Mecanismos moleculares implicados en la facilitacion e procesos cognitivos inducida por el bloqueo de receptores serotonergicos 5 ht 1a

Abstract

titulo: Mecanismos moleculares implicados en la facilitación DE procesos cognitivos inducida POR EL bloqueo DE receptores serotonergicos 5-HT lA Resumen: Hippocampal serotonin 5-HTlA receptors play a critica! role in cognition. stimülation of this 5-HT receptor subtype reduces ampa and NMDA glutamate receptor function and impairs memory retention, suggesting glutamatergic-serotonergic interactions. On the other nana, the selective 5-HTlA antagonist, WAY-100635, may alleviate cognitive deficits induced not only by 5-htla agonists, but also NMDA receptor blockade. On this basis, possible effects of 5-HTlA antagonism on molecular events associated to memory storage such as caMKii and pka activation, and ampa receptor phosphorylation and membrane insertion were further explored. In rat hippocampus, WAY-100635 enhanced CaMKii and pka function and increased ampa and NMDA receptor phosphorylation state, at Ser831 and Ser845 on the GluRl subunit, and at Ser897 on the NRl subunit, respectively. Using the passive avoidance task, pretraining administration of either a 5-HTlA receptor agonist, 8-OH-dpat, or an ampa receptor antagonist, NBQX, impaired memory retention and prevented the learning-specific increase in CaMKii function and membrane expression of ampa receptor subunits, GluR2/3 and phosphorylated GluRl. All of these effects were reversed by pretreatment with WAY-100635, a 5-HTlA antagonist. using the object recognition test, we found that pretraining administration of WAY-100635 enhanced memory retention and potentiated recognition training-induced increments in membrane ampa receptor subunits. Overail, the present data suggest that blockade of hippocampal 5-HTlA receptors favours molecular events critically involved in memory formation, and compensates the negative effect on cognitive processes of 5-HTlA overstimulation or glutamate receptor blockade. This study provides an additional in vivo molecular basis for the proposed utility of 5-HTlA receptor antagonists in the treatment of cognitive disorders.