BEHAVIOURAL CONTROL TRAINING AND ENDOCANNABINOID ENHANCEMENT LEAD TO ANTIDEPRESSANT/ANXIOLYTIC-LIKE REVERSAL OF CHRONIC STRESS-INDUCED BEHAVIOURAL DEFICITS
Bibliographic record
Abstract
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.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".