EXPRESSION OF MESSENGER-RNA FOR THE SEROTONIN 5-HYDROXYTRYPTAMINE(1D-BETA) RECEPTOR SUBTYPE IN HUMAN AND BOVINE CEREBRAL-ARTERIES

Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in the path ophysiology of migraine, and the clinical efficacy of the 5-HT1B/5-HT1 D receptor agonist sumatriptan points to neural and/or vascular 5-HT1D receptors as relevant targets in migraine therapy. We characterized t he human and/or bovine 5-HT1D receptor subtype in cerebral blood vesse ls pharmacologically by correlation analysis and molecularly by Northe rn blot hybridization of cerebrovascular RNA extracts. Pharmacological analysis showed that sumatriptan was less potent than 5-HT in inducin g contraction in freshly isolated human cerebral arteries and revealed an overall pharmacological profile positively and significantly corre lated with that published for the 5-HT1Dalpha (r = 0.746, p = 0.021) a nd 5-HT1Dbeta (r = 0.942, p = 0.0001) cloned human receptor subtypes. These results are suggestive of a contractile 5-HT1Dbeta receptor subt ype but are not conclusive. However, Northern blots revealed the prese nce of mRNA transcripts for the 5-HT1Dbeta subtype, but not the 5-HT1D alpha subtype, in bovine (approximately 2.2 kilobases) and human (appr oximately 4.5 kilobases) cerebral blood vessels. Expression of either subtype could not be detected in intraparenchymal microvessels or capi llaries isolated from bovine or human cerebral cortex. These results c learly indicate that the beneficial effect of sumatriptan in migraine attack, if vascularly related, is mediated by contractile 5-HT1Dbeta r eceptors most likely located on cerebral blood vessels at the surface of the brain. This study points to the 5-HT1Dbeta receptor subtype as the putative cerebrovascular target for migraine therapeutic agents.