Journal
LEARNING & MEMORY
Volume 13, Issue 6, Pages 770-776Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/lm.298006
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Funding
- NIA NIH HHS [R37 AG006036, R01 AG006036, AG06036] Funding Source: Medline
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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(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.
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