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

Ketamine is a multifunctional drug with clinical applications as an anesthetic, pain management medication, and a fast-acting antidepressant. However, it is also recreationally abused for its dissociative effects. Recent studies in rodents are revealing the neuronal mechanisms mediating its actions,...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2023-12, Vol.42 (12), p.113491-113491, Article 113491
Main Authors: Datta, Malika S., Chen, Yannan, Chauhan, Shradha, Zhang, Jing, De La Cruz, Estanislao Daniel, Gong, Cheng, Tomer, Raju
Format: Article
Language:English
Subjects:
Animals
antidepressant
Antidepressive Agents - pharmacology
Brain
Brain Mapping
dopamine
Dopamine - pharmacology
ketamine
Ketamine - pharmacology
Male
Mice
modulation
neural circuit adaptations
plasticity
whole-brain mapping
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Summary:Ketamine is a multifunctional drug with clinical applications as an anesthetic, pain management medication, and a fast-acting antidepressant. However, it is also recreationally abused for its dissociative effects. Recent studies in rodents are revealing the neuronal mechanisms mediating its actions, but the impact of prolonged exposure to ketamine on brain-wide networks remains less understood. Here, we develop a sub-cellular resolution whole-brain phenotyping approach and utilize it in male mice to show that repeated ketamine administration leads to a dose-dependent decrease in dopamine neurons in midbrain regions linked to behavioral states, alongside an increase in the hypothalamus. Additionally, diverse changes are observed in long-range innervations of the prefrontal cortex, striatum, and sensory areas. Furthermore, the data support a role for post-transcriptional regulation in enabling ketamine-induced neural plasticity. Through an unbiased, high-resolution whole-brain analysis, this study provides important insights into how chronic ketamine exposure reshapes brain-wide networks. [Display omitted] •Whole-brain mapping of chronic ketamine-induced sub-cellular plasticity in dopamine system•Dose-dependent divergent changes in midbrain and hypothalamic dopamine domains•Divergently altered innervation of prefrontal, striatum, and sensory cortices•Data supporting post-transcriptional regulation of ketamine-induced structural plasticity Datta et al. develop and use a whole-brain approach to reveal the impact of repeated ketamine exposure on the dopamine system. Findings also support post-transcriptional regulation of ketamine-induced neural network plasticity. This study provides crucial insights into how pharmacological agents like ketamine can reshape brain-wide networks in a non-uniform manner.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.113491