Animal model of posthypoxic myoclonus: effects of serotonergic antagonists

Neurology. 1999 Jan 1;52(1):16-21. doi: 10.1212/wnl.52.1.16.


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 posthypoxic 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-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 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-HT1B, 5-HT2A/2B, and possibly 5-HT1D 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Brain Chemistry / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ergolines / pharmacology
  • Heart Arrest / complications
  • Hypoxia / complications*
  • Hypoxia, Brain / complications*
  • Male
  • Methiothepin / pharmacology
  • Myoclonus / drug therapy*
  • Myoclonus / etiology*
  • Oxadiazoles / pharmacology
  • Piperazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / physiology
  • Serotonin Antagonists / pharmacology*


  • Ergolines
  • Oxadiazoles
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • GR 127935
  • Methiothepin
  • mesulergine