INVOLVEMENT OF THE 12-LIPOXYGENASE PATHWAY OF ARACHIDONIC-ACID METABOLISM IN HOMOSYNAPTIC LONG-TERM DEPRESSION OF THE RAT HIPPOCAMPUS

Low-frequency stimulation is associated with long-term depression (LTD ) of synaptic efficacy in various brain structures. Like long-term pot entiation (LTP), homosynaptic LTD in area CA1 of the hippocampus appea rs to require NMDA receptor activation, changes in postsynaptic calciu m concentration and phospholipase A(2) (PLA(2)) activation. Arachidoni c acid (AA) is released after the activation of calcium-dependent phos pholipases and free AA is rapidly metabolized to a family of bioactive products (the eicosanoids) which are thought to be both intracellular and extracellular messengers. In the present study, we investigated t he involvement of the cyclooxygenase and lipoxygenase pathways of AA m etabolism in the formation of homosynaptic LTD in the rat hippocampus. Stimulation at 1 Hz for 15 min was used to produce homosynaptic depre ssion in area CA1 of hippocampal slices. LTD induction was partially b locked by bromophenacyl bromide (50-100 mu M), a selective PLA(2) inhi bitor, and by the a nonselective lipoxygenase inhibitor nordihydroguai aretic acid (NDGA; 100 mu M). In contrast, the specific cyclooxygenase blocker indomethacin (100 mu M) did not significantly reduce hippocam pal LTD. Since NDGA interferes with LTD formation, we examined whether specific inhibitors of 5- and 12-lipoxygenases were capable of blocki ng LTD expression, The 12-lipoxygenase inhibitor baicalein at a concen tration of 50 mu M reduced LTP formation when given in the bath, an ef fect that was less pronounced with the 5-lipoxygenase inhibitor AA-861 . These data suggest that the activation of endogenous PLA(2) and the formation of 12-lipoxygenase metabolites of AA may be important factor s controlling the expression of hippocampal LTD.