HOT TOPICS ..................................................................................................................................................................... 369 limited due to its anesthetic actions at an acute increase in glutamatergic received by the University of Maryland higher doses, abuse liability, ataxic AMPA receptor activity, followed by Baltimore. effects, and capacity to produce changes a long-term upregulation of synaptic in sensation and dissociation even when AMPA receptors, likely resulting in Todd D Gould1,2,3, Panos Zanos1 and administered at sub-anesthetic antide- potentiation of excitatory synapses in Carlos A Zarate Jr4 1 pressant-effective doses. Ketamine’s mood-relevant brain regions. (2R,6R)- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; antidepressant action had been pre- HNK exerts these effects without the 2Department of Pharmacology, University of Maryland sumed to be via its anesthetic target, sensory-dissociation, ataxia, and abuse School of Medicine, Baltimore, MD, USA; 3 which is the inhibition of the NMDA liability of ketamine in animal tests. Department of Anatomy and Neurobiology, University et al of Maryland School of Medicine, Baltimore, MD, USA; glutamate receptor (Singh , 2014). In Overall, our findings, supported by 4Experimental Therapeutics and Pathophysiology contrast, although published clinical pharmacokinetic and chemical valida- Branch, Intramural Research Program, National studies to date have suggested modest tion, reveal that production of distinct Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA antidepressant efficacy of some alterna- metabolites of ketamine is necessary E-mail:
[email protected] tive NMDA receptor antagonists, thus and sufficient to produce ketamine’s far these drugs lack the robust rapid or antidepressant actions (Zanos et al, sustained efficacy of ketamine, and in 2016).