A1 and A2A receptor activation by endogenous adenosine is required for VIP enhancement of K+-evoked [3H]-GABA release from rat hippocampal nerve terminals

Vasoactive intestinal peptide (VIP) modulates GABA release from hippocampal nerve terminals and enhances hippocampal synaptic transmission through a pathway dependent on GABAergic transmission. Since VIP modulation of hippocampal synaptic transmission is dependent on the tonic actions of adenosine we investigated if endogenous adenosine could influence VIP enhancement of GABA release from isolated hippocampal nerve endings, and which adenosine receptors could be mediating this influence. When extracellular endogenous adenosine was removed using adenosine deaminase (ADA, 1 U/ml), the enhancement (57.2 ± 3.7%) caused by VIP on GABA release was prevented. Blockade of adenosine A1 receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nM) or of A2A receptors with ZM241385 (50 nM) abolished the effect of VIP. In the presence of ADA, selective A2A receptor-activation with CGS21680 (10 nM) readmitted most of the enhancement caused by VIP on GABA release (50.7 ± 5.3%). Also in the presence of ADA, A1 receptor activation with N6-cyclopentyladenosine (CPA, 50 nM) partially readmitted that effect of VIP (32.6 ± 3.8%). In conclusion, the enhancement of GABA release caused by VIP in hippocampal nerve terminals is dependent on the tonic actions of adenosine on both A1 and A2A receptors, and this action of adenosine is essential to VIP modulation of GABA release.