sodium-oxybate and gaboxadol

A number of animal models of generalized absence seizures in rodents are described. These include absence seizures induced by gamma-hydroxybutyrate (GHB), low dose pentylenetetrazole, penicillin, THIP, and AY-9944. All of these models share behavioral and EEG similarity to human absence seizures and show pharmacologic specificity for antiabsence drugs such as ethosuximide and trimethadione. Moreover, the absence seizures induced by these agents are exacerbated by GABAergic agonists, a property unique to experimental absence seizures. These models are predictable, reproducible, and easy to standardize. They are useful both in studying mechanisms of pathogenesis of absence seizures as well as in screening for antiabsence activity of potential antiepileptic drugs.

Topics: Animals; Disease Models, Animal; Epilepsy, Absence; Isoxazoles; Penicillins; Pentylenetetrazole; Rodentia; Sodium Oxybate; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride

The authors have postulated previously that general anesthetic agents act via a potentiation of the inhibitory action of gamma-aminobutyric acid (GABA) at central synapses. If the hypothesis is true, GABA should induce anesthesia, however, GABA itself does not pass through the blood-brain barrier. A GABA analog was sought as a substitute to test the authors' hypothesis. A new bicyclic GABA analog, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) was selected because its properties are similar to GABA in vitro. THIP was found to induce anesthesia in rodents, and its behavior was compared with that of thiopental, ketamine, midazolam, and gamma-hydroxybutyrate. Complete loss of righting reflex occurred with doses of THIP and thiopental just under 100 mumol/kg, with ketamine and midazolam less than 50 mumol/kg and with gamma-hydroxybutyrate of more than 6,000 mumol/kg. Complete recovery from thiopental and ketamine occurred in less than 5 min, with midazolam recovery required about half an hour and with gamma-hydroxybutyrate and THIP it took about 1 1/2 h. THIP induced analgesia as well as sedation and loss of righting reflex. Recovery was complete, and no adverse effects were noted in these rodents.

Topics: Analgesics; Anesthesia, Intravenous; Anesthetics; Animals; Benzodiazepines; gamma-Aminobutyric Acid; Isoxazoles; Ketamine; Male; Mice; Midazolam; Oxazoles; Rats; Rats, Inbred Strains; Sodium Oxybate; Time Factors