Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system
Malika S. Datta, Yannan Chen, Shradha Chauhan, Jing Zhang, Estanislao Daniel De La Cruz, Cheng Gong, Raju Tomer
bioRxiv Preprint Server April 12, 2023 preprint DOI: 10.1101/2023.04.12.536506 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Rodents |
| Intervention | Ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressant Drug effects Therapeutic actions Mechanism of action Neurobiology Brain regions Midbrain Hypothalamus Brain pathways Brain connections Neurotransmitters Dopamine systems Dopamine neurons Region-specific effects Differential impact Localized effects Brain mapping |
| Citations | 6 |
| Key findings | Repeated ketamine administration leads to a dosage-dependent decrease of dopamine neurons in the midbrain and an increase in the hypothalamus, with divergently altered innervations of prefrontal cortex, striatum, and sensory areas. |
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.