The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits.
J M Witkin, J A Monn, D D Schoepp, X Li, C Overshiner, S N Mitchell, G Carter, B Johnson, K Rasmussen, L M Rorick-Kehn
Journal of Pharmacology and Experimental Therapeutics July 2016 DOI: 10.1124/jpet.116.233627 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | CD1 mice and preclinical rodent models (electrophysiologic, neurochemical, and behavioral experiments) |
| Interventions | Ketamine LY341495 Citalopram Quinpirole 2 3 4-tetrahydro-6-nitro-2 3-dioxo-(9CI)-benzo[f]quinoxaline-7-sulfonamide |
| Topics | Esketamine Ketamine |
| Key findings | Acute ketamine and the mGlu2/3 receptor antagonist LY341495, but not citalopram, increased spontaneously active VTA dopamine neurons, raised extracellular dopamine in the nucleus accumbens and prefrontal cortex, and enhanced quinpirole-induced locomotion; both also reduced tail-suspension immobility in CD1 mice. An AMPA receptor antagonist blocked these effects, indicating AMPA dependence. The authors argue this shared dopamine-linked mechanism differentiates ketamine and mGlu2/3 antagonism from conventional antidepressants and supports potential rapid antidepressant action of mGlu2/3 antagonism in patients. |
Abstract
Ketamine is a rapidly acting antidepressant in patients with treatment-resistant depression (TRD). Although the mechanisms underlying these effects are not fully established, inquiry to date has focused on the triggering of synaptogenesis transduction pathways via glutamatergic mechanisms. Preclinical data suggest that blockade of metabotropic glutamate (mGlu2/3) receptors shares many overlapping features and mechanisms with ketamine and may also provide rapid efficacy for TRD patients. Central dopamine circuitry is recognized as an end target for mood regulation and hedonic valuation and yet has been largely neglected in mechanistic studies of antidepressant-relevant effects of ketamine. Herein, we evaluated the changes in dopaminergic neurotransmission after acute administration of ketamine and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid ] in preclinical models using electrophysiologic, neurochemical, and behavioral endpoints. When given acutely, both ketamine and LY341495, but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increased the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), increased extracellular levels of dopamine in the nucleus accumbens and prefrontal cortex, and enhanced the locomotor stimulatory effects of the dopamine D2/3 receptor agonist quinpirole. Further, both ketamine and LY341495 reduced immobility time in the tail-suspension assay in CD1 mice, which are relatively resistant to SSRI antidepressants. Both the VTA neuronal activation and the antidepressant phenotype induced by ketamine and LY341495 were attenuated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo- (9CI)-benzo[f]quinoxaline-7-sulfonamide, indicating AMPA-dependent effects. These findings provide another overlapping mechanism of action of ketamine and mGlu2/3 receptor antagonism that differentiates them from conventional antidepressants and thus support the potential rapidly acting antidepressant actions of mGlu2/3 receptor antagonism in patients.
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 44
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders Molecular Psychiatry October 3, 2017
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
- Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments The International Journal of Neuropsychopharmacology November 14, 2018
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Cites 13
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- 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 Journal of Neuroscience April 15, 1997
- Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
- Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression Translational Psychiatry October 14, 2014
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