Arnsten A F, Cai J X, Goldman-Rakic P S
Section of Neuroanatomy, Yale Medical School, New Haven, Connecticut 06510.
J Neurosci. 1988 Nov;8(11):4287-98. doi: 10.1523/JNEUROSCI.08-11-04287.1988.
The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.
本研究试图鉴定一种α2激动剂，它能改善老年非人灵长类动物的工作记忆，同时又不会产生可乐定所带来的明显的降压和镇静副作用。为此，在9只老年恒河猴中，将α2肾上腺素能激动剂B-HT920和胍法辛的降压、镇静及改变记忆的特性与可乐定的作用进行了比较。通过可变延迟空间延迟反应范式评估记忆能力，该范式要求动物在短时间间隔内记住信息，并在每次试验中更新此信息。结果发现，B-HT920产生的剂量反应曲线在性质上与可乐定相似，但比可乐定弱：低剂量损害记忆，并开始降低血压和产生镇静作用，而高剂量则改善记忆。相比之下，胍法辛产生的剂量反应曲线与可乐定相反：低剂量改善记忆而不引起低血压或镇静，而在高剂量时观察到该药物的损害记忆、降压和镇静特性。这三种激动剂降低血压的效力为可乐定 = B-HT920大于胍法辛；镇静作用受影响的顺序为可乐定大于B-HT920大于胍法辛；对于通过延迟反应任务的表现所衡量的记忆损害，效力的等级顺序为可乐定大于B-HT920大于胍法辛，而对于记忆改善则是胍法辛大于可乐定大于B-HT920。这些效力等级顺序的差异与最近提出的α2受体亚型一致，即一种对萝芙木碱敏感的位点（Rs），其与可乐定的结合能力大于B-HT920大于胍法辛，以及一种对萝芙木碱不敏感的位点（Ri），其与胍法辛的结合能力大于可乐定大于B-HT920（博亚简和莱斯利，1987年）。数据表明，α2激动剂的降压、镇静和损害记忆作用可能是由于作用于一种受体亚型（Rs），而这些药物的增强记忆作用可能是由于作用于另一种α2受体亚型，即Ri位点。低剂量胍法辛能够改善记忆而不引起低血压或镇静，这表明该激动剂可能是治疗人类记忆障碍的极佳候选药物。
