Ketamine Produces a Long-lasting Enhancement of Excitatory Synaptic Transmission  Grace N. Jang , M Bruce MacIver (Stanford University, Stanford, CA )   C20

Introduction: Ketamine has recently been shown to improve major depressive disorder (MDD) in patients that are unresponsive to other forms of treatment. The antidepressant effect occurs rapidly, often following a single exposure, and can outlast the presence of the drug, often for several weeks. Current evidence suggests that the mechanism for this effect does not involve NMDA receptor antagonism. Little is known about other molecular targets for ketamine. The present study examined the effects of ketamine on synaptic transmission at glutamate and GABA synapses, to determine whether changes in activity at these synapses contribute to the lasting effects produced by this drug. Methods: All procedures were approved by the Stanford University Animal Use Committee, male C57BL/6J mice weighing between 25-30 grams were used to prepare 400 ?m thick coronal brain slices. We studied the effects of ketamine and its major metabolites (2R, 6R & 2S, 6S)-hydroxynorketamine by electrically stimulating Shaffer-collateral axons while recording evoked responses from CA1 pyramidal neurons and GABA inhibitory interneurons using a paired-pulse paradigm. Results: Concentration dependent effects were observed over clinical ranges (from 1.0 ?M; antidepressant, to 350 ?M; anesthetic). Ketamine produced three effects: 1) an acute depression of population spike amplitudes, 2) an enhancement of GABA-A fast and/or tonic inhibition, and 3) a long-lasting increase in population spike amplitude. The long-lasting increase in amplitude was observed following drug washout and lasted for at least 8 hours (longest duration of recording). This effect was unlike other anesthetics that also produce an acute depression of population spike amplitudes, but do not produce long-lasting effects following washout. These effects were mimicked by the primary ketamine metabolites. A long-lasting effect was not observed on EPSP responses, indicating a postsynaptic site for ketamine's action. Conclusions: Our results agree with previous studies showing that ketamine produces an acute depression of population spike amplitudes with an increase in GABA-mediated inhibition. This is the first report to demonstrate a long-lasting increase in excitability following washout of ketamine from the brain slice. We suggest this long-lasting effect could be related to the long-lasting antidepressant effects produced by ketamine and its metabolites.