The brain is highly dependent on oxygen supply in order to maintain synaptic function and conductivity. Although a hypoxic event may lead to hippocampal neuronal death, an early neuroprotective response to this insult is the activation of adenosine₁ receptors (A₁R). The role of pro-inflammatory components in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. Recent evidence suggest a role for tumor necrosis factor-alpha (TNF-α) in protecting neuronal cells against hyperexcitability induced by hypoxic insults [1]. In the present study we have investigated the modulatory actions of TNF-α on synaptic transmission during and after hypoxia. We have also investigated the role of A₁R in this effect. Hippocampal slices (350 μm) were obtained from P21 male Wistar rats that were humanely killed under anesthetization (4% isoflurane, by inhalation). fEPSPs were elicited from the Shaffer collateral pathway in the CA1 region every 30 s. Long-term potentiation (LTP) was induced with 3 trains of 100 stimuli applied at 100Hz every 30 s. Statistical analysis was performed using Mann-Whitney test. All results are represented as mean±S.E.M. All fEPSP slope measurements are presented as a percentage of baseline recordings. Following a 2 hr hypoxic exposure with N₂ perfusion (PO₂ 37±2 mmHg above the slice; 30.8±10.4% compared to controls), the fEPSP returned to control levels. Inhibition of A₁Rs (8-cyclopentyl-1,3-dipropylxanthine; DPCPX; 200 nM) significantly reversed the hypoxia-induced synaptic depression (85.7±4.3%, versus controls; n=5, p<0.05) but impaired the maintenance of LTP after re-oxygenation (96.4±10.6% versus 143.8±8.2% in controls, 1 hr post tetanus; n=5; p<0.005). DPCPX also attenuated the hypoxic-induced depression of the pharmacological isolated NMDA fEPSP (40.5±5.2% versus 61.2±2.7%, n=5 p<0.05, 30 min after hypoxic exposure). 30 min TNF-α treatment (3ng/ml) during hypoxic exposure attenuated the recovery of the fEPSP after re-oxygenation (61.0±7.2% versus 86.7±6.6%; n=5; p<0.05). LTP induced after re-oxygenation was not affected by pre-treatment with TNF-α during hypoxia (138.0±8.3%, compared to controls, n=5). Liquid Chromatography and Mass Spectrometric analysis for cAMP was carried out in hippocampal slice homogenates to investigate if A₁Rs were activated after TNF-α treatment (3ng/ml) and re-oxygenation. Unexpectedly, an increase in cAMP was observed in TNF-α treated slices (20.6±2.3nM versus 11.4±1.5 nM controls; n=4; p< 0.05), an effect reversed by the p38 mitogen-activated protein kinase inhibitor (SB203580; 1 μM) (8.3±1.4 nM; n=4; p< 0.05). These data show that TNF-α can modulate synaptic transmission after a hypoxic exposure, an effect that does not seem to involve A₁R activation during re-oxygenation.