Alpha2A-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, alpha2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the alpha2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats...

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Bibliographic Details
Published in:Learning & memory (Cold Spring Harbor, N.Y.) N.Y.), 2006-11, Vol.13 (6), p.770-776
Main Authors: Ramos, Brian P, Stark, David, Verduzco, Luis, van Dyck, Christopher H, Arnsten, Amy F T
Format: Article
Language:English
Subjects:
Adrenergic alpha-Agonists - pharmacology
Aging - metabolism
Animals
Behavior, Animal - drug effects
Behavior, Animal - physiology
Cyclic AMP - metabolism
Guanfacine - pharmacology
Macaca mulatta
Memory, Short-Term - drug effects
Memory, Short-Term - physiology
Prefrontal Cortex - drug effects
Prefrontal Cortex - metabolism
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha-2 - drug effects
Receptors, Adrenergic, alpha-2 - metabolism
Second Messenger Systems - physiology
Signal Transduction - drug effects
Signal Transduction - physiology
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Summary:The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, alpha2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the alpha2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or intra-PFC infusion. Alpha2A-adrenoceptors are generally coupled to Gi, 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 alpha2A-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 alpha2A-adrenoceptor stimulation enhancing PFC working-memory function via inhibition of cAMP-mediated signaling.
ISSN:1072-0502