In the striatum, glutamate may preserve striatal synaptic plasticity and contribute to overexcitation leading to extrapyramidal disorders. Acting at presynaptic G-protein-coupled (GPC) receptors it regulates different signal transduction pathways. Earlier we have shown the potentiation of the striatal kainateevoked glutamate release by the G_sPC b-adrenoceptor agonist isoproterenol (ISO) and by Ca²⁺-free media. Here we studied the modulation of these potentiations by G_iPC metabotropic glutamate receptor (mGluR) ligands and adenylyl cyclase (AC) inhibitors in a closed superfusion system using D-[³H]aspartate and mouse striatal slices. Both selective agonists of group II and III mGluRs, LY354740 and L-AP4, respectively, failed to affect the kainate-evoked release but completely abolished its potentiation by ISO. The group II and III mGluR antagonists EGLU and CPPG blocked the effects of the respective agonists. The ISO effect was also thwarted by the AC inhibitor MDL12,330A and by the PKA inhibitor H-89. Alloxan, an another AC inhibitor, enhanced further the KA-evoked release facilitated by Ca²⁺-free media. Our results suggest that in striatal glutamatergic transmission the cAMP/PKA-dependent phosphorylation pathway is depressed by the Ca²⁺-dependent signalling pathway. In this respect, other preventive elements of Ca²⁺- and cAMP-dependent cross-talk will be discussed.