FORSKOLIN STIMULATION OF CYCLIC-AMP ACCUMULATION IN RAT-BRAIN CORTEX SLICES IS MARKEDLY ENHANCED BY ENDOGENOUS ADENOSINE

Stimulation of cyclic AMP (cAMP) accumulation in rat cortex slices by 1-mu-M forskolin (F) was markedly reduced (96%) by treatment with adenosine deaminase (ADA). The effect of ADA was progressively less at higher concentrations of F, but still inhibited the response by 50% at 100 mu-M F.ADA-mediated inhibition of the cAMP response to 1-mu-M F was completely reversed by 5-mu-M 2-chloroadenosine (CA), an ADA-resistant analogue. Stimulation by F (controls) and F plus CA (ADA treated) in cortex slices was significantly inhibited by 200-mu-M caffeine (CAF) and by 10-mu-M 8-phenyltheophylline. cAMP accumulation in ADA-treated cortex slices stimulated with CA at concentrations from 5 to 100-mu-M mu-M was markedly enhanced by 1-mu-M F. Neither ADA treatment nor 200-mu-M CAF significantly affected cAMP accumulation in slices stimulated by 1-mu-M vasoactive intestinal polypeptide or adenylate cyclase in membranes stimulated by 1-mu-M F. CAF (1 mM) did not significantly increase basal cAMP levels in cortex slices, whereas 1 mM 3-isobutyl-1-methylxanthine caused a significant 80% increase and 100-mu-M rolipram enhanced cAMP levels by 4.5-fold. F-stimulated cAMP accumulation (1-mu-M) in cortex slices was inhibited 98% by 1 mM CAF and 49% by 1 mM 3-isobutyl-1-methylxanthine, and was enhanced 2.5-fold by 100-mu-M rolipram. These data have been interpreted to indicate that the stimulation of cAMP accumulation in rat cortex slices by 1-mu-M F is predominantly due to synergistic interaction with endogenous adenosine and that the inhibition of this response by CAF is largely due to blockade of adenosine receptors.