The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions
Research Square October 3, 2023 C. Pittenger, Cheng Jiang, R. DiLeone et al.
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.