Natalia Gass1, Robert Becker2, Markus Sack2, Adam J Schwarz3,4, Jonathan Reinwald2, Alejandro Cosa-Linan5, Lei Zheng2, Christian Clemm von Hohenberg2, Dragos Inta6, Andreas Meyer-Lindenberg6, Wolfgang Weber-Fahr2, Peter Gass6, Alexander Sartorius2,6. 1. 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. 2. Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany. 3. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. 4. Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA. 5. Research Group In Silico Pharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 6. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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.
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.
Authors: Robert Becker; Natalia Gass; Lothar Kußmaul; Bernhard Schmid; Stefan Scheuerer; David Schnell; Cornelia Dorner-Ciossek; Wolfgang Weber-Fahr; Alexander Sartorius Journal: Psychopharmacology (Berl) Date: 2019-07-02 Impact factor: 4.530
Authors: Natalia Gass; Robert Becker; Jonathan Reinwald; Alejandro Cosa-Linan; Markus Sack; Wolfgang Weber-Fahr; Barbara Vollmayr; Alexander Sartorius Journal: Transl Psychiatry Date: 2019-06-28 Impact factor: 6.222