Dihydroergotamine and its metabolite, 8′‐hydroxy‐dihydroergo‐tamine, as 5‐HT 1A receptor agonists in the rat brain

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. Membrane binding assays with [ 3 H]8‐OH‐DPAT and [ 3 H]WAY 100635 as radioligands showed that both DHE (IC 50 =28–30 n M ) and 8′‐OH‐DHE (IC 50 =8–11 n M ) are high‐affinity 5‐HT 1A receptor ligands. Both DHE and 8′‐OH‐DHE enhanced the specific binding of [ 35 S]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. Both DHE (EC 50 =10.9±0.3 n M ) and 8′‐OH‐DHE (EC 50 =30.4±0.8 n M ) inhibited the firing of serotoninergic neurons in the dorsal raphe nucleus within brain stem slices. Intracellular recording showed that 8′‐OH‐DHE was more potent than DHE to hyperpolarize CA1 pyramidal cells in rat hippocampal slices. Both the stimulatory effects of DHE and 8′‐OH‐DHE on [ 35 S]GTP‐ γ ‐S binding and their electrophysiological effects were completely prevented by the selective 5‐HT 1A receptor antagonist WAY 100635. 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. 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.British Journal of Pharmacology (2003) 139 , 424–434. doi: 10.1038/sj.bjp.0705258