The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys

In aged monkeys with naturally occurring catecholamine depletion, alpha-2 adrenergic agonists such as guanfacine have repeatedly been shown to improve dorsolateral prefrontal cortical function, as assessed by the spatial delayed response task. Both low (0.0001-0.001 mg/kg) and high (0.5 mg/kg) but not intermediate (0.01-0.05 mg/kg) doses of guanfacine improve spatial working memory performance in aged animals. However, it is not known whether guanfacine would similarly improve performance in young animals. In the present study, the effects of guanfacine on delayed response performance were characterized in seven young adult rhesus monkeys. Low doses of guanfacine (0.0001-0.01 mg/kg) had no effect on task performance, while high doses of guanfacine (0.1-0.7 mg/kg) significantly improved task performance. The highest doses produced mild sedation that was independent of drug effects on delayed response. The most effective dose of guanfacine was challenged with the alpha-2 antagonist idazoxan (0.1 mg/kg). This dose of idazoxan had no effect on task performance when given alone. Consistent with an alpha-2 mechanism, idazoxan significantly decreased delayed response performance in guanfacine-treated animals. These results support the hypothesis that delayed response performance in young intact animals can be improved through actions at alpha-2 adrenergic receptors.