Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice.
T H Pham, Indira Mendez-David, Céline Defaix, B P Guiard, Laurent Tritschler, Denis J David, Alain M. Gardier
Neuropharmacology January 2017 DOI: 10.1016/j.neuropharm.2016.05.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Highly anxious BALB/cJ mice |
| Interventions | Ketamine Fluoxetine para-chlorophenylalanine (PCPA) NBQX |
| Dose | Ketamine 10 mg/kg i.p.; fluoxetine 18 mg/kg i.p.; intra-mPFCx ketamine 0.25 μg/side; intra-DRN NBQX (dose not stated) |
| Duration | 24 h post-administration assessment |
| Measures | Forced swim test (FST), extracellular serotonin levels ([5-HT]ext), 5-HT cell firing |
| Topics | Ketamine Serotonin Esketamine |
| Keywords | Antidepressant drug Dorsal raphe nucleus Medial prefrontal cortex Microdialysis Rapid antidepressant-like activity |
| Key findings | Ketamine (10 mg/kg) produced a long-lasting antidepressant-like effect in highly anxious BALB/cJ mice that was absent with fluoxetine, and this effect depended on serotonin release in the medial prefrontal cortex and on AMPA receptor activation in the dorsal raphe nucleus. The authors conclude that cortical serotonin release plays a key role in ketamine's antidepressant-like activity following NMDA receptor blockade. |
Abstract
Unlike classic serotonergic antidepressant drugs, ketamine, an NMDA receptor antagonist, exhibits a rapid and persistent antidepressant (AD) activity, at sub-anaesthetic doses in treatment-resistant depressed patients and in preclinical studies in rodents. The mechanisms mediating this activity are unclear. Here, we assessed the role of the brain serotonergic system in the AD-like activity of an acute sub-anaesthetic ketamine dose. We compared ketamine and fluoxetine responses in several behavioral tests currently used to predict anxiolytic/antidepressant-like potential in rodents. We also measured their effects on extracellular serotonin levels [5-HT]ext in the medial prefrontal cortex (mPFCx) and brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus involved in emotional behavior, and on 5-HT cell firing in the DRN in highly anxious BALB/cJ mice. Ketamine (10 mg/kg i.p.) had no anxiolytic-like effect, but displayed a long lasting AD-like activity, i.e., 24 h post-administration, compared to fluoxetine (18 mg/kg i.p.). Ketamine (144%) and fluoxetine (171%) increased mPFCx [5-HT]ext compared to vehicle. Ketamine-induced AD-like effect was abolished by a tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA) pointing out the role of the 5-HT system in its behavioral activity. Interestingly, increase in cortical [5-HT]ext following intra-mPFCx ketamine bilateral injection (0.25 μg/side) was correlated with its AD-like activity as measured on swimming duration in the FST in the same mice. Furthermore, pre-treatment with a selective AMPA receptor antagonist (intra-DRN NBQX) blunted the effects of intra-mPFCx ketamine on both the swimming duration in the FST and mPFCx [5-HT]ext suggesting that the AD-like activity of ketamine required activation of DRN AMPA receptors and recruited the prefrontal cortex/brainstem DRN neural circuit in BALB/c mice. These results confirm a key role of cortical 5-HT release in ketamine's AD-like activity following the blockade of glutamatergic NMDA receptors. Tight interactions between mPFCx glutamatergic and serotonergic systems may explain the differences in this activity between ketamine and fluoxetine in vivo. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
Comparable studies
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| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 58
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Ketamine and depression: a narrative review Drug Design, Development and Therapy August 1, 2019
- Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacology & Therapeutics July 1, 2019
and 53 more in the library
Cites 9
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and 4 more in the library