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Animal model of posthypoxic myoclonus: effects of serotonergic antagonists
E J Pappert1, C G Goetz, T Q Vu
1Department of Neurological Sciences, Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
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.
Insights
Specific serotonin receptor antagonists, methiothepin mesylate and mesulergine hydrochloride, effectively inhibited posthypoxic myoclonus in rats. These findings suggest potential therapeutic targets for conditions like Lance-Adams syndrome.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Serotonergic system dysfunction is implicated in posthypoxic myoclonus.
- Specific serotonin receptor subtypes involved are not fully understood.
Purpose of the Study:
- To investigate the efficacy of specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus.
- To identify which serotonin receptor subtypes are critical in the development of posthypoxic myoclonus.
Main Methods:
- A pharmacologic study was conducted using posthypoxic rats induced by cardiac arrest.
- Seven specific serotonin receptor antagonists were administered in a blinded manner.
- Drugs showing significant myoclonus reduction underwent dose-response studies.
Main Results:
- Methiothepin mesylate and mesulergine hydrochloride significantly reduced myoclonus compared to placebo.
- GR 127935 demonstrated a trend toward reducing myoclonus.
- Dose-response studies confirmed the inhibitory effects of methiothepin mesylate and mesulergine hydrochloride on myoclonus.
Conclusions:
- Serotonin receptor subtypes 5-HT1B, 5-HT2A/2B, and potentially 5-HT1D play a role in posthypoxic myoclonus.
- Specific 5-HT antagonists targeting these receptors are promising candidates for future research in posthypoxic myoclonus and Lance-Adams syndrome.