Functional interplay between adenosine A2A receptor and NMDA preconditioning in fear memory and glutamate uptake in the mice hippocampus

N-methyl D-aspartate (NMDA) administered at subtoxic dose plays a protective role against neuronal excitotoxicity, a mechanism described as preconditioning. Since the activation of adenosinergic receptors influences the achievement of NMDA preconditioning in the hippocampus, we evaluated the potential functional interplay between adenosine A(1) and A(2A) receptors (A(1)R and A(2A)R) activities and NMDA preconditioning. Adult male Swiss mice received saline (NaCl 0.9 g%, i.p.) or a nonconvulsant dose of NMDA (75 mg/kg, i.p.) and 24 h later they were treated with the one of the ligands: A(1)R agonist (CCPA, 0.2 mg/kg, i.p.) or antagonist (DPCPX, 3 mg/kg, i. p.), A(2A)R agonist (CGS21680, 0.05 mg/kg, i.p.) or antagonist (ZM241385, 0.1 mg/kg, i.p.) and subjected to contextual fear conditioning task. Binding properties and content of A(2A)R and glutamate uptake were assessed in the hippocampus of mice subjected to NMDA preconditioning. Treatment with CGS21680 increased the time of freezing during the exposure of animals to the new environment. NMDA preconditioning did not affect the freezing time of mice per se, but it prevented the response observed after the activation of A(2A)R. Furthermore, the activation of A(2A)R by CGS21680 after the preconditioning blocked the increase of glutamate uptake induced by NMDA preconditioning. The immunodetection of A(2A)R in total hippocampal homogenates showed no significant differences evoked by NMDA preconditioning and did not alter A(2A)R maximum binding for the selective ligand [H-3]CGS21680. These results demonstrate changes in A(2A)R functionality in mice following NMDA preconditioning.

Automated summary

This study investigated the relationship between adenosine A(1) and A(2A) receptors activities and NMDA preconditioning, revealing that activation of A(2A)R can block the increase of glutamate uptake induced by NMDA preconditioning and increase freezing time in a new environment. These results demonstrate changes in A(2A)R functionality in mice following NMDA preconditioning.