PMID- 29305627 OWN - NLM STAT- MEDLINE DCOM- 20190122 LR - 20190122 IS - 1432-2072 (Electronic) IS - 0033-3158 (Linking) VI - 235 IP - 4 DP - 2018 Apr TI - Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior. PG - 1055-1068 LID - 10.1007/s00213-017-4823-2 [doi] AB - 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. FAU - Gass, Natalia AU - Gass N AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. natalia.gass@zi-mannheim.de. FAU - Becker, Robert AU - Becker R AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. FAU - Sack, Markus AU - Sack M AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. FAU - Schwarz, Adam J AU - Schwarz AJ AD - Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. AD - Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA. FAU - Reinwald, Jonathan AU - Reinwald J AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. FAU - Cosa-Linan, Alejandro AU - Cosa-Linan A AD - Research Group In Silico Pharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Zheng, Lei AU - Zheng L AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. FAU - von Hohenberg, Christian Clemm AU - von Hohenberg CC AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. FAU - Inta, Dragos AU - Inta D AD - Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Meyer-Lindenberg, Andreas AU - Meyer-Lindenberg A AD - Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Weber-Fahr, Wolfgang AU - Weber-Fahr W AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. FAU - Gass, Peter AU - Gass P AD - Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Sartorius, Alexander AU - Sartorius A AD - Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. AD - Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. LA - eng GR - DFG GA 2109/2-1/Deutsche Forschungsgemeinschaft/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180105 PL - Germany TA - Psychopharmacology (Berl) JT - Psychopharmacology JID - 7608025 RN - 0 (Antidepressive Agents) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (NR2B NMDA receptor) RN - 0 (Phenols) RN - 0 (Piperidines) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Ro 25-6981) RN - 690G0D6V8H (Ketamine) SB - IM MH - Animals MH - Antidepressive Agents/pharmacology MH - Excitatory Amino Acid Antagonists/*pharmacology MH - Hippocampus/drug effects/physiology MH - Ketamine/pharmacology MH - Male MH - Nerve Net/drug effects/*physiology MH - Nucleus Accumbens/drug effects/physiology MH - Phenols/pharmacology MH - Piperidines/pharmacology MH - Prefrontal Cortex/drug effects/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/*physiology MH - *Reward OTO - NOTNLM OT - Graph theory OT - NMDA receptor OT - Rat OT - Resting-state fMRI EDAT- 2018/01/07 06:00 MHDA- 2019/01/23 06:00 CRDT- 2018/01/07 06:00 PHST- 2017/09/01 00:00 [received] PHST- 2017/12/27 00:00 [accepted] PHST- 2018/01/07 06:00 [pubmed] PHST- 2019/01/23 06:00 [medline] PHST- 2018/01/07 06:00 [entrez] AID - 10.1007/s00213-017-4823-2 [pii] AID - 10.1007/s00213-017-4823-2 [doi] PST - ppublish SO - Psychopharmacology (Berl). 2018 Apr;235(4):1055-1068. doi: 10.1007/s00213-017-4823-2. Epub 2018 Jan 5.