The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged monkeys

The alpha-1 adrenergic agonist, cirazoline, was examined for effects on spatial working memory performance in aged rhesus monkeys. Cirazoline has additional high affinity for imidazoline receptors and has good brain penetrance when administered systemically. Spatial working memory was assessed using the variable delayed response task, a test dependent upon prefrontal cortical function in monkeys. Low doses of cirazoline (0.00001-0.001 mg/kg) impaired delayed response performance significantly. This impairment did not appear to result from nonspecific changes in behavior, because cirazoline had no significant effect on performance of control trials where the delay was "0" s, and had no significant effect on behavioral ratings. Impairment was reversed by pretreatment with the alpha-1 adrenergic antagonist, prazosin, consistent with drug actions at alpha-1 adrenergic receptors. In contrast, preliminary data suggest that higher cirazoline doses (0.001-0.01 mg/kg) occasionally produced improved performance that was not reversed by prazosin, but rather, by the imidazoline/alpha-2 adrenergic antagonist, idazoxan. The finding that alpha-1 adrenergic receptor stimulation impairs spatial working memory performance complements previous research demonstrating that alpha-2 adrenergic receptor stimulation improves working memory, and suggests that norepinephrine may have opposing actions at alpha-1 vs. alpha-2 receptors in the prefrontal cortex as it does in the hypothalamus and thalamus.