The synaptic modifications underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in various brain structures may result from changes in the properties of the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. In the present study, we report that treatment of rat synaptoneurosomes with increasing concentrations of phospholipase A 2 (PLA 2 ) produces a biphasic effect on AMPA receptor binding, with low concentrations causing a decrease and high concentrations an increase in agonist binding. Analysis of the saturation kinetics of 3 H-AMPA binding revealed that the biphasic effect of PLA 2 was due to modifications in receptor affinity and not to changes in the maximum number of binding sites for AMPA receptors. The 12-lipoxygenase inhibitors preferentially reduced PLA 2 -induced decrease in AMPA binding and treatment of hippocampal synaptoneurosomes with arachidonic acid (AA) or 12-HPETE, the first metabolite generated from the hydrolysis of AA by 12-lipoxygenases, decreased 3 H-AMPA binding. Moreover, electrophysiological experiments indicated that the 12-lipoxygenase inhibitor baicalein totally blocked LTD formation in area CA 1 of hippocampal slices. The decrease in 3 H-AMPA binding elicited by low concentrations of PLA 2 , as well as the level of LTD, were partially reduced by AA-861, a 5lipoxygenase inhibitor, while the cyclooxygenase inhibitor indomethacin did not prevent LTD formation or the effects of PLA 2 on 3 H-AMPA binding. Our results provide evidence for a possible involvement of lipoxygenase metabolites in the regulation of AMPA receptor during synaptic depression. In addition, they strongly support the idea that the same biochemical pathway, i.e., NMDA receptor activation and endogenous PLA 2 stimulation, may represent a common mechanism resulting in AMPA receptor alterations for both LTP and LTD formation.