Respiratory depressant effects of GABA alpha- and beta-receptor agonists in the cat

The aim of this study was to evaluate the cardiorespiratory effects of intravenously administered gamma-aminobutyric acid (GABA) alpha-(4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, THIP) and beta-(baclofen) receptor agonists and to locate the site of action of these drugs in the brain. THIP and baclofen were administered to alpha-chloralose-anesthetized cats while minute ventilation (VE), arterial blood pressure (AP), and heart rate were monitored. THIP, in doses of 0.5 to 2 mg/kg decreased VE, tidal volume (VT), and AP. No changes in respiratory rate (f) or inspiratory (TI) or expiratory (TE) duration were observed. Baclofen, in doses of 0.5 to 4 mg/kg, decreased VE, f, and AP. VT and TI increased and an "apneustic" breathing pattern was seen. THIP (9.5 micrograms), applied bilaterally to the glycine-sensitive area of the ventral medulla, reproduced the effects seen with intravenous administration. Application of 10 micrograms of bicuculline bilaterally to this area reversed the effects of intravenous THIP but not those of baclofen. Baclofen (5.6-56 micrograms), administered by the intracisternal route, produced the same respiratory effects seen with intravenous administration. We conclude that activation of GABA alpha- and beta-receptors produces cardiorespiratory depression. However, this is accomplished by different mechanisms and by actions exerted at different central nervous system sites.