Region-specific changes in 5-HT1A agonist-induced Extracellular signal-Regulated Kinases 1/2 phosphorylation in rat brain: a quantitative ELISA study.
Brain serotonin 5-HT(1A) receptor, a traditional target for the treatment of mood disorders, modulates intracellular signalling pathways, such as the Extracellular signal-Regulated Kinases 1/2 (ERK1/2) pathway. The present studies are the first to determine levels of phospho-ERK1/2 (pERK1/2) in brain using a quantitative Enzyme Linked-Immuno-Sorbent Assay. We examined pERK1/2 levels in rat brain following administration of (+)8-OH-DPAT, buspirone as well as of the more selective, high-efficacy 5-HT(1A) agonists F13640 and F13714. Intraperitoneal injection of these compounds increased pERK1/2 in prefrontal cortex and hypothalamus, with a maximum at 5-15min and a significant effect lasting until 30-60min post-injection. However, these compounds reduced hippocampal pERK1/2 with a maximum effect at 30min, persisting until 60min post-injection. In hippocampus, F13640, F13714 and buspirone inhibited pERK1/2 in a dose-dependent manner as of 0.04, 0.04 and 2.5mg/kg, respectively. Given these low doses, this response is likely related to activation of sensitive presynaptic 5-HT(1A) receptors in the raphe nucleus. 4- and 16-fold higher doses of these compounds were necessary to stimulate pERK1/2 in prefrontal cortex and hypothalamus, respectively, via direct 5-HT(1A) receptor activation. In contrast, (+)8-OH-DPAT was active at similar doses (0.63mg/kg) in these different regions. Pretreatment with the 5-HT(1A) antagonist, WAY100635, completely blocked the effects of these compounds, with the exception of buspirone-induced pERK1/2 increases in hypothalamus. Thus, 5-HT(1A) agonist-induced changes in pERK1/2 in rat brain are time- and dose-dependent and region-specific. Furthermore, F13640, F13714, buspirone, but not (+)8-OH-DPAT, exert their effects via preferential activation of presynaptic 5-HT(1A) receptors.
Buritova
Jaroslava
J
Department of Cellular and Molecular Biology, Pierre Fabre Research Center, 17 Avenue Jean Moulin, F-81106 Castres Cedex, France.
Berrichon
Geraldine
G
Cathala
Claudie
C
Colpaert
Francis
F
Cussac
Didier
D
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013997:Time Factors
D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3