THE ALPHA-1-ADRENERGIC AGONIST, CIRAZOLINE, IMPAIRS SPATIAL WORKING-MEMORY PERFORMANCE IN AGED MONKEYS

The alpha-1 adrenergic agonist, cirazoline, was examined for effects o n spatial working memory performance in aged rhesus monkeys. Cirazolin e has additional high affinity for imidazoline receptors and has good brain penetrance when administered systemically. Spatial working memor y was assessed using the variable delayed response task, a test depend ent upon prefrontal cortical function in monkeys. Low doses of cirazol ine (0.00001-0.001 mg/kg) impaired delayed response performance signif icantly. This impairment did not appear to result from nonspecific cha nges in behavior, because cirazoline had no significant effect on perf ormance of control trials where the delay was ''0'' s, and had no sign ificant effect on behavioral ratings, Impairment was reversed by pretr eatment with the alpha-1 adrenergic antagonist, prazosin, consistent w ith drug actions at alpha-1 adreneigic receptors. In contrast, prelimi nary data suggest that higher cirazoline doses (0.001-0.01 mg/kg) occa sionally produced improved performance that was not reversed by prazos in, but rather, by the imidazoline/alpha-2 adrenergic antagonist, idaz oxan. The finding that alpha-1 adrenergic receptor stimulation impairs spatial working memory performance complements previous research demo nstrating that alpha-2 adrenergic receptor stimulation improves workin g memory, and suggests that norepinephrine may have opposing actions a t alpha-1 vs. alpha-2 receptors in the prefrontal cortex as it does in the hypothalamus and thalamus. (C) 1997 Elsevier Science Inc.