Dihydroergotamine and its metabolite, 8′-hydroxy-dihydroergotamine, as 5-HT 1A 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 [ 3H]8-OH-DPAT and [ 3H]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 [ 35S]GTP-γ-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 [ 35S]GTP-γ-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.