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). .............................................................................................. Adams JD Jr., Baillie TA, Trevor AJ, Castagnoli N Jr. some cases (eg, memantine) they have Based on these data, we propose that (1981). Studies on the biotransformation of keta- been proven clinically ineffective ketamine, and individually (S)-keta- mine. 1-Identification of metabolites produced (Newport et al, 2015). This suggests that mine and (R)-ketamine enantiomers, in vitro from rat liver microsomal preparations. Biomed Mass Spectrom 8: 527–538. it is unlikely ketamine exerts its anti- exert NMDA receptor inhibition- Desta Z, Moaddel R, Ogburn ET, Xu C, Ramamoorthy A, depressant actions solely via inhibition independent antidepressant actions Venkata SL et al (2012). Stereoselective and regio- of the NMDA receptor. via metabolism to their respective specific hydroxylation of ketamine and norketamine. Xenobiotica 42:1076–1087. Ketamine is rapidly metabolized in HNKs. Validation of the relevance of Newport DJ, Carpenter LL, McDonald WM, Potash JB, the liver via multiple cytochrome P450 HNK metabolites to the clinical anti- Tohen M, Nemeroff CB et al (2015). Ketamine and isoforms to norketamine, dehydronor- depressant actions of ketamine in Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. Am J Psychiat ketamine, hydroxyketamines, and a humans will require human clinical 172:950–966. number of hydroxynorketamines trials, which are currently in Singh NS, Zarate CA Jr., Moaddel R, Bernier M, (HNKs) in a stereoselective manner preparation. Wainer IW (2014). What is hydroxynorketamine and et al et al what can it bring to neurotherapeutics? Expert Rev (Adams , 1981; Desta , 2012). Neurother 14: 1239–1242. This presents the possibility that keta- FUNDING AND DISCLOSURE Zanos P, Moaddel R, Morris PJ, Georgiou P, mine acts as a prodrug, whereby Fischell J, Elmer GI et al (2016). NMDAR in vivo inhibition-independent antidepressant actions of metabolic conversions result This work was supported by the U.S. ketamine metabolites. Nature 533:481–486. in the biologically active drug. We National Institute of Health (NIH) grant Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, recently reported that the metabolism MH107615 to TDG and the National Ameli R, Luckenbaugh DA et al (2006). A rando- mized trial of an N-methyl-D-aspartate antagonist in of ketamine is essential for its anti- Institute of Mental Health NIH intra- treatment-resistant major depression. Arch Gen depressant actions in mice (Zanos et al, mural research program (CAZ). CAZ is Psychiatry 63: 856–864. 2016). Specific HNK metabolites of listed as a co-inventor on a patent for the 2S,6S 2R,6R 2R,6R ketamine, ( )-HNK and ( )- use of ( )-hydroxynorketamine, Neuropsychopharmacology Reviews (2017) 42, 368–369; HNK, produced from (S)-ketamine or (S)-dehydronorketamine, and other doi:10.1038/npp.2016.210 (R)-ketamine, respectively, do not bind stereoisomeric dehydro- and hydroxy- to or functionally inhibit the NMDA lated metabolites of (R,S)-ketamine me- receptor at antidepressant-relevant tabolites in the treatment of depress- concentrations, but do exert antide- ion and neuropathic pain. CAZ, TDG, The Direct and Indirect pressant behavioral effects similar to and PZ are listed as co-inventors on a Pathways of the Nucleus 2R,6R that observed following administration patent application for the use of ( )- Accumbens are not of ketamine itself. Administration of hydroxynorketamine and (2S,6S)-hydro- the (2R,6R)-HNK enantiomer to mice xynorketamine in the treatment of What You Think fully reproduces the antidepressant depression, anxiety, anhedonia, suicidal (and anti-anhedonic) behavioral and ideation, and post-traumatic stress dis- According to current concepts, moti- biochemical actions of ketamine. orders. CAZ has assigned his patent vated and addictive behaviors across (2R,6R)-HNK exerts unique electro- rights to the U.S. government species depend on the activity of the physiological actions that provide an but will share a percentage of any nucleus accumbens (NAc), and speci- explanation for ketamine’s antidepres- royalties that may be received by the fically on two groups of projection sant efficacy (Zanos et al, 2016). government. TG and PZ have assigned medium spiny neurons (MSNs). Those Although the pharmacological target their patent rights to the University of that directly inhibit the dopaminergic of these HNKs have not been identified Maryland Baltimorebutwillsharea ventral mesencephalon (VM) (the ‘di- yet, our data support a critical role of percentage of any royalties that may be rect pathway’) express the D1 ................................................................................................................................................... Neuropsychopharmacology HOT TOPICS ..................................................................................................................................................................... 370 the reward system, and particularly of the understudied VP. In conclusion, the traditional view of the reward system as being comprised of two distinct cell-type-specific pathways is an oversimplification. Emerging data requires developing a new perspective of the circuitry of the reward system that will guide future treatment strategies for addic- tion and other related mental health disorders. FUNDING AND DISCLOSURE The authors declare no conflict of Figure 1. Past and novel concepts of the direct and indirect pathways of the nucleus accumbens. interest. Left—canonical concept. D1-MSNs and D2-MSNs are completely segregated to direct and indirect pathways. Right—updated concept. Both D1-MSNs and D2-MSNs participate in direct and indirect pathways. Note that MSNs projecting to the VP may be part of a direct or indirect pathway, depending on the target of their downstream VP neuron. ACKNOWLEDGMENTS This research was supported by US Public Health Service grants DA03906, dopamine receptor (D1-MSNs), disin- evidence that the direct and indirect DA12513 and DA015369, the Israel hibit the thalamus and promote moti- pathways of the NAc are not coded by Science Foundation grant 1381/15, and vated behavior. The others, considered MSN cell types (Figure 1). Using a fellowship from the Neuroscience to be solely D2-MSNs, inhibit the optogenetics in transgenic mice com- Institute, Medical University of South ventral pallidum (VP), which inhibits bined with neural tracing tools we Carolina. the VM (the ‘indirect pathway’), this showed that D1-MSNs comprise a results in the inhibition of the thala- significant portion of the classical Yonatan M Kupchik1 and mus and motivated behavior indirect pathway by synapsing on VP 2 Peter W Kalivas (Figure 1). Importantly, these path- neurons that project to the VM. Con- 1Department of Medical Neurobiology, The Institute ways were originally described for the versely, we showed that NAc D2-MSNs for Medical Research Israel-Canada, Faculty of dorsal Medicine, The Hebrew University of Jerusalem, Israel; striatum in times of relatively target VP neurons that innervate the 2 et al Department of Neurosciences, The Medical limited technology (Albin , 1989), thalamus directly. Thus, these D2-MSNs University of South Carolina, Charleston SC, USA and were assumed to be true also for make a direct pathway through the VP E-mail: [email protected] the NAc. that disinhibits the thalamus. These .............................................................................................. Recent developments in cell-type- findings are not restricted