Rationale: There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the preBotzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. Objective: We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid- and barbiturate-induced respiratory depression. Methods: Respiratory frequency and amplitude were measured using the following rat models; i) perinatal in vitro brainstem-spinal cord, ii) neonatal in vitro medullary slice, iii) juvenile in situ perfused, working heart-brainstem preparation and, iv) newborn and adult in vivo. Results: The administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not older animals (>postnatal day 0). Further, pharmacological depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering suppressing analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus. Conclusions: CX546 effectively reverses opioid- and barbituate-induced respiratory depression without reversing analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify a potential for ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea.