Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on decision-making biases in rodents
Ca Hales, Jm Bartlett, Roberto Arban, Bastian Hengerer, Esj Robinson
bioRxiv (Cold Spring Harbor Laboratory) January 23, 2020 preprint DOI: 10.1101/2020.01.22.915132 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Rodents (rats) |
| Interventions | Ketamine CP-101 606 scopolamine other NMDA antagonists muscimol |
| Topics | Ketamine |
| Keywords | Prefrontal cortex Nmda receptor Antagonist Cognition Antidepressant Hippocampus Mechanism biology Glutamate receptor Scopolamine Working memory Mechanism of action |
| Key findings | Ketamine and other rapid-acting antidepressants induce a positive affective bias in decision-making that is localized to the medial prefrontal cortex, whereas non-rapid-acting NMDA antagonists do not produce this effect. |
Abstract
Abstract Major Depressive Disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABA A agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism.
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
Cites 12
- 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
- Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder The Journal of Clinical Psychiatry July 13, 2010
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
and 7 more in the library