 tested whether chronic administration of galantamine (2.0 mg/kg; PD 11–30) could attenuate alcohol-induced learning deficits in the context pre-exposure facilitation effect (CPFE; PD 30–32). Neither chronic galantamine nor postnatal alcohol exposure influenced performance in the CPFE task. Immunohistochemistry was used to measure expression of choline acetyltransferase (ChAT; medial septum), vesicular acetylcholine transporter (vAChT; ventral CA1), and the alpha7 nicotinic acetylcholine receptor (α7 nAChR; ventral CA1) following microdialysis (Exp. 1) or chronic galantamine and behavioral testing (Exp. 2). Neither alcohol exposure nor behavioral testing significantly altered the density of vAChT or α7 nAChRs in the ventral CA1 region of the hippocampus. The average number of ChAT+ cells was increased in the ET animals that displayed the context-shock association; there were no changes in the IC and NC animals that learned the context-shock association or in any of the animals that were in the control task that entailed no learning. Taken together, these results indicate that the hippocampal acetylcholine system is significantly disrupted under conditions of pharmacological manipulations (e.g., galantamine) in alcohol-exposed animals. Furthermore, ChAT was up-regulated in alcohol-exposed animals that learned to associate the context and shock, which may account for their ability to perform this task. Developmental alcohol exposure may disrupt learning and memory in adolescence via a cholinergic mechanism.
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