Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on decision-making biases in rodents
Ca Hales, Jm Bartlett, R Arban, B Hengerer, Esj Robinson
bioRxiv (Cold Spring Harbor Laboratory) January 23, 2020 preprint DOI: 10.1101/2020.01.22.915132 via OpenAlex
Summary
Ketamine and certain NMDA antagonists like CP-101,606 and scopolamine can alter decision-making by modifying affective biases in a specific way, localized to the medial prefrontal cortex (mPFC). In contrast, other NMDA antagonists did not show these effects. The study highlights that while ketamine has rapid antidepressant effects, its mechanism may involve unique interactions within the mPFC that are not replicated by all NMDA antagonists.
Study at a glance
| Key finding | Ketamine and specific NMDA antagonists positively influence decision-making through modulation of affective biases in the medial prefrontal cortex. |
|---|
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.