Hodges H, Allen Y, Sinden J, Mitchell S N, Arendt T, Lantos P L, Gray J A
Department of Psychology (MRC Brain, Behaviour and Psychiatry Research Group), London, U.K.
Behav Brain Res. 1991 Apr 18;43(1):7-28. doi: 10.1016/s0166-4328(05)80048-8.
Chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors; animals with high (above the median of 100 mg/100 ml) blood alcohol concentrations (BACs) during treatment were significantly more impaired than those with BACs below the median. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses which did not affect controls. These effects were more pronounced for working than reference memory, and not manifest with the peripherally acting antagonists hexamethonium and N-methylscopolamine. Transplants into cortex and hippocampus of cholinergic-rich basal forebrain (BF) and ventral mesencephalon (VM) foetal neural tissue improved radial maze performance of alcohol-treated rats to control level over a period of 9-12 weeks after grafting. Cholinergic-poor foetal hippocampal (HC) grafts were without effect. BF and VM, but not HC, grafts showed dense acetylcholinesterase (AChE) staining, tyrosine-hydroxylase staining was most pronounced in VM sections and dopamine-beta-hydroxylase staining was minimal in all grafts. Choline acetyltransferase (ChAT) activity was significantly reduced in cortex and hippocampus of alcohol-treated rats, except those given cholinergic-rich transplants. Alcohol treatment also significantly reduced AChE-positive cell counts in the nucleus basalis, medial septal and diagonal band brain areas, at the sources of the forebrain cholinergic projection system (FCPS). Cortical levels of noradrenaline were significantly reduced in all alcohol-treated rats, regardless of transplant, whereas cortical dopamine content was significantly elevated in all rats receiving transplants, regardless of behavioural effect, but not in alcohol-treated controls. Forebrain serotonin levels were not significantly altered by grafting or alcohol treatment. These results suggest that damage to the FCPS, as shown by reduced ChAT activity in target areas, and reduced AChE cell counts in projection areas, played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge, and cholinergic-rich transplants from two different sites in foetal brain elevated ChAT activity and restored cognitive function. In contrast alcohol- or graft-induced alterations in other transmitter systems did not correlate with the pattern of behavioural deficit and recovery.
慢性酒精（饮用水中20% v/v，持续28周）通过增加试验内工作记忆和长期参考记忆错误，损害了放射状迷宫空间任务和联想任务的习得；治疗期间血液酒精浓度（BAC）高（高于100 mg/100 ml中位数）的动物比BAC低于中位数的动物受损更严重。酒精处理的大鼠在用胆碱能激动剂（槟榔碱和尼古丁）治疗后以及用拮抗剂（东莨菪碱和美加明）低剂量阻断后，放射状迷宫表现有所改善，而这些剂量对对照组无影响。这些作用在工作记忆方面比参考记忆更明显，且外周作用的拮抗剂六甲铵和N-甲基东莨菪碱未表现出此作用。将富含胆碱能的基底前脑（BF）和腹侧中脑（VM）胎儿神经组织移植到皮层和海马，可使酒精处理大鼠的放射状迷宫表现移植后9至12周内恢复到对照水平。胆碱能缺乏的胎儿海马（HC）移植则无效果。BF和VM移植，但HC移植无此现象，显示出密集的乙酰胆碱酯酶（AChE）染色，酪氨酸羟化酶染色在VM切片中最明显，多巴胺-β-羟化酶染色在所有移植中最少。酒精处理大鼠的皮层和海马中胆碱乙酰转移酶（ChAT）活性显著降低，但接受富含胆碱能移植的大鼠除外。酒精处理还显著减少了前脑胆碱能投射系统（FCPS）来源的基底核、内侧隔区和斜角带脑区的AChE阳性细胞计数。所有酒精处理大鼠的皮层去甲肾上腺素水平均显著降低，无论是否移植，而所有接受移植的大鼠，无论行为效应如何，皮层多巴胺含量均显著升高，但酒精处理的对照组未升高。移植或酒精处理对前脑血清素水平无显著影响。这些结果表明，如目标区域ChAT活性降低和投射区域AChE细胞计数减少所示，FCPS受损在酒精处理大鼠表现出的放射状迷宫缺陷中起重要作用，因为这些动物对胆碱能药物激发敏感，且来自胎儿脑两个不同部位的富含胆碱能移植可提高ChAT活性并恢复认知功能。相比之下，酒精或移植引起的其他递质系统改变与行为缺陷和恢复模式无关。
