Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents
Bibliographic record
Abstract
Background: Pathological anxiety is the most common type of psychiatric disorder. The current first-line anti-anxiety treatment, selective serotonin/noradrenaline reuptake inhibitors, produces a delayed onset of action with modest therapeutic and substantial adverse effects, and long-term use of the fast-acting anti-anxiety benzodiazepines causes severe adverse effects. Inhibition of the fatty acid amide hydrolase (FAAH), the endocannabinoid N-arachidonoylethanolamine (AEA) degradative enzyme, produces anti-anxiety effects without substantial “unwanted effects” of cannabinoids, but its anti-anxiety mechanism is unclear. Methods: We used behavioural, electro-physiological, morphological and mutagenesis strategies to assess the anti-anxiety mechanism of the FAAH inhibitors PF3845 and URB597. Results: PF3845 exerts rapid and long-lasting anti-anxiety effects in mice exposed acutely to stress or chronically to the stress hormone corticosterone. PF3845-induced anti-anxiety effects and in vivo long-term depression (LTD) of synaptic strength at the prefrontal cortical input onto the basolateral amygdala neurons are abolished in mutant mice without CB1 cannabinoid receptors (CB1R) in brain astroglial cells, but are conserved in mice without CB1R in glutamatergic neurons. Blockade of glutamate N-methyl-d-aspartate receptors and of synaptic trafficking of glutamate AMPA receptors also abolishes PF3845-induced anti-anxiety effects in mice and LTD production in rats. URB597 produces similar anti-anxiety effects, which are abolished by blockade of LTD induction in mice. Limitations: The determination of FAAH in which types of brain cells contribute to AEA degradation for the maintenance of amygdala interstitial AEA has yet to be determined. Conclusion: We propose that the rapid anti-anxiety effects of FAAH inhibition are due to AEA activation of astroglial CB1R and subsequent basolateral amygdala LTD in vivo.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".