Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal α4β2*-nAChRs stimulation in aged mice.
The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4β2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy.
CNRS, Univ. Bordeaux, INCIA UMR 5287, Bordeaux, France.
Matthias
M
Vandesquille
Mathieu
M
Baudonnat
Laurence
L
Decorte
Caroline
C
Louis
Pierre
P
Lestage
Daniel
D
Béracochéa
D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism*; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000096:biosynthesis*
D002800:Cholinesterase Inhibitors; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases