Inducing Anesthesia with a GABA Analog, THIP

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Abstract
General anesthetic agents act via a potentiation of the inhibitory action of 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 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 induced anesthesia in rats, 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 .mu.mol/kg, with ketamine and midazolam < 50 .mu.mol/kg and with .gamma.-hydroxybutyrate of > 6000 .mu.mol/kg. Complete recovery from thiopental and ketamine occurred in < 5 min, with midazolam recovery required .apprx. 1/2 h and with .gamma.-hydroxybutryrate and THIP it took .apprx. 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.