Role of hippocampal CaMKII in serotonin 5-HT(1A) receptor-mediated learning deficit in rats.
The serotonin 5-HT(1A) receptor agonist, 8-OH-DPAT (8-hydroxy-2-di-n-propylamino-tetralin), impairs retention performance in a passive avoidance learning task in rats. In the hippocampus of rats trained on this procedure and killed 1 h after the acquisition trial, an increase in the membrane levels of both Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, as well as in total and Ca2+-independent enzyme activity in tissue lysates was found. These effects were learning-specific as no changes in CaMKII levels or activity were found in rats receiving a footshock identical to the trained rats. The effect of training on CaMKII was prevented by a low 8-OH-DPAT dose. The 5-HT(1A) agonist also reduced protein kinase A (PKA) activity and increased the membrane levels of phosphatase 1 (PP1) and PP1 enzyme activity in the hippocampus. All of the changes induced by 8-OH-DPAT were reversed by the selective 5-HT(1A) antagonist WAY-100635, indicating receptor-specific effects. We suggest that 5-HT(1A) receptor-mediated disruption of retention performance is a consequence of the reduced PKA activity and the ensuing enhancement in PP1 activity, possibly through decreased phosphorylation/activation of endogenous PP1 inhibitors, that cause a reduced activity of phosphorylated CaMKII, a key enzyme in early stages of memory formation. This study provides an in vivo molecular basis for the cognitive deficits induced by stimulation of hippocampal 5-HT(1A) receptors.
Moyano
Sonia
S
Department of Pharmacology, School of Medicine, University of Navarra, Apartado 177, Pamplona, Spain.
Del Río
Joaquín
J
Frechilla
Diana
D
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins; D007859:Learning Disabilities / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; C491293:Ppp1r5 protein, rat; D011725:Pyridines; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium