Facilitation of GABA release by arachidonic acid in rat hippocampal synaptosomes

Arachidonic acid (AA) is proposed to be a facilitatory retrograde messenger in hippocampal glutamatergic synapses. In this study, we found that AA (10 mu M) increased the basal outflow (19 +/- 4%) and the K+-evoked release of [H-3]GABA (38 +/- 3%) from rat hippocampal synaptosomes. This effect is li kely to be a direct action of AA, as it was not mimicked by arachidic acid (10 mu M) and was not modified by inhibition of either lipooxygenase with n ordihydroguaiaretic acid (50 mu M) or cyclooxygenase with indomethacin (100 mu M). Activation of protein kinase C may be involved, as chelerythrine (6 mu M), a protein kinase C inhibitor, attenuated the AA (10 mu M)-facilitat ion of K+-evoked [H-3]GABA release by 58 +/- 5%, Phospholipase A(2) (2 U/mL ), an enzyme that releases AA, and melittin (1 mu M), a phospholipase A(2) activator, mimicked the AA-facilitation of evoked [3H]GABA release (70 +/- 6% and 76 +/- 7% facilitation, respectively). These results show that exoge nously added and endogenously produced AA increased basal outflow and K+-ev oked release of [H-3]GABA from rat hippocampal synaptosomes. Thus, AA can n o longer be considered solely a facilitatory neuromodulator in the hippocam pus, as this AA-facilitation of the release of the main inhibitory neurotra nsmitter may predominate under certain circumstances.