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

Repeated ketamine administration causes opposite effects on dopamine neurons in different brain regions: a decrease in midbrain areas linked to behavior states and an increase in the hypothalamus. It also alters nerve connections to the prefrontal cortex, striatum, and sensory areas. The findings suggest post-transcriptional regulation of structural plasticity. An unbiased whole-brain analysis reveals divergent brain-wide impacts of chronic ketamine on association and sensory pathways.

Study at a glance

Abstract

Ketamine is a multifunctional drug with clinical applications as an anesthetic, as a pain management medication and as a transformative fast-acting antidepressant. It is also abused as a recreational drug due to its dissociative property. Recent studies in rodents are revealing the neuronal mechanisms that mediate the complex actions of ketamine, however, its long-term impact due to prolonged exposure remains much less understood with profound scientific and clinical implications. Here, we develop and utilize a high-resolution whole-brain phenotyping approach to show that repeated ketamine administration leads to a dosage-dependent decrease of dopamine (DA) neurons in the behavior state-related midbrain regions and, conversely, an increase within the hypothalamus. Congruently, we show divergently altered innervations of prefrontal cortex, striatum, and sensory areas. Further, we present supporting data for the post-transcriptional regulation of ketamine-induced structural plasticity. Overall, through an unbiased whole-brain analysis, we reveal the divergent brain-wide impact of chronic ketamine exposure on the association and sensory pathways.