A subanesthetic dose of ketamine suppresses somatostatin-expressing (SST) interneurons in the medial prefrontal cortex of awake mice, leading to deficient dendritic inhibition. This causes greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, the authors show that this dendritic inhibitory mechanism affects frontal cortex-dependent behaviors and cortico-cortical connectivity. The results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as key local-circuit alterations driven by subanesthetic ketamine.
In a qualitative study of the first randomized placebo-controlled trial of psilocybin for treatment-refractory obsessive-compulsive disorder (OCD), interviews with 12 participants revealed four major themes: influences on the psilocybin experience (set and setting), acute effects (perceptual, metacognitive, emotional, and impact on OCD), post-dosing changes in OCD symptoms and perceptions, and post-dosing changes beyond OCD symptoms. Acute effects were often lower in intensity, possibly due to interference by OCD symptoms. Some acute and post-dosing effects mapped onto mechanisms of evidence-based psychotherapies like exposure and response prevention and acceptance and commitment therapy, suggesting potential for integrating psilocybin with structured psychotherapy for OCD.
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.