Dextromethorphan (DM) abuse produces mania-like symptoms in humans. ERK/Akt signaling activation involved in manic potential can be attenuated by the inhibition of ouabain-like cardiac steroids. In this study, increased phosphorylations of ERK/Akt and hyperlocomotion induced by DM (30mg/kg, i.p./day × 7) were significantly protected by the ouabain inhibitor rostafuroxin (ROSTA), suggesting that DM induces the manic potential. ROSTA significantly attenuated DM-induced protein kinase C δ (PKCδ) phosphorylation, GluN2B (i.e., MDA receptor subunit) expression, and phospho-PKCδ/GluN2B interaction. DM instantly upregulated the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent system. However, DM reduced Nrf2 nuclear translocation, Nrf2 DNA binding activity, γ-glutamylcysteine mRNA expression, and subsequent GSH/GSSG level and enhanced oxidative parameters following 1-h of administration. ROSTA, PKCδ inhibitor rottlerin, and GluN2B inhibitor traxoprodil significantly attenuated DM-induced alterations in Nrf2-related redox parameters and locomotor activity induced by DM in wild-type mice. Importantly, in PKCδ knockout mice, DM failed to alter the above parameters. Further, ROSTA and traxoprodil also failed to enhance PKCδ depletion effect, suggesting that PKCδ is a critical target for the anti-manic potential of ROSTA or GluN2B antagonism. Our results suggest that ROSTA inhibits DM-induced manic potential by attenuating ERK/Akt activation, GluN2B/PKCδ signalings, and Nrf2-dependent system.
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