Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats.
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.
Marrs
William
W
Department of Psychology, University of California at Los Angeles, Los Angeles, CA 90095-1563, USA.
Kuperman
Julie
J
Avedian
Tahlin
T
Roth
Robert H
RH
Jentsch
J David
JD
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001596:Benzylamines / Q000494:pharmacology; D003000:Clonidine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D016316:Guanfacine / Q000008:administration & dosage; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000187:drug effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010622:Phencyclidine; D051381:Rats; D020318:Rats, Long-Evans; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012737:Sex Factors; D013037:Spatial Behavior / Q000187:drug effects*
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001596:Benzylamines; D007093:Imidazoles; D014179:Neurotransmitter Uptake Inhibitors; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D016316:Guanfacine; D010622:Phencyclidine; D003000:Clonidine; C012102:DSP 4