Stimulation of a2A-adrenoceptors strengthens the working memory functions of the prefrontal cortex (PFC). Improvement in working memory has been demonstrated across species, including mice, rats, monkeys, and humans, thus documenting the relevance of the animal research to human cognitive experience. Mice with a functional knockout of the a2A-adrenoceptor have weakened working memory, and are unresponsive to the enhancing effects of the a2A-adrenoceptor agonist, guanfacine. Research in monkeys has shown that infusion of guanfacine into dorsolateral PFC produces a delay-related improvement in working memory, while blockade of these receptors with yohimbine markedly worsens working memory performance. Similar results have been shown at the cellular level: iontophoresis of yohimbine erodes delay-related activity, the cellular measure of working memory, without altering baseline firing rate. Conversely, iontophoresis of an a2-adrenoceptor agonist, clonidine, increases delay-related activity. This latter finding is especially important, as this is the only pharmacological treatment known to increase delay-related firing. Understanding how a2A-adrenoceptor stimulation increases delay-related activity may provide important clues regarding the second messenger and ionic regulation of persistent cell activity during delay-related firing. a2A-Adrenoceptors commonly couple through Gi to inhibit adenylyl cylcase, reducing cAMP production and decreasing protein kinase A activity. Reductions in cAMP may reduce Ih currents and enhance cortical connectivity as shown by the McCormick lab. Alternatively, reductions in PKA activity can alter potassium and calcium channels. For example, in the amygdala, a2A-adrenoceptor stimulation impairs the induction of long-term depression by a Gi/o mediated inhibition of presynaptic N-type Ca2+-channels and activation of inwardly-rectifying K+-channels. a2A-Adrenoceptors can also couple through Gi to activate phospholipase C, potentially altering intracellular calcium release via IP3 receptor mechanisms, and in platelets, alterations in voltage-gated calcium channels. Although the molecular actions of a2A-adrenoceptor stimulation has been studied extensively in peripheral tissues, there have been no studies of these mechanisms in PFC. The proposed research will begin to explore these mechanisms in awake behaving rats and monkeys performing working memory tasks.