THE ANTIMIGRAINE DRUGS ERGOTAMINE AND DIHYDROERGOTAMINE ARE POTENT 5-HT1C RECEPTOR AGONISTS IN PIGLET CHOROID-PLEXUS

1 Fozard & Gray (1989) proposed that migraine is mediated by stimulation of 5-HT(IC) receptors. We have examined the interaction of two effective anti-migraine agents, ergotamine and dihydroergotamine (DHE), with these receptors. Binding (inhibition of labelling by [H-3]-mesulergine) and agonist activity (phosphoinositide hydrolysis) were measured in piglet choroid plexus, a tissue rich in 5-HT1C receptors. 2 The pK(D) for [H-3]-mesulergine binding was 8.4. Ergotamine and DHE both inhibited [H-3]-mesulergine binding with a pK(D) of 7.1. This was similar to the potency of m-chlorophenylpiperazine (m-CPP) (pK(D) 7.4) and rather less than that of 5-hydroxytryptamine (5-HT) (pK(D) 8.1). 3 Both ergotamine and DHE were full agonists (pEC50S 7.5 and 7.6 respectively) with potencies similar to that of 5-HT (pEC50 7.7) and greater than that of m-CPP (pEC50 7.1). Mesulergine 10(-7) M produced near-parallel rightward shifts of the concentration-response curves for all these agents of 1.8-2.2 log units, consistent with an action of the agonists at the same receptor. 4 There was no effect of prazosin, spiperone, mepyramine or atropine on the phosphoinositide hydrolysis induced by ergotamine, ruling out an action via alpha-1-adrenoceptors, 5-HT2, histamine H-1, or muscarinic receptors. 5 It is concluded that, together with 5-HT, ergotamine and DHE are the most potent 5-HT1C agonists reported so far. These findings do not support the theory that 5-HT1C receptor activation causes migraine.