POSTSYNAPTIC ALPHA-2 RECEPTOR STIMULATION IMPROVES MEMORY IN AGED MONKEYS - INDIRECT EFFECTS OF YOHIMBINE VERSUS DIRECT EFFECTS OF CLONIDINE

Very low doses (0.00001 mg/kg) of the alpha-2 adrenergic antagonist, yohimbine, improved working memory performance in a subset of aged monkeys. Improvement appeared to result from increased norepinephrine (NE) release onto postsynaptic alpha-2 adrenoceptors, as the response was blocked by the ''postsynaptic'' alpha-2 antagonist, SKF104078. Cognitive-enhancing effects of low dose yohimbine treatment may depend on aged animals retaining an intact, endogenous NE system. In contrast to yohimbine, the alpha-2 agonist, clonidine, has improved working memory in air aged animals examined. In the present study, clonidine's beneficial effects were also blocked by the postsynaptic antagonists SKF104078 and SKF104856, suggesting that clonidine acts by directly stimulating postsynaptic alpha-2 adrenoceptors. Beneficial doses of clonidine (0.01 mg/kg) and yohimbine (0.00001 mg/kg) were combined to see if they would produce additive effects on memory enhancement. This strategy was successful in young monkeys with intact NE systems but was not effective in the aged monkeys. These findings demonstrate that drugs that indirectly stimulate postsynaptic alpha-2 receptors by increasing NE release are not as reliable in aged monkeys as directly acting agonists that can replace NE at postsynaptic alpha-2 receptors.

Effect of huperzine A on working memory in reserpine- or yohimbine-treated monkeys

The effect of huperzine A, a reversible and selective acetylcholinesterase inhibitor, on reserpine- or yohimbine-induced spatial working memory deficits in monkeys has been examined using the delayed response task that depends on the integrity of prefront

Extract of Ginkgo biloba leaves reverses yohimbine-induced spatial working memory deficit in rats

Extract of Ginkgo biloba is used to alleviate age-related decline in cognitive function, which may be associated with the loss of catecholamines in the prefrontal cortex. The purpose of this study was to verify whether alpha-2 adrenergic activity is involved in the facilitative effects of extract of Ginkgo biloba on prefrontal cognitive function. Male Wistar rats were trained to reach criterion in the delayed alternation task (0, 25, and 50-s delay intervals). A pilot study found that 3 or 4 mg/kg of yohimbine (intraperitoneal) reduced the choice accuracy of the delayed alternation task in a dose and delay-dependent manner, without influencing motor ability or perseverative behaviour. Acute oral pre-treatment with doses of 50, 100, or 200 mg/kg (but not 25 mg/kg) of extract of Ginkgo biloba prevented the reduction in choice accuracy induced by 4 mg/kg yohimbine. These data suggest that the prefrontal cognition-enhancing effects of extract of Ginkgo biloba are related to its actions on alpha-2-adrenoceptors.

猴前额叶皮层内注射α_2肾上腺素能拮抗剂损害延缓GO／NO－GO任务操作

训练两只猕猴进行延缓ＧＯ／ＮＯ－ＧＯ任务操作。猴坐在定制的猴椅中，正前方４０ｃｍ处放着计算机显示器。显示器下方装有一压板。猴按压板０．５ｓ后，显示器屏幕右下角或左下角出现一白色方块信号（１．５ｃｍ×１．５ｃｍ），持续０．５ｓ。这一信号为暗示信号。暗示信号消失后，延缓０．０－４．０ｓ，然后在显示器屏幕的下方正中处出现一红色方块信号（１．５ｃｍ×１．５ｃｍ）。这一信号为反应信号。如果暗示信号出现在右边，则要求猴在０．８ｓ内放开一直按着的压板（ＧＯ反应）；如果暗示信号出现在左边，则要求猴继续按住压板１．２ｓ（ＮＯ－ＧＯ反应）。正确操作后，猴得到一滴水的奖励。在这一行为任务中，延缓期内的短时工作记忆是“非空间表象”（ｎｏｎ－ｓｐａｔｉａｌｌｙｒｅｐｒｅｓｅｎｔａｔｉｏａｌ）短时工作记忆。前额叶皮层背外侧部（Ｗａｌｋｅｔ４６区、９区）内注射α２受体拮抗剂ｙｏｈｉｍｂｉｎｅ（１０μｇ／２μｌ）使猴的任务操作正确率下降。延缓期越长，下降的幅度越大。注射Ｙｏｈｉｍｂｉｎｅ后，猴的操作错误率升高主要表现在“交叉”反应率升高，即应该作ＧＯ反应时作ＮＯ－ＧＯ反应，反之亦然。注射α１受体桔抗剂Ｐｒａｚｏｓｉｎ（１０μｇ／２μｌ）或