Serotonin 5-HT1A receptor activation preventsphosphorylation of NMDA receptor NR1subunit in cerebral ischemia

ABSTRACT

The mechanisms involved in the neuroprotective effect of serotonin 5-HT1Areceptor agonists on brain damage induced by ischemia remain to be fully elucidated.Given that serotonergic drugs may regulate N-methyl-D-aspartate (NMDA)receptor function, which is implicated in events leading to ischemia-induced neuronalcell death, this study sought to determine the effects of the selective 5-HT1Areceptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on thelevels of NMDA receptor NR1 subunit in gerbil hippocampus after transient globalcerebral ischemia. Pretreatment with 8-OH-DPAT (1 mg/kg) prevented the neuronalloss in CA1 subfield 72 h after ischemia. NMDA receptor NR1 levels in wholehippocampus were not affected 24 h after ischemia, but the levels of the subunitphosphorylated at the protein kinase A (PKA) site, pNR1(Ser897), were significantlyincreased, and this increase was prevented by the same 8-OH-DPAT dose, a probableconsequence of the increased phosphatase 1 (PP1) enzyme activity found inischemic gerbils pretreated with the 5-HT1A receptor agonist. The results suggestthat NR1 subunit phosphorylation plays a role in the neuroprotective effect of 8-OH-DPAT on cell damage induced by global cerebral ischemia in the gerbil hippocampusand support the potential interest of 5-HT1A receptor activation in thesearch for neuroprotective strategies (AU)