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Animal model of posthypoxic myoclonus

Effects of serotonergic antagonists

From the Departments of Neurological Sciences (Drs. Pappert and Goetz), Pharmacology (Drs. Vu, Ling, and Carvey), and Preventive Medicine (Dr. Leurgans and R. Raman), Rush Medical College, Rush-Presbyterian–St. Luke’s Medical Center, Chicago, IL.

Address correspondence and reprint requests to Dr. Eric J. Pappert, Movement Disorders Section, Department of Neurological Sciences, Rush-Presbyterian–St. Luke’s Medical Center, 1725 West Harrison Street, Suite 1106, Chicago, IL 60612.

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-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 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.

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