Ramos Brian P, Colgan Lesley, Nou Eric, Ovadia Shira, Wilson Steven R, Arnsten Amy F T
Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8001, USA.
Biol Psychiatry. 2005 Dec 1;58(11):894-900. doi: 10.1016/j.biopsych.2005.05.022. Epub 2005 Jul 25.
Previous studies have indicated that beta adrenergic receptor stimulation has no effect on the cognitive functioning of the prefrontal cortex (PFC). Blockade of beta-1 and beta-2 receptors in the PFC with the mixed beta-1/beta-2 antagonist, propanolol, had no effect on spatial working memory performance. However, more selective blockade of beta-1 or beta-2 receptors might show efficacy if the two receptors have opposite effects on PFC function. The current study examined the effects of the selective beta-1 antagonist, betaxolol, on working memory in rats and monkeys.
In rats, betaxolol (.0011-1.11 microg/.5 microL) was infused into the PFC 5 min before delayed alternation testing. Monkeys were systemically injected with betaxolol (.0000011-.11 mg/kg) 2 hours before delayed response testing.
Betaxolol produced a dose-related improvement in working memory performance following either direct PFC infusion in rats, or systemic administration in monkeys. However, some aged monkeys developed serious pancreatic problems over the course of this study.
These findings suggest that endogenous activation of the beta-1 adrenergic receptor impairs PFC cognitive function. These results may have therapeutic relevance to post-traumatic stress disorder or other disorders with excessive noradrenergic activity and PFC dysfunction. Pancreatic side effects in aged subjects taking betaxolol warrants further investigation.
先前的研究表明，β肾上腺素能受体刺激对前额叶皮质（PFC）的认知功能没有影响。使用β-1/β-2混合拮抗剂普萘洛尔阻断PFC中的β-1和β-2受体，对空间工作记忆表现没有影响。然而，如果这两种受体对PFC功能有相反的作用，那么对β-1或β-2受体进行更具选择性的阻断可能会显示出效果。本研究考察了选择性β-1拮抗剂倍他洛尔对大鼠和猴子工作记忆的影响。
在大鼠中，于延迟交替测试前5分钟将倍他洛尔（0.0011 - 1.11微克/0.5微升）注入PFC。猴子在延迟反应测试前2小时全身注射倍他洛尔（0.0000011 - 0.11毫克/千克）。
在大鼠中直接向PFC注入倍他洛尔或在猴子中全身给药后，倍他洛尔均使工作记忆表现出现剂量相关的改善。然而，在本研究过程中，一些老年猴子出现了严重的胰腺问题。
这些发现表明，β-1肾上腺素能受体的内源性激活会损害PFC的认知功能。这些结果可能与创伤后应激障碍或其他具有去甲肾上腺素能活动过度和PFC功能障碍的疾病的治疗相关。服用倍他洛尔的老年受试者出现的胰腺副作用值得进一步研究。
