The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant

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...... 221 Ingelheim. Dr Cunningham declares no conflict of interest.

ACKNOWLEDGMENTS We thank Ms Christina Merritt for the design of the figure.

F Gerard Moeller1 and Kathryn A Cunningham2 1Department of Psychiatry, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA; 2Department of Pharmacology and Toxicology, Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA E-mail: [email protected] or [email protected]

Figure 1. Either a μ-opioid receptor partial agonist, a full 5-HT receptor (5-HT R) agonist, or a ...... 2C 2C Cunningham KA, Anastasio NC (2014). Serotonin at combination may afford gains in reducing relapse vulnerability and extending abstinence in opioid use the nexus of impulsivity and cue reactivity in μ disorder (OUD). Partial agonist actions at the -opioid receptor reduce the rewarding effects of cocaine addiction. Neuropharmacology 76 Pt B: opioids and withdrawal. The selective 5-HT2CR full agonist lorcaserin suppresses oxycodone intake 460–478. and associated cue reactivity as well as impulsivity. Low-dose combinations of a μ-opioid receptor Lutfy K, Cowan A (2004). Buprenorphine: a unique partial agonist plus the non-opioid lorcaserin may provide an additional new avenue to support drug with complex pharmacology. Curr Neurophar- recovery in OUD patients. While the brain locus for a potential receptor–receptor interaction is macol 2: 395–402. Neelakantan H, Holliday ED, Fox RG, Stutz SJ, unknown, both the μ-opioid receptor and 5-HT2CR are co-expressed in nodes of the limbic- corticostriatal circuitry engaged in drug reward and relapse vulnerability. The FDA-approved OUD Comer SD, Haney M et al (2017). Lorcaserin suppresses oxycodone self-administration and medication buprenorphine is a μ-opioid receptor partial agonist, but is not selective given its complex δ κ relapse vulnerability in rats. ACS Chem Neurosci 8: actions at -, -, and nociceptin/opioid receptor-like receptors (NOP or ORL-1) (Lutfy and Cowan, 1065–1073. μ 2004). Thus, other -opioid partial agonists may be needed to test the hypothesis that low-dose Shanahan WR, Rose JE, Glicklich A, Stubbe S, combinations with lorcaserin may add value in OUD medication-assisted therapy. Sanchez-Kam M (2016). Lorcaserin for smoking cessation and associated weight gain: a precipitated withdrawal following events, for example. It is also possible randomized 12-week clinical trial. Nicotine Tob Res 2016 Nov 4. ppi: ntw301. (e-pub ahead chronic opioid exposure in mice that low doses of lorcaserin adminis- of print). (Wu et al, 2015). Thus, the non- tered in combination with a partial μ- Volkow ND, Frieden TR, Hyde PS, Cha SS opioid medication lorcaserin acts as a opioid agonist, with limited abuse (2014). Medication-assisted therapies–tackling the opioid-overdose epidemic. NEnglJMed370: 5-HT2CR agonist to influence aspects liability but efficacy to suppress 2063–2066. of opioid-evoked behaviors, suggest- opioid-induced euphoria and withdra- Wu X, Pang G, Zhang YM, Li G, Xu S, Dong L et al ing that the 5-HT Rsystemmay wal may reduce relapse risk via regula- (2015). Activation of serotonin 5-HT(2C) receptor 2C suppresses behavioral sensitization and naloxone- play a key role in the shared mechan- tion of two signaling pathways. The precipitated withdrawal symptoms in heroin- isms for addiction and relapse vul- neurochemical mechanisms and sites treated mice. Neurosci Lett 607:23–28. nerability across psychostimulant of action for 5-HT2CR systems to Neuropsychopharmacology Reviews (2018) 43, 220–221. andopioiddrugclasses. control opioid-related behaviors are doi:10.1038/npp.2017.192 The development of pain medica- also of interest. Finally, preclinical tions with analgesic efficacy, but re- studies to evaluate low-dose combina- μ duced abuse liability, remains a high tions of a partial -opioid agonist plus priority. Of equally high priority is the lorcaserin will provide insight into the The Ketamine identification of therapeutic interven- potential for translational value in Metabolite 2R,6R- tions that increase the maintenance of clinical trials geared to reduce the abstinence after cessation of opioid devastation of opioid overdose Hydroxynorketamine intake, even in high drug cue environ- and OUD. Blocks NMDA Receptors ments. A selective 5-HT2CR agonist, and Impacts such as lorcaserin, may provide a new Downstream Signaling avenue to add value to the outcomes of FUNDING AND DISCLOSURE medication-assisted treatment in OUD Drs Moeller and Cunningham are Linked to Antidepressant (Figure 1). The next step is to expand supported by grants NIDA U54 Effects the present data set to definitively test DA038999 and NIDA P50 DA033935. the hypotheses that lorcaserin inhibits Dr Moeller is an uncompensated con- Clinical studies have demonstrated a opioid withdrawal and countermands sultant for INDIVIOR and receives reproducible rapid antidepressant stress- and/or opioid-triggered relapse research support from Boehringer- effect of low-dose ketamine in patients

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...... 222 with depressive symptoms. However, signaling pathway and effects on role of NMDAR-block-mediated sig- ketamine’s dissociative side effects AMPAR-mediated potentiation—sans naling in triggering the antidepressant and abuse potential has led to the NMDAR block—prompted us to in- effects of ketamine and 2R,6R-HNK. search for identification of alternative vestigate the impact of 2R,6R-HNK on compounds that trigger rapid antide- NMDAR-mediated neurotransmis- FUNDING AND DISCLOSURE pressant effects without the psychoto- sion. In recent experiments, we mimetic side effects. A successful showed that 2R,6R-HNK can swiftly This work was supported by National effort will require elucidation of the inhibit NMDAR transmission up to Institutes of Health Grants MH070727 molecular mechanisms that elicit the 50% at concentrations needed to (LMM) and MH066198 (ETK). LMM antidepressant effects of ketamine. In trigger the intracellular signaling path- is a consultant for Fortress Biotech. 2011, our group proposed a synaptic way involved in the potentiation of ETK declares no conflict of interest. signaling pathway that can account for synaptic AMPAR responses, strongly ketamine’s antidepressant-like effects supporting a role for NMDAR- Ege T Kavalali1 and Lisa M Monteggia1 1 in preclinical animal models (Autry blockade in this effect (Suzuki et al, Department of Neuroscience, the University of Texas Southwestern Medical Center, Dallas, TX, USA et al, 2011). Specifically, we showed 2017). Further characterization E-mail: [email protected] that ketamine-mediated block of showed that the effect of 2R,6R-HNK resting synaptic NMDA receptor on individual NMDA-mEPSCs mi- (NMDAR) activity—driven by sponta- micked those of ketamine, demonstrat- ...... — — — Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, neous glutamate release leads to de- ing that 2R,6R HNK like ketamine Cheng P et al (2011). NMDA receptor blockade at activation of eEF2 kinase resulting in selectively inhibits NMDARs while they rest triggers rapid behavioural antidepressant dephosphorylation of its sole known are open (Suzuki et al, 2017). Our study responses. Nature 275:91–95. μ Maeng S, Zarate CA Jr, Du J, Schloesser RJ, target eEF2. The dephosphorylation of demonstrated that 50 M 2R,6R-HNK McCammon J, Chen G et al (2008). Cellular eEF2 results in desuppresion of den- blocks synaptic NMDARs and thus mechanisms underlying the antidepressant effects dritic protein translation and a rapid 2R,6R-HNK is not ‘NMDAR-indepen- of ketamine: role of alpha-amino-3-hydroxy-5- ’ methylisoxazole-4-propionic acid receptors. Biol subsequent increase in brain-derived dent in its action. Although we used a Psychiatry 63: 349–352. neurotrophic factor (BDNF) expres- higher concentration than the 10 μM Nosyreva E, Szabla K, Autry AE, Ryazanov AG, sion. Released BDNF activates TrkB 2R,6R-HNK—suggested as the brain Monteggia LM, Kavalali ET (2013). Acute suppres- sion of spontaneous neurotransmission drives receptors and triggers a subsequent concentration in rodents following a synaptic potentiation. J Neurosci 33: 6990–7002. potentiation of AMPA receptor (AM- behaviorally effective antidepressant Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, PAR)-mediated synaptic transmission dose of 10 mg/kg 2R,6R-HNK (Zanos Monteggia LM (2017). The ketamine metabolite — hydroxynorketamine impacts downstream signal- in the hippocampus, providing a et al, 2016) a recent study was not ing via NMDA receptor inhibition. Nature 546: synaptic basis for the antidepressant able to detect antidepressant effects of E1–E3. effects of ketamine (Autry et al,2011; 10 mg/kg 2R,6R-HNK in the same Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K (2017). (R)-Ketamine shows greater potency and Nosyreva et al, 2013). Consistent with behavioral paradigms (Yang et al, longer lasting antidepressant effects than its the premise, ketamine’s antidepressant 2017) used by Zanos and colleagues, metabolite (2R,6R)-hydroxynorketamine. Biol Psy- effects have previously been shown to raising questions about the dose of chiatry 82:e43–e44. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell require AMPARs as NBQX, an AM- 2R,6R-HNK necessary to mediate anti- J, Elmer GI et al (2016). NMDAR inhibition- PAR antagonist, attenuates the anti- depressant effects and the brain con- independent antidepressant actions of ketamine depressant effects in rodents (Maeng centration necessary to trigger the metabolites. Nature 533:481–486.

et al, 2008; Autry et al, 2011). Im- molecular pathway. Moreover, a me- Neuropsychopharmacology Reviews (2018) 43, 221–222. portantly, the model we proposed can chanism, other than the demonstrated doi:10.1038/npp.2017.210 account for the ineffectiveness of the NMDAR-blockade of 2R,6R-HNK, re- NMDAR blocker memantine as an mains to be demonstrated. The selec- antidepressant in the clinic, as mem- tive action of 2R,6R-HNK on open antine—unlike ketamine—has a lim- NMDARS indicate its efficacy as an Cognitive Signaling in ited ability to block resting NMDAR antidepressant will strongly depend on Cerebellar Granule Cells function. However, a recent study factors that impact synaptic NMDAR challenged a key component of the channel opening. These factors may The cerebellum contains over three model by suggesting that ketamine’s include glutamate release-probability, quarters of the neurons in the human antidepressant action is mediated by subunit composition of synaptic brain (Herculano-Houzel, 2010), but it its metabolite 2R,6R-hydroxynorketa- NMDARs, as well as levels of co- has traditionally been studied mainly mine (2R,6R-HNK), via the same agonists. Future studies will need to in sensorimotor contexts. Yet in hu- signaling pathway and AMPAR- take into account these synaptic factors mans, cerebellar circuits activate dur- mediated synaptic potentiation as out- to elucidate the specific circuits in- ing and are required for verbal and line above (Autry et al,2011)butina volved in the antidepressant action of spatial processing tasks (eg, Stoodley NMDAR-independent manner (Zanos ketamine as well as 2R,6R-HNK. Over- et al (2012)), and multiple lines et al, 2016). Validation of the same all, our findings demonstrate a critical of evidence point to cerebellar links

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