Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on decision-making biases in rodents

Ketamine and other rapid-acting antidepressants (RAADs) like CP-101,606 and scopolamine produce a positive bias in decision-making in rodents, shifting choices toward more optimistic outcomes. This effect is localized to the medial prefrontal cortex (mPFC), as targeted infusions into this brain region replicate the bias. In contrast, other NMDA receptor antagonists that lack rapid antidepressant effects do not induce this positive bias. Temporary inactivation of the mPFC with muscimol caused general behavioral disruptions rather than the specific positive bias seen with RAADs. These findings suggest that ketamine and similar RAADs act through a distinct mechanism involving the mPFC to alter affective biases, which may underlie their therapeutic action in major depressive disorder.

Study at a glance

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.