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 mammalian central nervous system. When intact hippocampal slices were incubated in artificial cerebrospinal fluid, 12-hydroxyeicosatetraenoic acid and two isomers of hepoxilin A(3) (8R and 8S) were released as measured by gas chromatography-mass spectrometry. These compounds were released in greater amounts in the presence of noradrenaline or when arachidonic acid was added to the slices. The neuronal actions of chemically derived preparations of 8R and 8S hepoxilins and the glutathione conjugate, hepoxilin A(3)-C, were examined using intracellular and whole-cell 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 afterhyperpolarizations and increased inhibitory postsynaptic potentials or currents. A synthetic analog of hepoxilin A(3)-C, in which the glutathione moiety 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 effect at 3 nM (n = 21) and maximal effects at 10 nM (n = 33). There were no significant differences between the responses to either the 8R or 8S isomers, or between hepoxilin A(3) and hepoxilin A(3)-C. These data suggest that hepoxilins formed by the brain have significant neuromodulatory actions. We conclude that interhippocampal transfer of lateralized place learning is easily induced, is equal if the transfer is facultative or imperative, and involves both trans-commissural read-out and write-in processes.