Ventilatory effects of negative GABA(A) modulators in rhesus monkeys

This study examined changes in ventilation produced by negative γ-aminobutyric acid(A) (GABA(A)) modulators in rhesus monkeys. The effects of Ro 15-4513, β-CCE and β-CCM were examined in four rhesus monkeys breathing air or 5% CO₂ in air. When monkeys breathed CO₂, minute volume (V(E) ) and frequency (f) increased, on average, to 158 and 140% of control (air), respectively. Ro 15-4513 did not modify ventilation in monkeys breathing either gas mixture; however, β-CCE and β-CCM increased V(E) and f in monkeys breathing air to between 123 and 141% of control and had no effect on ventilation of 5% CO₂. Increased ventilation produced by the negative GABA(A) modulators appeared to be maximal, because ventilation was not further enhanced when the dose was increased three-fold. Each of the three negative GABA(A) modulators reversed the decreases in ventilation produced by diazepam, suggesting that these drugs are acting at benzodiazepine receptors; however, the increased ventilation produced by β-CCE and β-CCM might suggest that they have more negative efficacy than Ro 15-4513. These data extend previous findings by showing that some negative GABA(A) modulators (Ro 15-4513) do not alter ventilation and further indicate that changes in ventilation can be used to evaluate efficacy differences among GABA(A) modulators. Copyright (C) 1998 Elsevier Science Inc.