The purpose of our study was to test the hypothesis that 5-hydroxytryptamine (5-HT)_1A receptor agonists counteract morphine-induced respiratory depression. Studies were conducted in anesthetized rats, and respiratory activity was monitored with diaphragm electromyography. Morphine was administered i.v. in doses that produce apnea. Once apnea was established, i.v. administration of the 5-HT_1A receptor agonist drug 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) at 10 or 100 μg/kg restored normal breathing in each animal (n = 24). This antagonistic effect of 8-OH-DPAT on morphine-induced respiratory depression was observed in both spontaneously breathing and artificially ventilated animals. Results obtained with 8-OH-DPAT were mimicked by buspirone (50 μg/kg i.v.), another 5-HT_1A receptor agonist drug. Pretreatment with 4-(2′-methoxyphenyl)-1-[2′[N-(2′-pyridinyl]-p-iodo-benzamido]ethyl]piperazine, an antagonist of 5-HT_1A receptors, prevented 8-OH-DPAT from counteracting morphine-induced apnea. These results indicate that activation of central nervous system 5-HT_1A receptors is an effective way of reversing morphine-induced respiratory depression. Most important, this is the third model of disturbed respiratory function in which drugs that stimulate 5-HT_1A receptors have been shown to restore breathing to near-normal levels.