[alpha]2A-Adrenoceptor Stimulation Improves Prefrontal Cortical Regulation of Behavior through Inhibition of cAMP Signaling in Aging Animals

The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, [alpha]2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the [alpha]2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and r...

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Bibliographic Details
Published inLearning & memory (Cold Spring Harbor, N.Y.) Vol. 13; no. 6; pp. 770 - 776
Main Authors Verduzco, Luis, van Dyck, Christopher H, Arnsten, Amy F. T, Ramos, Brian P, Stark, David
Format Journal Article
LanguageEnglish
Published Cold Spring Harbor Laboratory Press 2006
Subjects
Aging (Individuals)
Animals
Behavioral Science Research
Brain
Cognitive Ability
Inhibition
Memory
Neurological Impairments
Program Effectiveness
Stimulation
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Summary:The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, [alpha]2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the [alpha]2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or intra-PFC infusion. [alpha]2A-adrenoceptors are generally coupled to G[subscript i], which can inhibit adenylyl cyclases and reduce the production of cAMP. However, no study has directly examined whether the working-memory enhancement observed with guanfacine or other [alpha]2A-adrenoceptor agonists results from cAMP inhibition. The current study confirmed this hypothesis in both rats and monkeys, showing that treatments that increase cAMP-mediated signaling block guanfacine's beneficial effects. In aged rats, guanfacine was infused directly into the prelimbic PFC and was challenged with co-infusions of the cAMP analog, Sp-cAMPS. In aging monkeys, systemically administered guanfacine was challenged with the phosphodiesterase 4 inhibitor, rolipram, using intramuscular doses known to have no effect on their own. In both studies, agents that mimicked the actions of cAMP (rats) or increased endogenous cAMP (monkeys) completely blocked the enhancing effects of guanfacine on working-memory performance. These results are consistent with [alpha]2A-adrenoceptor stimulation enhancing PFC working-memory function via inhibition of cAMP-mediated signaling.
ISSN:1072-0502