Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats

被引:49
作者
Marrs, W
Kuperman, J
Avedian, T
Roth, RH
Jentsch, JD
机构
[1] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA
[2] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA
[3] Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA
关键词
clonidine; noradrenaline; cognition; NMDA;
D O I
10.1038/sj.npp.1300700
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, such as phencyclidine (PCP), induce behavioral abnormalities (locomotor hyperactivity, sensorimotor gating deficits, impairments of cognition) in animals that are thought to model aspects of schizophrenia. The administration of PCP increases noradrenaline transmission in the rat prefrontal cortex, a brain structure required for normal cognitive processes. Noradrenaline, in turn, works through a set of receptors that have themselves been implicated directly in NMDA antagonist-induced deficits; we recently reported that the alpha-2 agonist, clonidine, is effective at preventing PCP-induced deficits of working memory and visual attention in rats. Here, we further investigated the role for alpha-2 adrenoreceptors in the effects of PCP on spatial working memory performance. The alpha-2 agonist clonidine (0.001-0.01 mg/kg, subcutaneously (s.c.)) produced a significant amelioration of PCP-induced working memory deficits; the effects of PCP (1.0 mg/kg, s.c.), but not clonidine, were reduced in noradrenaline-depleted rats. In addition, the alpha-2A-preferring agonist guanfacine (0.05-1.0 mg/kg, s.c.) dose-dependently prevented the deficits of spatial working memory performance produced by PCP. Although the highly selective alpha-2 receptor antagonist, atipamezole (ATI), failed to affect spatial working memory on its own, at the doses studied (0.1-0.5 mg/kg, s.c.), it dramatically enhanced the working memory deficit produced by PCP. These data indicate that alpha-2 adrenoreceptors tonically inhibit PCP-induced deficits of spatial working memory, suggesting an important role for these receptors in cognitive deficits associated with NMDA receptor hypofunction.
引用
收藏
页码:1500 / 1510
页数:11
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