Is Febuxostat Use Associated With Increased Risk of Cardiovascular Disease Events? The Answer Is Crystal Clear
Bibliographic record
Abstract
Corticosteroids have been widely used in anti-inflammatory medication. Chronic corticosteroid (CORT) treatment can cause mesocorticolimbic system dysfunctions which is known to play a key role for the development of psychiatric disorders. The ventral tegmental area (VTA) is a critical site in the mesocorticolimbic pathway and is responsible for motivation and reward-seeking behaviors. However, the mechanism by which chronic CORT alters VTA dopamine neuronal activity is largely unknown. We treated peri-adolescent male mice with either vehicle, 1d, or 7d CORT in the drinking water, examined behavioral impacts with light/dark box, elevated plus maze, operant chamber and open field tests, measured the effects of CORT on VTA dopamine neuronal activity using patch clamp electrophysiology and dopamine concentration using fast-scan cyclic voltammetry, and tested the effects of dopamine D2 receptor (D2R) blockade by intra-VTA infusion of a D2R antagonist. CORT treatment induced anxiety-like behavior as well as decreased food-seeking behaviors. We show that chronic CORT treatment decreased excitability and excitatory synaptic transmission onto VTA dopamine neurons. Furthermore, chronic CORT increased somatodendritic dopamine concentration. The D2R antagonist sulpiride restored decreased excitatory transmission and excitability of VTA dopamine neurons. Furthermore, sulpiride decreased anxiety-like behaviour and rescued food-seeking behaviour in mice with chronic CORT exposure. Taken together, 7d CORT treatment induces anxiety-like behavior and impairs food-seeking in a mildly aversive environment. D2R signaling in the VTA might be a potential target to ameliorate chronic CORT induced anxiety and reward-seeking deficits. SIGNIFICANCE STATEMENT With widespread anti-inflammatory effects throughout body, corticosteroids (CORT) have been used in a variety of therapeutic conditions. However, long term corticosteroid treatment causes cognitive impairments and neuropsychiatric disorders. The impact of chronic CORT on the mesolimbic system has not been elucidated. Here, we demonstrate that 7-day CORT treatment increases anxiety-like behavior and attenuates food-seeking behavior in a mildly aversive environment. By elevating local dopamine concentration in the ventral tegmental area (VTA), a region important for driving motivated behaviour, CORT treatment suppresses excitability and synaptic transmission onto VTA dopamine neurons. Intriguingly, blockade of D2 receptor signaling in the VTA restores neuronal excitability and food-seeking and alleviates anxiety-like behaviors. Our findings provide a potential therapeutic target for corticosteroid induced reward deficits.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".