FORMATION AND ELECTROPHYSIOLOGICAL ACTIONS OF THE ARACHIDONIC ACID METABOLITES, HEPOXILINS, AT NANOMOLAR CONCENTRATIONS IN RAT HIPPOCAMPAL SLICES

Metabolites of arachidonic acid are known to be formed in the mammalia n central nervous system. When intact hippocampal slices were incubate d in artificial cerebrospinal fluid, 12-hydroxyeicosatetraenoic acid a nd two isomers of hepoxilin A(3) (8R and 8S) were released as measured by gas chromatography-mass spectrometry. These compounds were release d in greater amounts in the presence of noradrenaline or when arachido nic acid was added to the slices. The neuronal actions of chemically d erived preparations of 8R and 8S hepoxilins and the glutathione conjug ate, hepoxilin A(3)-C, were examined using intracellular and whole-cel l electrophysiological recordings in hippocampal CA1 neurons in vitro. All compounds had the excitatory effects of lowering spike threshold and decreasing spike frequency adaptation, and the inhibitory actions of membrane hyperpolarization, enhanced postspike train afterhyperpola rizations and increased inhibitory postsynaptic potentials or currents . A synthetic analog of hepoxilin A(3)-C, in which the glutathione moi ety is placed at carbon position 9 instead of carbon position 11 as in hepoxilin A(3)-C, was inactive. The actions of the hepoxilins showed a sharp dose-response relationship, with minimal threshold or no effec t at 3 nM (n = 21) and maximal effects at 10 nM (n = 33). There were n o significant differences between the responses to either the 8R or 8S isomers, or between hepoxilin A(3) and hepoxilin A(3)-C. These data s uggest that hepoxilins formed by the brain have significant neuromodul atory actions. We conclude that interhippocampal transfer of lateraliz ed place learning is easily induced, is equal if the transfer is facul tative or imperative, and involves both trans-commissural read-out and write-in processes.