title: Dihydroergotamine and its metabolite, 8'-hydroxy-dihydroergotamine, as 5-HT1A receptor agonists in the rat brain.
abstract: 1 In addition to stopping migraine attacks, dihydroergotamine (DHE) is an efficient drug for migraine prophylaxis. Whether 5-HT(1A) receptors could contribute to the latter action was assessed by investigating the effects of DHE and its metabolite, 8'-OH-DHE, on these receptors in the rat brain. 2 Membrane binding assays with [(3)H]8-OH-DPAT and [(3)H]WAY 100635 as radioligands showed that both DHE (IC(50)=28-30 nM) and 8'-OH-DHE (IC(50)=8-11 nM) are high-affinity 5-HT(1A) receptor ligands. 3 Both DHE and 8'-OH-DHE enhanced the specific binding of [(35)S]GTP-gamma-S to the dorsal raphe nucleus and the hippocampus in brain sections, but to a lower extent than 5-carboxamido-tryptamine (5-CT) in the latter area. 4 Both DHE (EC(50)=10.9+/-0.3 nM) and 8'-OH-DHE (EC(50)=30.4+/-0.8 nM) inhibited the firing of serotoninergic neurons in the dorsal raphe nucleus within brain stem slices. 5 Intracellular recording showed that 8'-OH-DHE was more potent than DHE to hyperpolarize CA1 pyramidal cells in rat hippocampal slices. 6 Both the stimulatory effects of DHE and 8'-OH-DHE on [(35)S]GTP-gamma-S binding and their electrophysiological effects were completely prevented by the selective 5-HT(1A) receptor antagonist WAY 100635. 7 As expected of 5-HT(1A) receptor partial agonists, DHE and 8'-OH-DHE prevented any subsequent hyperpolarization of CA1 pyramidal cells by 5-HT or 5-CT. 8 Through their actions at 5-HT(1A) auto- (in the dorsal raphe nucleus) and hetero-(notably in the hippocampus) receptors, DHE, and even more its metabolite 8'-OH-DHE, can exert both an inhibitory influence on neuronal excitability and anxiolytic effects which might contribute to their antimigraine prophylactic efficiency.
authors.affiliation: INSERM U288, Neuropsychopharmacology, Faculty of Medicine Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75634 Paris Cedex 13, France.
authors.forename: N
authors.initials: N
authors.lastname: Hanoun
authors.forename: F
authors.initials: F
authors.lastname: Saurini
authors.forename: L
authors.initials: L
authors.lastname: Lanfumey
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: S
authors.initials: S
authors.lastname: Bourgoin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004087:Dihydroergotamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004594:Electrophysiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004087:Dihydroergotamine; C041535:8'-hydroxydihydroergotamine