Inducing anesthesia with a GABA analog, THIP

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.