Animal model of posthypoxic myoclonus Effects of serotonergic antagonists

Objective: To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus. Background: Although serotonergic system dysfunction is implicated in post-hypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated. Methods: The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague–Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at −30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT 1A ), methiothepin mesylate (5-HT 1B/1D/2 ), mesulergine hydrochloride (5-HT 2A/2B ), GR 127935 (5-HT 1D ), SR 46349 (5-HT 2 ), ondansetron (5-HT 3 ), or GR 125487 (5-HT 4 ). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose–response study with six doses across a range from the original dose studied to 10% of that dose. Results: Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose–response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively. Conclusions: 5-HT 1B , 5-HT 2A/2B , and possibly 5-HT 1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance–Adams syndrome.