BEHAVIOURAL CONTROL TRAINING AND ENDOCANNABINOID ENHANCEMENT LEAD TO ANTIDEPRESSANT/ANXIOLYTIC-LIKE REVERSAL OF CHRONIC STRESS-INDUCED BEHAVIOURAL DEFICITS
Authors: Strand *Tadhg McManamon , Afonso Gavin , Oliveria Caio , Cavatti Matheus , Nobrega José , Bambico Francis 
Published: February 2025

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
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