Interaction between metabotropic receptors and purinergic transmission in rat hippocampal slices

Inhibition of forskolin-stimulated cAMP formation by (1 S,3 R)-1-aminocyclopentane-1,3-dicar☐ylic acid (ACDP) in rat hippocampal slices was partially obliterated by the adenosine-depleting enzyme, adenosine deaminase, or by the adenosine receptor agonist, 5′-( N-ehtylcar☐amido)-adenosine, suggesting that activation of metabotropic glutamate receptors (mGluRs) modulates the release of endogenous adenosine. Consistent with this hypothesis, forskolin stimulated the release of purines from rat hippocampal slices, and this effect was reduced by 1 S,3 R-ACPD. To establish which transduction pathway is involved in the modulation of forskolin-stimulated purine release, we have tested the novel mGluR2 agonist, (2 S,1′ R,2′ R,3′ R)-2-(2,3-dicar☐ycyclopropyl)glycine (DCG-IV), which reduced forskolin-stimulated cAMP formation but, as opposed to 1 S,3 R-ACDP, did not stimulated polyphosphoinositide hydrolysis. DCG-IV was highly potent and more efficacious than 1 S,3 R-ACDP in inhibiting forskolin-stimulated purine release. Neither DCG-IV nor 1 S,3 R-ACDP reduced the release of purines stimulated by depolarizing concentrations of K +, suggesting that their effect was stimulus-specific. These results indicate that, in rat hippocampal slices, activation of mGluR2 receptors attenuates the release of purines induced by forskolin, a process that amplifies the final effect of forskolin on cAMP formation as a result of A2 purinergic receptor activation. Thus, the final effect of mGluR agonists on forskolin-stimulated cAMP formation in hippocampal slices depends on both a direct inhibition of adenyl cyclase and the inhibition of adenosine release.