Adenosine A1 receptor activation modulates N-methyl-d-aspartate (NMDA) preconditioning phenotype in the brain

Abstract N-methyl- d -aspartate (NMDA) preconditioning is induced by subtoxic doses of NMDA and it promotes a transient state of resistance against subsequent lethal insults. Interestingly, this mechanism of neuroprotection depends on adenosine A 1 receptors (A 1 R), since blockade of A 1 R precludes this phenomenon. In this study we evaluated the consequences of NMDA preconditioning on the hippocampal A 1 R biology ( i.e. expression, binding properties and functionality). Accordingly, we measured A 1 R expression in NMDA preconditioned mice (75 mg/kg, i.p.; 24 h) and showed that neither the total amount of receptor, nor the A 1 R levels in the synaptic fraction was altered. In addition, the A 1 R binding affinity to the antagonist [ 3 H] DPCPX was slightly increased in total membrane extracts of hippocampus from preconditioned mice. Next, we evaluated the impact of NMDA preconditioning on A 1 R functioning by measuring the A 1 R-mediated regulation of glutamate uptake into hippocampal slices and on behavioral responses in the open field and hot plate tests. NMDA preconditioning increased glutamate uptake into hippocampal slices without altering the expression of glutamate transporter GLT-1. Interestingly, NMDA preconditioning also induced antinociception in the hot plate test and both effects were reversed by post-activation of A 1 R with the agonist CCPA (0.2 mg/kg, i.p.). NMDA preconditioning or A 1 R modulation did not alter locomotor activity in the open field. Overall, the results described herein provide new evidence that post-activation of A 1 R modulates NMDA preconditioning-mediated responses, pointing to the importance of the cross-talk between glutamatergic and adenosinergic systems to neuroprotection.