Animal model of posthypoxic myoclonus - Effects of serotonergic antagonists

Objective: To study specific serotonin (5-hydroxytryptamine [5-HT]) recepto r subtype antagonists in an animal model of posthypoxic myoclonus. Backgrou nd: Although serotonergic system dysfunction is implicated in posthypoxic m yoclonus, anatomic specificity and linkage to receptor subtypes are not del ineated. Methods: The authors performed a pharmacologic study to identify s pecific serotonin receptor subtype antagonists effective in inhibiting myoc lonus in posthypoxic rats. Sprague-Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, anim als were rated every 10 minutes at -30 minutes to time 0 (drug injection) a nd from +60 to +150 minutes. Using a blinded methodology, animals were inje cted with normal saline, vehicle, or one of seven serotonin antagonists giv en at a dose that maintains serotonin receptor subtype specificity: WAY1001 35 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose-response study with six d oses across a range from the original dose studied to 10% of that dose. Res ults: Two drugs were significantly different from placebo: methiothepin mes ylate and mesulergine hydrochloride. GR 127935 showed a trend toward reduci ng myoclonus. Dose-response studies showed that all doses of methiothepin m esylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively. Conclusions: 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specifi c 5-HT antagonists that affect these receptor subtypes are candidates for f uture testing in this model and in Lance-Adams syndrome.