5-HT(7) receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons

• Published in: Neuroscience Vol. 102; no. 2; pp. 361 - 367
• Main Authors: Errico, M, Crozier, R A, Plummer, M R, Cowen, D S
• Format: Journal Article
• Language: English
• Published: United States 2001
• Subjects: Animals; Cells, Cultured; GTP-Binding Proteins - metabolism; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Pertussis Toxin; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Serotonin - metabolism; Serotonin - pharmacology; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Virulence Factors, Bordetella - pharmacology
• ISSN: 0306-4522

Medications that selectively increase 5-hydroxytryptamine are currently the most commonly prescribed antidepressants. 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-HT(7) 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-HT(1/7) receptor-selective agonist 5-carboxamidotryptamine maleate (5-CT) as well as the 5-HT(1A/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 EC(50) for 8-OH-DPAT was approximately 200-fold greater than that of 5-HT, a difference in potency consistent with the pharmacology of 5-HT(7), but not 5-HT(1A), receptors. Additionally, pretreatment with pertussis toxin, which would be expected to block the actions of 5-HT(1,) but not 5-HT(7,) 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-cyclohexanecarb oxamide maleate (WAY-100635), antagonists selective for 5-HT(1A) 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-HT(7) receptors couple to activation of extracellular signal-regulated kinase in hippocampal neurons suggests a possible role for 5-HT(7) receptors in mediating some of the actions of antidepressants that increase 5-hydroxytryptamine.