title: Blockade of voltage-sensitive Na(+) channels by the 5-HT(1A) receptor agonist 8-OH-DPAT: possible significance for neuroprotection.
abstract: The present study was undertaken to determine whether 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonists interact with voltage-sensitive Na(+) or N- and P/Q-type Ca(2+) channels to reduce the influx of Na(+) and/or Ca(2+). The 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) inhibited both [3H]batrachotoxinin binding to neurotoxin site 2 of the Na(+) channel in rat cortical membranes (IC(50)=5.1 microM) and veratridine-stimulated Na(+) influx into rat synaptosomes (EC(50)=20. 8 microM). The 5-HT(1A) receptor agonist flesinoxan and the 5-HT(1A) receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635) also displaced [3H]batrachotoxinin binding with similar affinities to 8-OH-DPAT, but were much less effective in reducing veratridine-stimulated Na(+) influx. All three serotonergic agents also increased [3H]saxitoxin binding to neurotoxin site 1 of the Na(+) channel. In contrast, none of these agents interacted with radioligand binding to N- or P/Q-type Ca(2+) channels. These data show that 8-OH-DPAT directly interacts with voltage-sensitive Na(+) channels to reduce Na(+) influx so providing an additional mechanism to explain how it functions as a neuroprotectant.
authors.affiliation: Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, OX2 6AW, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Melena
authors.forename: G
authors.initials: G
authors.lastname: Chidlow
authors.forename: N N
authors.initials: NN
authors.lastname: Osborne
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012530:Saxitoxin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D020960:omega-Conotoxins / Q000378:metabolism
chemical_list: D001496:Batrachotoxins; D018696:Neuroprotective Agents; D010879:Piperazines; D011725:Pyridines; D017366:Serotonin Receptor Agonists; D026941:Sodium Channel Blockers; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D012530:Saxitoxin; C056895:flesinoxan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C031775:batrachotoxinin A 20-alpha-benzoate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012964:Sodium; D002118:Calcium