The perinatal development of respiratory rhythm generation and its modulation by adenosinergic drugs have been examined in rats from embryonic d 18 (E18) to postnatal d 3 using an in vitro brain stem-spinal cord preparation. Generation of rhythmic respiratory activity in the medulla oblongata and inhibition of this activity by pontine structures were evident on E18. The adenosine A(1)-receptor agonist, N(6)-(2-phenylisopropyl) adenosine, R (-) isomer (R-PIA) (1 microM), induced an age-dependent reduction of respiratory frequency that could be reversed by the adenosine antagonist theophylline (55 microM). The effect of R-PIA was reduced 24 h after birth compared with E21 and 2 h postnatal age. In preparations from pups that had been exposed to a low dose of caffeine (0.3 g/L in drinking water to dams), pontine inhibition of respiratory rhythm generation in the medulla was more pronounced. When the pons was removed, the respiratory frequency was higher than in the control group. Adenosine A(1)-mRNA and A(1)-receptor development in pons and medulla were studied, and by E18, mRNA, receptor protein, and functional coupling to G-proteins were confirmed using guanylyl-5'-O-(gamma-[(35)S]thio)-triphosphate binding. There were no major changes in receptor numbers or distribution of A(1) receptors or mRNA in rat pups subjected to caffeine exposure. We conclude that respiration is already modulated by adenosine A(1) receptors at the level of the medulla oblongata in the fetal period in an age-dependent manner. Furthermore, long-term maternal caffeine intake during gestation seems to increase the pontine inhibition of, and the activity of, respiratory rhythm-generating neuronal networks in medulla oblongata without detectable changes in expression of A(1)-receptor number or A(1)-receptor mRNA.