The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions

A single dose of ketamine's antidepressant-like effects in rats require the brain's own opioid system, specifically β-endorphin and mu-opioid receptors in the medial prefrontal cortex (mPFC). Blocking opioid receptors with naltrexone, either throughout the body or directly in the mPFC, prevented ketamine's behavioral effects and associated molecular changes. Ketamine rapidly increased β-endorphin levels and mu-opioid receptor gene expression in the mPFC, as well as the gene for β-endorphin's precursor in the hypothalamus. Neutralizing β-endorphin in the mPFC with a specific antibody before ketamine also abolished both behavioral and molecular effects, demonstrating that activation of mPFC opioid receptors is necessary for ketamine's antidepressant-like actions.

Study at a glance

Abstract

Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) were blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupted the behavioral effects of ketamine. Ketamine treatment rapidly increased levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of the gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the hypothalamus, in vivo. Finally, neutralization of β-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolished both behavioral and molecular effects. Together, these findings indicate that presence of β-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.