5-HT7 receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons

Medications that selectively increase 5-hydroxytryptamine are currently the most commonly prescribed anti depressants, However, it is not known which receptors for 5-hydroxytryptamine, nor which post-receptor cellular signals, mediate the antidepressant actions of 5-hydroxytryptamine. The hippocampus is highly innervated by serotonergic neurons and appears to be an ideal region of the brain for studying the antidepressant role of 5-hydroxytryptamine. Treatment with antidepressants has been shown to cause increased expression of proteins in the hippocampus that appear to be protective against stress-induced atrophy. This suggests a role for pathways, such as mitogen-activated protein kinase, that regulate protein synthesis. In the present study we found that 5-HT7 receptors, expressed by cultured rat hippocampal neurons, couple to stimulation of the mitogen-activated protein kinase extracellular signal-regulated kinases ERK1 and ERK2. The 5-HT1/7 receptor-selective agonist 5-carboxamidotryptamine maleate (5-CT) as well as the 5-HT1A/7 receptor-selective agonists 8-hydroxy-N,N-dipropyl aminotetralin (8-OH-DPAT) and N.N-dipropyl-5-carboxamidotryptamine maleate (dipropyl-5-CT) were found to activate extracellular signal-regulated kinase with equal efficacy to 5-HT. However, the EC50 for 8-OH-DPAT was approximately 200-fold greater than that of 5-HT, a difference in potency consistent with the pharmacology of 5-HT7, but not 5-HT1A, receptors. Additionally, pretreatment with pertussis toxin, which would be expected to block the actions of 5-HT1. but not 5-HT7, receptors caused no inhibition. 4-Iodo-N-[2-[4-(methoxyphenyl)- 1-piperazinyl]ethyl]N-2-pyridinyl benzamide hydrochloride (p-MPPI) and N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl] -N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635), antagonists selective for 5-HT1A receptors, similarly caused no inhibition of the activity of 5-HT. In summary, these studies are the first to demonstrate that 5-hydroxytryptamine activates the mitogen-activated protein kinase ERK in primary neuronal cultures. That 5-HT7 receptors couple to activation of extracellular signal-regulated kinase in hippocampal neurons suggests a possible role for 5-HT7 receptors in mediating some of the actions of antidepressants that increase 5-hydroxytryptamine, (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.