Abstract
Rationale
Evidence indicates that ketamine’s rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile.
Objectives
We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action.
Methods
The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties.
Results
Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect.
Conclusions
The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.
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References
Albert DJ, Walsh ML, White R (1984) Rearing rats with mice prevents induction of mouse killing by lesions of the septum but not lesions of the medial hypothalamus or medial accumbens. Physiol Behav 32(1):143–145. https://doi.org/10.1016/0031-9384(84)90087-8
Baas JM, Milstein J, Donlevy M, Grillon C (2006) Brainstem correlates of defensive states in humans. Biol Psychiatry 59(7):588–593. https://doi.org/10.1016/j.biopsych.2005.09.009
Becker R, Braun U, Schwarz AJ, Gass N, Schweiger JI, Weber-Fahr W, Schenker E, Spedding M, Clemm von Hohenberg C, Risterucci C, Zang Z, Grimm O, Tost H, Sartorius A, Meyer-Lindenberg A (2016) Species-conserved reconfigurations of brain network topology induced by ketamine. Transl Psychiatry 6:e786. https://doi.org/10.1038/tp.2016.53
Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, Axmacher N, Lemke M, Cooper-Mahkorn D, Cohen MX, Brockmann H, Lenartz D, Sturm V, Schlaepfer TE (2010) Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry 67(2):110–116. https://doi.org/10.1016/j.biopsych.2009.09.013
Bewernick BH, Kayser S, Sturm V, Schlaepfer TE (2012) Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology 37:1975–1985. https://doi.org/10.1038/npp.2012.44
Brandao ML, Troncoso AC, de Souza Silva MA, Huston JP (2003) The relevance of neuronal substrates of defense in the midbrain tectum to anxiety and stress: empirical and conceptual considerations. Eur J Pharmacol 463(1-3):225–233. https://doi.org/10.1016/S0014-2999(03)01284-6
Bruns A, Mueggler T, Kunnecke B, Risterucci C, Prinssen EP, Wettstein JG, von Kienlin M (2015) “Domain gauges”: a reference system for multivariate profiling of brain fMRI activation patterns induced by psychoactive drugs in rats. NeuroImage 112:70–85. https://doi.org/10.1016/j.neuroimage.2015.02.032 [doi].
Capper-Loup C, Rebell D, Kaelin-Lang A (2009) Hemispheric lateralization of the corticostriatal glutamatergic system in the rat. J Neural Transm (Vienna) 116:1053–1057. DOI: 10.1007/s00702-009-0265-2, 9
Chen VC, Shen CY, Liang SH, Li ZH, Tyan YS, Liao YT, Huang YC, Lee Y, McIntyre RS, Weng JC (2016) Assessment of abnormal brain structures and networks in major depressive disorder using morphometric and connectome analyses. J Affect Disord 205:103–111. https://doi.org/10.1016/j.jad.2016.06.066
Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE Jr, Akil H, Watson SJ, Jones EG (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102(43):15653–15658. https://doi.org/10.1073/pnas.0507901102
DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr (2010) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71:1605–1611. https://doi.org/10.4088/JCP.09m05327blu
Dogra S, Kumar A, Umrao D, Sahasrabuddhe AA, Yadav PN (2016) Chronic kappa opioid receptor activation modulates NR2B: implication in treatment resistant depression. Sci Rep 6(1):33401. https://doi.org/10.1038/srep33401
Epstein J, Pan H, Kocsis JH, Yang Y, Butler T, Chusid J, Hochberg H, Murrough J, Strohmayer E, Stern E, Silbersweig DA (2006) Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. Am J Psychiatry 163:1784–1790
Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, Yang J, Pittenger C, Sanacora G, Krystal JH, Parsey RV, Carson RE, DeLorenzo C (2017) Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Mol Psychiatry. https://doi.org/10.1038/mp.2017.58
Gass N, Schwarz AJ, Sartorius A, Schenker E, Risterucci C, Spedding M, Zheng L, Meyer-Lindenberg A, Weber-Fahr W (2014) Sub-anesthetic ketamine modulates intrinsic BOLD connectivity within the hippocampal-prefrontal circuit in the rat. Neuropsychopharmacology 39(4):895–906. https://doi.org/10.1038/npp.2013.290
Gass N, Becker R, Schwarz AJ, Weber-Fahr W, Clemm von Hohenberg C, Vollmayr B, Sartorius A (2016) Brain network reorganization differs in response to stress in rats genetically predisposed to depression and stress-resilient rats. Transl Psychiatry 6:e970. https://doi.org/10.1038/tp.2016.233
Goebel DJ, Poosch MS (1999) NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Brain Res Mol Brain Res 69(2):164–170. https://doi.org/10.1016/S0169-328X(99)00100-X
Gorwood P (2008) Neurobiological mechanisms of anhedonia. Dialogues Clin Neurosci 10(3):291–299
Gozzi A, Schwarz A, Crestan V, Bifone A (2008) Drug-anaesthetic interaction in phMRI: the case of the psychotomimetic agent phencyclidine. Magn Reson Imaging 26(7):999–1006. https://doi.org/10.1016/j.mri.2008.01.012
Guo H, Cao X, Liu Z, Li H, Chen J, Zhang K (2012) Machine learning classifier using abnormal brain network topological metrics in major depressive disorder. Neuroreport 23(17):1006–1011. https://doi.org/10.1097/WNR.0b013e32835a650c
Hansen KB, Ogden KK, Yuan H, Traynelis SF (2014) Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81(5):1084–1096. https://doi.org/10.1016/j.neuron.2014.01.035 [doi].
Hasler G, Northoff G (2011) Discovering imaging endophenotypes for major depression. Mol Psychiatry 16(6):604–619. https://doi.org/10.1038/mp.2011.23
Hodkinson DJ, de Groote C, McKie S, Deakin JF, Williams SR (2012) Differential effects of Anaesthesia on the phMRI response to acute ketamine challenge. Br J Med Med Res 2(3):373–385. https://doi.org/10.9734/BJMMR/2012/1412
Hou Z, Wang Z, Jiang W, Yin Y, Yue Y, Zhang Y, Song X, Yuan Y (2016) Divergent topological architecture of the default mode network as a pretreatment predictor of early antidepressant response in major depressive disorder. Sci Rep 6(1):39243. https://doi.org/10.1038/srep39243
Inta D, Trusel M, Riva MA, Sprengel R, Gass P (2009) Differential c-Fos induction by different NMDA receptor antagonists with antidepressant efficacy: potential clinical implications. Int J Neuropsychopharmacol 12(08):1133–1136. https://doi.org/10.1017/S1461145709990319
Jimenez-Sanchez L, Campa L, Auberson YP, Adell A (2014) The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 39(11):2673–2680. https://doi.org/10.1038/npp.2014.123
Kawakami R, Shinohara Y, Kato Y, Sugiyama H, Shigemoto R, Ito I (2003) Asymmetrical allocation of NMDA receptor epsilon2 subunits in hippocampal circuitry. Science 300(5621):990–994. https://doi.org/10.1126/science.1082609
Kim SI (2013) Neuroscientific model of motivational process. Front Psychol 4:98. https://doi.org/10.3389/fpsyg.2013.00098
Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA (2014) Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4:e469. https://doi.org/10.1038/tp.2014.105
Lanfermann H, Schindler C, Jordan J, Krug N, Raab P (2015) Pharmacological MRI (phMRI) of the human central nervous system. Clin Neuroradiol 25(Suppl 2):259–266. https://doi.org/10.1007/s00062-015-0457-0
Levanen J, Makela ML, Scheinin H (1995) Dexmedetomidine premedication attenuates ketamine-induced cardiostimulatory effects and postanesthetic delirium. Anesthesiology 82(5):1117–1125. https://doi.org/10.1097/00000542-199505000-00005
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964. https://doi.org/10.1126/science.1190287
Liebrenz M, Stohler R, Borgeat A (2009) Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression. World J Biol Psychiatry 10(4-2):640–643. https://doi.org/10.1080/15622970701420481
Lord B, Wintmolders C, Langlois X, Nguyen L, Lovenberg T, Bonaventure P (2013) Comparison of the ex vivo receptor occupancy profile of ketamine to several NMDA receptor antagonists in mouse hippocampus. Eur J Pharmacol 715(1-3):21–25. https://doi.org/10.1016/j.ejphar.2013.06.028
Luykx JJ, Laban KG, van den Heuvel MP, Boks MP, Mandl RC, Kahn RS, Bakker SC (2012) Region and state specific glutamate downregulation in major depressive disorder: a meta-analysis of (1)H-MRS findings. Neurosci Biobehav Rev 36(1):198–205. https://doi.org/10.1016/j.neubiorev.2011.05.014
Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63(4):349–352. https://doi.org/10.1016/j.biopsych.2007.05.028
Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45(5):651–660. https://doi.org/10.1016/j.neuron.2005.02.014
Meng C, Brandl F, Tahmasian M, Shao J, Manoliu A, Scherr M, Schwerthoffer D, Bauml J, Forstl H, Zimmer C, Wohlschlager AM, Riedl V, Sorg C (2014) Aberrant topology of striatum's connectivity is associated with the number of episodes in depression. Brain 137(2):598–609. https://doi.org/10.1093/brain/awt290
Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, Hall BJ (2014) GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife 3:e03581. https://doi.org/10.7554/eLife.03581
Mony L, Kew JN, Gunthorpe MJ, Paoletti P (2009) Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. Br J Pharmacol 157(8):1301–1317. https://doi.org/10.1111/j.1476-5381.2009.00304.x
Mutel V, Buchy D, Klingelschmidt A, Messer J, Bleuel Z, Kemp JA, Richards JG (1998) In vitro binding properties in rat brain of [3H]Ro 25-6981, a potent and selective antagonist of NMDA receptors containing NR2B subunits. J Neurochem 70(5):2147–2155
Myers-Schulz B, Koenigs M (2012) Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. Mol Psychiatry 17(2):132–141. https://doi.org/10.1038/mp.2011.88
Nasrallah FA, Tan J, Chuang KH (2012) Pharmacological modulation of functional connectivity: alpha2-adrenergic receptor agonist alters synchrony but not neural activation. Neuroimage 60:436–446. https://doi.org/10.1016/j.neuroimage.2011.12.026
Nicholson KL, Mansbach RS, Menniti FS, Balster RL (2007) The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys. Behav Pharmacol 18(8):731–743. https://doi.org/10.1097/FBP.0b013e3282f14ed6
Oikonomidis L, Santangelo AM, Shiba Y, Clarke FH, Robbins TW, Roberts AC (2017) A dimensional approach to modeling symptoms of neuropsychiatric disorders in the marmoset monkey. Dev Neurobiol 77(3):328–353. https://doi.org/10.1002/dneu.22446
Park CH, Wang SM, Lee HK, Kweon YS, Lee CT, Kim KT, Kim YJ, Lee KU (2014) Affective state-dependent changes in the brain functional network in major depressive disorder. Soc Cogn Affect Neurosci 9(9):1404–1412. https://doi.org/10.1093/scan/nst126
Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28(6):631–637. https://doi.org/10.1097/JCP.0b013e31818a6cea
Pujara M, Koenigs M (2014) Mechanisms of reward circuit dysfunction in psychiatric illness: prefrontal-striatal interactions. Neuroscientist 20(1):82–95. https://doi.org/10.1177/1073858413499407
Rosburg T, Kreitschmann-Andermahr I (2016) The effects of ketamine on the mismatch negativity (MMN) in humans—a meta-analysis. Clin Neurophysiol 127(2):1387–1394. https://doi.org/10.1016/j.clinph.2015.10.062
Rubinov M, Sporns O (2010) Complex network measures of brain connectivity: uses and interpretations. NeuroImage 52(3):1059–1069. https://doi.org/10.1016/j.neuroimage.2009.10.003
Rubinov M, Sporns O (2011) Weight-conserving characterization of complex functional brain networks. NeuroImage 56(4):2068–2079. https://doi.org/10.1016/j.neuroimage.2011.03.069
Sacchet MD, Prasad G, Foland-Ross LC, Thompson PM, Gotlib IH (2014) Elucidating brain connectivity networks in major depressive disorder using classification-based scoring. Proc IEEE Int Symp Biomed Imaging 2014:246–249. https://doi.org/10.1109/ISBI.2014.6867855
Schwarz AJ, Danckaert A, Reese T, Gozzi A, Paxinos G, Watson C, Merlo-Pich EV, Bifone A (2006) A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: application to pharmacological MRI. NeuroImage 32(2):538–550. https://doi.org/10.1016/j.neuroimage.2006.04.214
Shaffer CL, Osgood SM, Smith DL, Liu J, Trapa PE (2014) Enhancing ketamine translational pharmacology via receptor occupancy normalization. Neuropharmacology 86:174–180. https://doi.org/10.1016/j.neuropharm.2014.07.008
Shinohara Y, Hirase H, Watanabe M, Itakura M, Takahashi M, Shigemoto R (2008) Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors. Proc Natl Acad Sci U S A 105(49):19498–19503. https://doi.org/10.1073/pnas.0807461105
Shumake J, Poremba A, Edwards E, Gonzalez-Lima F (2000) Congenital helpless rats as a genetic model for cortex metabolism in depression. Neuroreport 11(17):3793–3798. https://doi.org/10.1097/00001756-200011270-00040
Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, Tadic A, Sienaert P, Wiegand F, Manji H, Drevets WC, Van Nueten L (2016) Intravenous Esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry 80(6):424–431. https://doi.org/10.1016/j.biopsych.2015.10.018
Sivarao DV, Chen P, Yang Y, Li YW, Pieschl R, Ahlijanian MK (2014) NR2B antagonist CP-101,606 abolishes pitch-mediated deviance detection in awake rats. Front Psychiatry 5:96. https://doi.org/10.3389/fpsyt.2014.00096
Talishinsky A, Rosen GD (2012) Systems genetics of the lateral septal nucleus in mouse: heritability, genetic control, and covariation with behavioral and morphological traits. PLoS One 7(8):e44236. https://doi.org/10.1371/journal.pone.0044236
Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC (2000) Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry 57(12):1139–1147. https://doi.org/10.1001/archpsyc.57.12.1139
Vertes RP (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51(1):32–58. https://doi.org/10.1002/syn.10279
Vollenweider FX, Kometer M (2010) The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11(9):642–651. https://doi.org/10.1038/nrn2884
Wang J, Wang L, Zang Y, Yang H, Tang H, Gong Q, Chen Z, Zhu C, He Y (2009) Parcellation-dependent small-world brain functional networks: a resting-state fMRI study. Hum Brain Mapp 30(5):1511–1523. https://doi.org/10.1002/hbm.20623
Weed MR, Bookbinder M, Polino J, Keavy D, Cardinal RN, Simmermacher-Mayer J, Cometa FN, King D, Thangathirupathy S, Macor JE, Bristow LJ (2016) Negative allosteric modulators selective for the NR2B subtype of the NMDA receptor impair cognition in multiple domains. Neuropsychopharmacology 41(2):568–577. https://doi.org/10.1038/npp.2015.184
Williams KA, Magnuson M, Majeed W, LaConte SM, Peltier SJ, Hu X, Keilholz SD (2010) Comparison of alpha-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat. Magn Reson Imaging 28(7):995–1003. https://doi.org/10.1016/j.mri.2010.03.007
Xu T, Cullen KR, Mueller B, Schreiner MW, Lim KO, Schulz SC, Parhi KK (2016) Network analysis of functional brain connectivity in borderline personality disorder using resting-state fMRI. Neuroimage Clin 11:302–315. https://doi.org/10.1016/j.nicl.2016.02.006
Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (2015) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5:e632. https://doi.org/10.1038/tp.2015.136
Yang C, Ren Q, Qu Y, Zhang JC, Ma M, Dong C, Hashimoto K (2017) Mechanistic target of rapamycin-independent antidepressant effects of (R)-Ketamine in a social defeat stress model. Biol Psychiatry
Ye M, Yang T, Qing P, Lei X, Qiu J, Liu G (2015) Changes of functional brain networks in major depressive disorder: a graph theoretical analysis of resting-state fMRI. PLoS One 10(9):e0133775. https://doi.org/10.1371/journal.pone.0133775
Young CB, Chen T, Nusslock R, Keller J, Schatzberg AF, Menon V (2016) Anhedonia and general distress show dissociable ventromedial prefrontal cortex connectivity in major depressive disorder. Transl Psychiatry 6:e810. https://doi.org/10.1038/tp.2016.80
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481–486. https://doi.org/10.1038/nature17998
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864. https://doi.org/10.1001/archpsyc.63.8.856
Zhang J, Wang J, Wu Q, Kuang W, Huang X, He Y, Gong Q (2011) Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder. Biol Psychiatry 70(4):334–342. https://doi.org/10.1016/j.biopsych.2011.05.018
Zhang XH, Liu SS, Yi F, Zhuo M, Li BM (2013) Delay-dependent impairment of spatial working memory with inhibition of NR2B-containing NMDA receptors in hippocampal CA1 region of rats. Mol Brain 6:13-6606-6-13. https://doi.org/10.1186/1756-6606-6-13
Acknowledgements
The authors thank Felix Hörner and Claudia Falfan-Melgoza for their excellent technical assistance. The authors thank Derek Buhl and Christopher L. Shaffer from Pfizer for providing data on CP-101,606 receptor occupancy values.
Funding
This work was supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft): DFG GA 2109/2-1 to N.G., as well as IN168/3-1 to D.I. and P.G. Additionally, grants to D.I. were provided by the Ingeborg Ständer Foundation and the Research Fund of the UPK Basel.
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The authors declare no conflict of interest. Dr. Schwarz is an employee and shareholder of Eli Lilly and Company.
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Gass, N., Becker, R., Sack, M. et al. Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior. Psychopharmacology 235, 1055–1068 (2018). https://doi.org/10.1007/s00213-017-4823-2
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DOI: https://doi.org/10.1007/s00213-017-4823-2