Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system

Introduction

Ketamine is a clinically used dissociative anaesthetic and a fast-acting antidepressant, but it also has recreational abuse potential and produces dissociative effects. Pharmacologically it acts broadly in the brain, most prominently as a non-competitive antagonist of N-methyl-D-aspartate receptors (NMDARs) and also via effects on HCN1 channels and possibly opioid receptors. Earlier rodent studies have shown that acute or single-dose ketamine modulates synaptogenesis in prefrontal cortex and increases firing of ventral tegmental area (VTA) dopamine (DA) neurons with enhanced DA release in frontal cortex and striatum, but the long-term, brain-wide consequences of repeated or chronic ketamine exposure across a range of doses remain poorly understood despite clinical and public-health importance. S. and colleagues set out to map systematically how chronic (R,S)-ketamine exposure alters the entire dopaminergic modulatory system in mouse brain. Using sub-hypnotic doses (30 and 100 mg/kg) administered daily and a high-resolution, whole-brain phenotyping pipeline, they aimed to quantify changes in tyrosine hydroxylase (TH)+ cell bodies and TH+ projections across the brain, and to probe whether post-transcriptional regulation of TH mRNA contributes to any observed structural plasticity. The work seeks to reveal dose-dependent and region-specific adaptations of DA-related systems after repeated ketamine treatment.