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 μM) and veratridine-stimulated Na + influx into rat synaptosomes (EC 50=20.8 μM). 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.
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