Mapping the central effects of (±)-ketamine and traxoprodil using pharmacological magnetic resonance imaging in awake rats.
Haiying Tang, Daniel Kukral, Yu-Wen Li, Matthew Fronheiser, Harold Malone, Adrienne Pena, Rick Pieschl, Kurex Sidik, Gabriel Tobon, Patrick L Chow, Linda J Bristow, Wendy Hayes, Feng Luo
Journal of Psychopharmacology February 2018 DOI: 10.1177/0269881117746901 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacological magnetic resonance imaging study Peer reviewed |
|---|---|
| Population | Awake rats |
| Interventions | (±)-ketamine traxoprodil |
| Dose | 3 mg/kg (±)-ketamine; traxoprodil 0.3 mg/kg, 5 mg/kg, and 15 mg/kg |
| Measures | pharmacological magnetic resonance imaging, blood oxygen level dependent signal, ex vivo [3H]Ro 25-6981 binding |
| Topics | Esketamine Ketamine |
| Keywords | ±-ketamine Awake rats Traxoprodil |
| Key points | Traxoprodil produced dose-dependent brain activation in rats: 5 mg/kg activated medial prefrontal, ventral orbital, and anterior cingulate cortices, while 15 mg/kg produced widespread cortical and subcortical responses similar to those of 3 mg/kg (±)-ketamine. Both 5 and 15 mg/kg achieved greater than 80% N-methyl-D-aspartate receptor subtype 2B occupancy. |
Abstract
Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect. Efforts have also focused on the development of selective N-methyl-D-aspartate receptor subtype 2B antagonists which may retain antidepressant activity but have lower potential for dissociative/psychotomimetic effects. In the present study, we examined the central nervous system effects of acute, intravenous administration of (±)-ketamine or the N-methyl-D-aspartate receptor subtype 2B antagonist, traxoprodil, in awake rats using pharmacological magnetic resonance imaging. The study contained five treatment groups: vehicle, 3 mg/kg (±)-ketamine, and three doses of traxoprodil (0.3 mg/kg, 5 mg/kg, and 15 mg/kg). Non-linear model fitting was performed on the temporal hemodynamic pharmacological magnetic resonance imaging data to generate brain activation maps as well as regional responses based on blood oxygen level dependent signal changes for group analysis. Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [3H]Ro 25-6981 binding. The middle dose of traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous).
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 3
- Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study Brain Structure and Function August 7, 2021
- Dose-dependent effects of esketamine on brain activity in awake mice: A BOLD phMRI study. Pharmacology Research & Perspectives December 1, 2022
- The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacology & Therapeutics October 2018
Cites 9
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Glutamate and the Neural Basis of the Subjective Effects of Ketamine Archives of General Psychiatry February 1, 2008
- NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS Depression and Anxiety March 10, 2014
- Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. Journal of Psychiatry and Neuroscience June 2017
and 4 more in the library