SOMATOSTATIN INHIBITION OF HIPPOCAMPAL CA1 PYRAMIDAL NEURONS - MEDIATION BY ARACHIDONIC-ACID AND ITS METABOLITES

We used electrophysiological methods in a slice preparation to study t he mechanisms of somatostatin (SS) effects on hippocampal pyramidal ne urons. SS hyperpolarizes hippocampal pyramidal neurons in part by augm enting the time- and voltage-dependent M-current (I(M)), which has bee n shown to be reduced by muscarinic agonists. The SS effects are aboli shed by the phospholipase A2 inhibitors 4-bromophenacyl bromide and qu inacrine. Arachidonic acid (AA) mimics all the effects of SS on hippoc ampal pyramidal neurons. The effects of AA and SS on I(M) are blocked by the lipoxygenase inhibitor nordihydroguaiaretic acid but not by the cyclooxygenase inhibitor indomethacin. Prostaglandins E2, F2alpha, an d I2 do not increase I(M). However, the specific 5-lipoxygenase inhibi tors 5,6-methanoleukotriene A4 methylester and 5,6-dehydroarachidonic acid both blocked the I(M)-augmenting action of either SS or AA. Leuko triene C4 (but not leukotriene B4) increases 1, to the same extent as AA. I(M) was not altered by the 12-lipoxygenase product 12-hydroperoxy eicosatetraenoic acid, and SS effects were not altered by the 12-lipox ygenase inhibitor baicalein. These data implicate 5-lipoxygenase metab olite(s) (probably leukotriene C4) as a mediator for the I(M)-augmenti ng effect of SS. In addition, when the I(M) effect is blocked by lipox ygenase inhibitors, both SS and AA elicit another outward current that is not blocked by either lipoxygenase or cyclooxygenase inhibitors, s uggesting a direct role of AA itself distinct from the I(M) effect. SS did not alter significantly Ca2+-dependent action potentials or, in w hole-cell recordings, inward currents likely to represent high-thresho ld Ca2+ currents. The combined results of these studies suggest that S S hyperpolarizes hippocampal neurons by two mechanisms, both mediated through the AA system. However, one mechanism (I(M)) involves a metabo lite of AA and is most effective at slightly depolarized potentials, w hereas the other may involve AA itself and be more effective at membra ne potentials near rest.