Vannucchi M G, Scali C, Kopf S R, Pepeu G, Casamenti F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Neuroscience. 1997 Aug;79(3):837-46. doi: 10.1016/s0306-4522(97)00091-2.
Brain acetylcholine release and memory performance were investigated in young (three- to six-months) and old (20- to 24-months) rats. Acetylcholine release was measured in vivo in the cortex and hippocampus of freely-moving animals, under basal conditions and in the presence of the following muscarinic antagonists: scopolamine, (+/-)-5,11-dihydro-11-[[(2-[2-[(dipropylamino) methyl]-1-piperidinyl]ethyl) amino] carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepine-6-one (AFDX 384) and pirenzepine. The amount of acetylcholine released from the cortex and hippocampus of old rats was significantly reduced. In the presence of scopolamine and AFDX 384 but not of pirenzepine, the acetylcholine release was significantly higher in the old than the young rats, suggesting that changes in presynaptic M2/M4 muscarinic receptor function occur with ageing in the two brain regions. Cognitive capacities were evaluated using two different behavioural tasks: object recognition and passive avoidance response. Old rats were unable to discriminate between familiar and novel objects and had impaired performance in the passive avoidance test. AFDX 384 restored the performance in both tests. Furthermore, in young rats AFDX 384 reversed the impairment of both object recognition and passive avoidance response induced by scopolamine. The effect of AFDX 384 on acetylcholine release and behaviour in the old rats offers further support to a relationship between the age-related cholinergic hypofunction and cognitive impairment and indicates the blockade of presynaptic muscarinic receptors as a possible selective target for therapeutic strategies aimed at improving age-associated memory deficits.
研究了年轻（3至6个月）和老年（20至24个月）大鼠的脑乙酰胆碱释放及记忆表现。在自由活动动物的皮质和海马体中，于基础条件下以及在存在以下毒蕈碱拮抗剂的情况下，对乙酰胆碱释放进行体内测量：东莨菪碱、（±）-5,11-二氢-11-[[(2-[2-[(二丙基氨基)甲基]-1-哌啶基]乙基)氨基]羰基]-6H-吡啶并(2,3-b)(1,4)-苯并二氮杂卓-6-酮（AFDX 384）和哌仑西平。老年大鼠皮质和海马体释放的乙酰胆碱量显著减少。在存在东莨菪碱和AFDX 384但不存在哌仑西平的情况下，老年大鼠的乙酰胆碱释放显著高于年轻大鼠，这表明两个脑区随着衰老，突触前M2/M4毒蕈碱受体功能发生了变化。使用两种不同的行为任务评估认知能力：物体识别和被动回避反应。老年大鼠无法区分熟悉和新奇的物体，并且在被动回避测试中的表现受损。AFDX 384恢复了两项测试中的表现。此外，在年轻大鼠中，AFDX 384逆转了由东莨菪碱诱导的物体识别和被动回避反应的损伤。AFDX 384对老年大鼠乙酰胆碱释放和行为的影响进一步支持了与年龄相关的胆碱能功能减退和认知障碍之间的关系，并表明阻断突触前毒蕈碱受体是旨在改善与年龄相关的记忆缺陷的治疗策略的可能选择性靶点。
