Behavioural control training promotes antidepressant/anxiolytic-like reversal of chronic stress-induced behavioural deficits: Endocannabinoidergic and prolactinergic mechanisms

A cognitive model of stress posits that psycho-affective disorders can arise from a perceived lack of stress control. Uncontrollability is linked to perturbed prefrontocortical (PFC)-limbic signalling of endocannabinoids (anandamide) and altered hormonal activity (prolactin and glucocorticoids). Behavioural therapies such as cognitive-behavioural/remediation therapies ameliorate symptoms by enhancing perceived controllability. There is also evidence that augmenting endocannabinoid and hormonal levels results in antidepressant/anti-stress action. Based on a modified version of the rodent Morris water maze and the yoked inescapable stress-escapable stress paradigm, we developed a model of cognitive remediation. We first exposed animals to 6-weeks chronic unpredictable stress (CUS). They were then subjected to behavioural control training (BCT), where BCT+ animals learned to escape stressors, while BCT- were unable to. CUS animals exhibited depressive-/anxiety-like reactivity, and altered serum/brain corticosterone/prolactin levels. We performed glucose-PFC-biosensor monitoring in response to the cannabinoid CB1 receptor antagonist, AM251; effects of prolactin receptor ligands are under investigation. CUS-induced deficits were reversed by 8-10 days, but not by 3 days of BCT+, which was associated with blunting of AM251-induced PFC activational decrease. We assessed neuro-physiological changes in the PFC, hypothalamus and monoaminergic nuclei (data to follow). Lastly, we found that an inert dose of the anandamide-enhancing drug, URB597 (0.05 mg/kg, ip), when combined with 3-days BCT+, reversed deficits. Prolactin-endocannabinoid interactions are being investigated. These data show that BCT+ and URB597 may have synergistic therapeutic activity, providing a preclinical framework with which to test whether combination treatment can yield faster onset and more stable expression of the therapeutic response.