Serotonergic effects and extracellular brain levels of eletriptan, zolmitriptan and sumatriptan in rat brain

In vivo microdialysis was used to assess the central serotonergic effects a nd extracellular brain levels of the 5-HT1B/1D receptor agonists eletriptan , zolmitriptan and sumatriptan in rats after intravenous and intracerebral administration, while their binding affinities and functional potencies wer e determined at 5-HT1B, 5-HT1D and 5-HT1A receptors. In vitro studies showe d that all three triptans are high affinity, full agonists at 5-HT1B/1D rec eptors, but that sumatriptan is functionally less potent as a 5-HT1B/1D ago nist than zolmitriptan and eletriptan. Local intracortical perfusion with t he compounds via the dialysis probe decreased cortical 5-HT (5-hydroxytrypt amine, serotonin) release with ED50 values of approximately 0.1 muM for ele triptan and zolmitriptan and 0.5 muM for sumatriptan. At 3.2 mg/kg i.v., bo th eletriptan and zolmitriptan decreased 5-HT levels by about 35%, while su matriptan had no effect, despite the fact that maximal sumatriptan concentr ations in cortical dialysates were higher (8.8 nM at 20 min) than those of zolmitriptan (5.9 nM at 20 min) and eletriptan (2.6 nM at 40 min). The obse rvation that eletriptan and zolmitriptan produce almost identical central s erotonergic effects, after intracerebral as well as after systemic administ ration, is in agreement with their comparable functional 5-HT1B/1D receptor agonist potencies and their free levels in cortical dialysates after 3.2 m g/kg i.v. On the other hand, the lack of central serotonergic effects of 3. 2 mg/kg i.v. sumatriptan is likely due to its weaker functional 5-HT1B/1D r eceptor agonist potency than eletriptan and zolmitriptan, rather than lower brain levels, consistent with sumatriptan's fivefold lower potency after i ntracerebral administration. (C) 2001 Elsevier Science B.V. All rights rese rved.