GABA_A receptors mediate postnatal depression of respiratory frequency by barbiturates

We tested the hypothesis that barbiturates depress respiratory motor output by actions on the GABA_A receptor. We examined the influence of pentobarbital sodium on nerve activity recorded from a fourth cervical (C4) ventral root (phrenic motoneuron output) in the in vitro brainstem-spinal cord preparation of neonatal rats aged 1-3 days. Bath application of pentobarbital slowed the respiratory rhythm but this effect could be reversed by drug washout or by simultaneous application of 8 μM bicuculline methiodide, a GABA _A receptor antagonist. Pentobarbital up to a concentration of 80 μM (or 20 mg/l) did not change the magnitude of C4 nerve bursts. The GABA_A receptor agonist muscimol evoked similar changes. The results support the hypothesis that respiratory depression by barbiturates is due to GABA_A receptor-mediated inhibition, with the principal effects on rhythm generation. In the light of recent studies suggesting that GABA _A receptors may be excitatory in the early neonatal period, we examined postnatal changes in the GABAergic slowing of respiratory rhythm. Stimulation of GABA_A receptors slowed respiratory rhythm from the first postnatal day, with no change in efficacy over the first 3 days of life.