A study, published this month in the journal Cell Reports, was based on the repeated use of ketamine in male mice. “Ketamine is a multifunctional drug with clinical applications as an anesthetic, pain management medication, and a fast-acting antidepressant,” the researchers wrote in the summary of the study. “However, it is also recreationally abused for its dissociative effects.” They noted that recent studies on rodents “are revealing the neuronal mechanisms mediating its actions Read more
A study, published this month in the journal Cell Reports, was based on the repeated use of ketamine in male mice. “Ketamine is a multifunctional drug with clinical applications as an anesthetic, pain management medication, and a fast-acting antidepressant,” the researchers wrote in the summary of the study. “However, it is also recreationally abused for its dissociative effects.” They noted that recent studies on rodents “are revealing the neuronal mechanisms mediating its actions, but the impact of prolonged exposure to ketamine on brain-wide networks remains less understood.” As such, in their study, the researchers developed “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,” they continued. “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.” Ultimately, the experiment enabled the researchers to develop a “high-resolution whole-brain phenotyping of ketamine-treated animals.” “We established a complete pipeline for whole-brain labeling, high-resolution imaging, and comparative phenotyping of the entire dopaminergic modulatory system, and we utilized it to study the dose-dependent effects of daily (R,S)-ketamine exposure (30 and 100 mg/kg; 1, 5, and 10 days) and saline control intraperitoneal (i.
p.) injections,” they explained. The results “revealed no significant cell death in the brain,” they said. “We used an unbiased, high-resolution whole-brain mapping approach to systematically investigate the adaptability of the DA system to repeated ketamine exposure,” the researchers explained. “We found that chronic ketamine exposure leads to a dosage-dependent decrease in DA neurons counts within midbrain regions related to behavior state and increase within hypothalamic domains, along with altered long-range innervation of the association and sensory areas by TH+ neuronal projections.
Such structural plasticity of brain-wide modulatory system may facilitate significant reconfiguration of the neuronal networks to eventually result in long-lasting cognitive behavioral changes.” As the outlet PsyPost explained, the study’s “findings provide evidence of significant structural plasticity in the brain’s dopaminergic system in response to chronic ketamine exposure.” “In other words, the study shows that repeated use of ketamine can lead to major changes in the areas of the brain that deal with dopamine, a neurotransmitter that plays a pivotal role in mood, motivation, and reward systems,” PsyPost reported.
The researchers behind the study said that it “sheds light on the brain-wide effects of chronic ketamine exposure on the dopamine system and provides insight into the structural plasticity that underlies these effects.” “The finding that ketamine exposure leads to divergent alterations in specific brain regions, rather than a uniform activating impact, is particularly intriguing and could have significant implications for the development of treatments for depression, schizophrenia, and psychosis,” they said.
“Moreover, such non-monolithic brain-wide impact further underscores the need for unbiased investigations of on/off-target effects of ketamine treatment at a range of doses, as well as the urgency to develop targeted pharmacological intervention approaches (e.g., focused ultra sound-based approaches 43,44) for treatment of complex brain disorders.” But despite those eye-opening revelations, the authors said that the study “also has a few limitations.” “Firstly, the study did not examine the progressive changes in TH expression levels over varying durations of ketamine exposure.
Instead, a binary approach of presence or absence was employed. In future research, the development of strategies for whole-brain expression signal normalization will be essential to enable a more comprehensive analysis of the gradual effects of prolonged ketamine exposure on the DA system,” the researchers explained. “Secondly, it’s crucial to note that TH is not exclusive to dopaminergic neurons but is also present in other catecholaminergic neurons, such as norepinephrine and epinephrine.
While it is generally accepted that these neurons are primarily localized in specific regions of the hindbrain, some of the neuronal projections labeled as TH+ in this study may potentially originate from these other catecholaminergic neurons. Future studies will be necessary to precisely determine the neurotransmitter identity (whether DA or noradrenergic) of the affected neuronal projections.” They continued, “Thirdly, this study does not provide specific insights into the physiological mechanisms that may be mediating the impact of chronic ketamine exposure on the DA system.
Fourthly, to ensure the practical feasibility of performing sub-cellular resolution comparative phenotyping, this initial whole-brain study utilized male mice to minimize potential sources of variability. Future research, building upon these initial important findings and tools, will be needed to explore any potential sex-specific impact of ketamine exposure.45 Lastly, it should be noted that the current study employed a mixture of (R,S) enantiomers of ketamine. Future follow-up studies will be necessary to understand the relative impacts of the two ketamine enantiomers.
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