BEHAVIOURAL CONTROL TRAINING AND ENDOCANNABINOID ENHANCEMENT LEAD TO ANTIDEPRESSANT/ANXIOLYTIC-LIKE REVERSAL OF CHRONIC STRESS-INDUCED BEHAVIOURAL DEFICITS
Notice bibliographique
Résumé
Abstract Background A cognitive model of stress posits that psycho-affective disorders can arise from a perceived lack of control over stressors [1]. Stress uncontrollability is linked to perturbed prefrontocortical (PFC)-raphe signaling of endocannabinoids, e.g., anandamide [2]. Conversely, behavioural therapies such as cognitive-behavioural and remediation therapies ameliorate mood-related symptoms by enhancing perceived stress controllability [3]. There is also evidence that pharmacologically augmenting brain endocannabinoid levels results in antidepressant and anti-stress action [2],[3].Objectives: We developed a rodent model of cognitive remediation based on the yoked inescapable stress (IES)– escapable stress (ES) paradigm, and on a modified Morris water maze (with vs. without an escape platform). Methods: Animals were first exposed to 6 weeks of chronic unpredictable stress (CUS), then were submitted to behavioural control training (BCT), where BCT+ animals were repeatedly allowed to learn to evade the stressors, while BCT- were subjected to inescapable stressors. CUS-exposed animals exhibited depressive-like (sucrose preference, fruit loops and forced swim tests) and anxiety-like reactivity (novelty-suppressed feeding and elevated plus maze), and increased serum corticosterone levels. Some mice were subjected to in vivo glucose biosensor monitoring of the PFC in response to a challenge injection of the cannabinoid CB1 receptor antagonist, AM251 (1 mg/kg, ip). Results CUS-induced behavioral deficits were reversed by 8-10 days but not by 3 days of BCT in CUS- exposed BCT+ animals and not in CUS-exposed BCT- animals. In non-CUS animals, BCT+ and BCT- led to slight and transient behavioural deficits. We have determined that behavioural improvements in BCT+ were associated with a blunting of AM251-induced decrease in PFC glucose levels. We therefore assessed changes in the PFC by electrophysiological recordings of PFC and raphe neuronal activity after CUS and BCT (BCT+ vs. BCT-; data to follow). Lastly, we found that in CUS mice, a behaviorally inert dose of the anandamide-enhancing fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.05 mg/kg, ip) when combined with 3 days of BCT reversed the CUS deficits.Discussion: These data show that cognitive therapies and BCT can be modeled in rodents, and that these effects may be mediated by increased endocannabinoid signaling in the PFC, similar to those induced by the fast-acting antidepressant ketamine [4]. BCT and URB597 may therefore have synergistic therapeutic activity. Because there may be issues associated with the repeated use of ketamine in the clinic [5], this combinatory strategy could serve as a promising alternative.Conclusion: This study provides a preclinical framework with which to test whether cognitive therapies and endocannabinoid enhancing drugs could be combined to yield faster onset and more stable expression of the therapeutic response. References [1]Maier, S.F. (1984) 'Learned helplessness and animal models of depression’, Progress in Neuro- Psychopharmacology and Biological Psychiatry, 8(3), pp. 435–446. Available at: https://doi.org/10.1016/S0278-5846(84)80032-9. [2]Bambico, F.R. and Gobbi, G. (2008) 'The cannabinoid CB1 receptor and the endocannabinoid anandamide: possible antidepressant targets’, Expert Opinion on Therapeutic Targets, 12(11), pp. 1347–1366. Available at: https://doi.org/10.1517/14728222.12.11.1347. [3]Addis, M.E. and Carpenter, K.M. (2000) 'The treatment rationale in cognitive behavioral therapy: Psychological mechanisms and clinical guidelines’, Cognitive and Behavioral Practice, 7(2), pp. 147–156. Available at: https://doi.org/10.1016/S1077-7229(00)80025-5. [3]Gobbi, G. et al. (2005) 'Antidepressant-Like Activity and Modulation of Brain Monoaminergic Transmission by Blockade of Anandamide Hydrolysis’, Proceedings of the National Academy of Sciences of the United States of America, 102(51), pp. 18620–18625. [4]Browne, C. and Lucki, I. (2013) 'Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants’, Frontiers in Pharmacology, 4. Available at: https://www.frontiersin.org/articles/10.3389/fphar.2013.00161 (Accessed: 14 October 2023). [5]Morgan, C.J.A., Curran, H.V. and Drugs (ISCD), the I.S.C. on (2012) 'Ketamine use: a review’, Addiction, 107(1), pp. 27–38. Available at: https://doi.org/10.1111/j.1360-0443.2011.03576.x.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».