کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2494248 | 1115555 | 2009 | 12 صفحه PDF | دانلود رایگان |
Brain serotonin 5-HT1A 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-HT1A agonists F13640 and F13714. Intraperitoneal injection of these compounds increased pERK1/2 in prefrontal cortex and hypothalamus, with a maximum at 5–15 min and a significant effect lasting until 30–60 min post-injection. However, these compounds reduced hippocampal pERK1/2 with a maximum effect at 30 min, persisting until 60 min post-injection. In hippocampus, F13640, F13714 and buspirone inhibited pERK1/2 in a dose-dependent manner as of 0.04, 0.04 and 2.5 mg/kg, respectively. Given these low doses, this response is likely related to activation of sensitive presynaptic 5-HT1A 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-HT1A receptor activation. In contrast, (+)8-OH-DPAT was active at similar doses (0.63 mg/kg) in these different regions. Pretreatment with the 5-HT1A antagonist, WAY100635, completely blocked the effects of these compounds, with the exception of buspirone-induced pERK1/2 increases in hypothalamus.Thus, 5-HT1A 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-HT1A receptors.
Journal: Neuropharmacology - Volume 56, Issue 2, February 2009, Pages 350–361