Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats.

The pathophysiology of major depressive disorder (MDD) is diverse and multi-factorial, yet treatment strategies remain limited. While women are twice as likely to develop the disorder as men, many animal model studies of antidepressant response rely solely on male subjects. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. Cannabidiolic Acid-Methyl Ester (CBDA-ME, EPM-301) demonstrated anti-depressive-like effects in male rats. Here, we explored acute effects of CBDA-ME and some possible mediating mechanisms, using a depressive-like genetic animal model, the Wistar-Kyoto (WKY) rat. In Experiment 1, Female WKY rats underwent the Forced swim test (FST) following acute CBDA-ME oral ingestion (1/5/10 mg/kg). In Experiment 2, Male and female WKY rats underwent the FST after injection of CB1 (AM-251) and CB2 (AM-630) receptor antagonists 30 min before acute CBDA-ME ingestion (1 mg/kg, males; 5 mg/kg, females). Serum levels of Brain-Derived Neurotrophic Factor (BDNF), numerous endocannabinoids and hippocampal Fatty Acid Amide Hydrolase (FAAH) levels were assessed. Results indicate that females required higher doses of CBDA-ME (5 and 10 mg/kg) to induce an anti-depressive-like effect in the FST. AM-630 blocked the antidepressant-like effect in females, but not in males. The effect of CBDA-ME in females was accompanied by elevated serum BDNF and some endocannabinoids and low hippocampal expression of FAAH. This study shows a sexually diverse behavioral anti-depressive response to CBDA-ME and possible underlying mechanisms in females, supporting its potential use for treating MDD and related disorders.

A Potential Animal Model of Maladaptive Palatable Food Consumption Followed by Delayed Discomfort.

Introduction: Binging is the consumption of larger amounts of food in a briefer period of time than would normally be consumed under similar circumstances. Binging requires palatable food (PF) to trigger abnormal eating, probably reflecting gene × environment interactions. In this study we examined the impact of trait binge eating (BE) and its compulsive nature on the conflict between hedonic eating of PF and anticipation of a delayed aversive effect. We used female rats as an animal model similar to other models of BE. A novel aspect of this model in this paper is the use of a delayed internal aversive effect produced by lactose ingestion. Establishing this model will allow us to better understand the nature of the conflict between immediate reward and its delayed aversive implications. We hypothesized that BE prone (BEP) rats will demonstrate maladaptive decision making, presenting higher motivation toward PF even when this is associated with delayed discomfort. Method: (Phase 1) 52 female adult Wistar rats were divided to two eating profiles: resistant and prone binge eaters (BER/BEP) based on intake of liquid PF (Ensure). Next, all subjects underwent a Lactose Conditioning Protocol (LCP) that included 4 h tests, one baseline and 3 conditioning days (Phase 2), in which solid PF (Oreo cookies) was paired with glucose (control-no internal aversive effect) or lactose, dissolved in liquid PF. Index for PF motivation was PF consumption during the 4 h LCP. To test for memory of lactose conditioning, we performed another LCP with glucose only (anticipation, but no actual lactose-induced discomfort), a week after the last conditioning session. Results: Lactose conditioned BEP showed higher motivation toward PF compared to lactose conditioned BER faced with delayed aversive effects. Only lactose conditioned BER rats devaluated the PF over LCP days, indicating an association between PF and abdominal discomfort. In addition, only lactose conditioned BER presented an adaptive dynamic behavior, by varying PF intake according to consequences. Furthermore, solid PF consumption was predicted by binge size of liquid PF, only for lactose conditioned rats. Conclusions: We established an animal model for a common eating conflict in humans using delayed internal aversive unconditional stimuli.

The Effect of Sleep Problems on Suicidal Risk among Young Adults in the Presence of Depressive Symptoms and Cognitive Processes.

We aimed to investigate the effect of sleep problems, depression, and cognitive processes on suicidal risk among 460 young adults. They completed self-report questionnaires assessing suicidal behavior, sleep quality, depressive symptoms, emotion regulation, rumination, and impulsivity. Suicidal participants exhibited higher rates of depressive symptoms, sleep problems, expressive suppression, rumination, and impulsivity. A confirmatory factor analysis model revealed pathways to suicidal risk that showed no direct pathways between sleep problems and suicidal risk. Instead, sleep was related to suicidal risk via depression and rumination, which in turn increased suicidal risk. These results suggest that addressing sleep problems will be useful in either the treatment or prevention of depressive and rumination symptoms and reduction in suicidal risk.