Methylxanthines modulate adenosine release from slices of cerebral cortex

Using slices of mouse or rat cerebral cortex incubated with [3H]adenosine or [3H]adenine and/or [14C]GABA we have examined factors affecting the release of these compounds, and especially the influence of methylxanthines. Although release of purines and GABA could be induced by ouabain (10(-4) M), or p-hydroxymercuribenzoate (5 x 10(-4) M) no release was produced by ethacrynic acid (10(-3) or 10(-4) M) phenytoin (10(-3) M), noradrenaline or SC 13504. Release is probably not therefore related to (Na+, K+) ATPase or Mg2+-ATPase inhibition. At concentrations of 10(-3) and 10(-4) M, caffeine, theophylline, aminophylline and isobutyl-methylxanthine (IBMX) markedly depressed the release of purines evoked by ouabain. Non-xanthine inhibition of phosphodiesterase had much weaker though statistically significant effects. The methylxanthines had no significant effect on GABA release. It is suggested that the results can be explained on the basis of a positive feedback system in which released adenosine activates membranal adenylate cyclase, and the increased concentration of cyclic AMP which results form or origin of much of the adenosine released subsequently. However, we cannot exclude the existence of an intracellular receptor for methylxanthines which causes directly the inhibition of purine release.