Cannabidiol Modulates Alterations in PFC microRNAs in a Rat Model of Depression.

Cannabidiol (CBD) is a potential antidepressant agent. We examined the association between the antidepressant effects of CBD and alterations in brain microRNAs in the unpredictable chronic mild stress (UCMS) model for depression. UCMS male rats were injected with vehicle or CBD (10 mg/kg) and tested for immobility time in the forced swim test. Alterations in miRNAs (miR16, miR124, miR135a) and genes that encode for the 5HT1a receptor, the serotonergic transporter SERT, ß-catenin, and CB1 were examined. UCMS increased immobility time in a forced swim test (i.e., depressive-like behavior) and altered the expression of miRNAs and mRNA in the ventromedial prefrontal cortex (vmPFC), raphe nucleus, and nucleus accumbens. Importantly, CBD restored UCMS-induced upregulation in miR-16 and miR-135 in the vmPFC as well as the increase in immobility time. CBD also restored the UCMS-induced decrease in htr1a, the gene that encodes for the serotonergic 5HT1a receptor; using a pharmacological approach, we found that the 5HT1a receptor antagonist WAY100135 blocked the antidepressant-like effect of CBD on immobility time. Our findings suggest that the antidepressant effects of CBD in a rat model for depression are associated with alterations in miR-16 and miR-135 in the vmPFC and are mediated by the 5HT1a receptor.

Modulation of Endocannabinoid System Components in Depression: Pre-Clinical and Clinical Evidence.

Depression is characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. First-line medications for mood disorders mostly target the monoaminergic system; however, many patients do not find relief with these medications, and those who do suffer from negative side effects and a discouragingly low rate of remission. Studies suggest that the endocannabinoid system (ECS) may be involved in the etiology of depression and that targeting the ECS has the potential to alleviate depression. ECS components (such as receptors, endocannabinoid ligands, and degrading enzymes) are key neuromodulators in motivation and cognition as well as in the regulation of stress and emotions. Studies in depressed patients and in animal models for depression have reported deficits in ECS components, which is motivating researchers to identify potential diagnostic and therapeutic biomarkers within the ECS. By understanding the effects of cannabinoids on ECS components in depression, we enhance our understanding of which brain targets they hit, what biological processes they alter, and eventually how to use this information to design better therapeutic options. In this article, we discuss the literature on the effects of cannabinoids on ECS components of specific depression-like behaviors and phenotypes in rodents and then describe the findings in depressed patients. A better understanding of the effects of cannabinoids on ECS components in depression may direct future research efforts to enhance diagnosis and treatment.

Rapamycin prevents the long-term impairing effects of adolescence Δ-9-tetrahydrocannabinol on memory and plasticity in male rats.

Long-lasting cognitive impairment is one of the most central negative consequences related to the exposure to cannabis during adolescence and particularly of Δ-9-tetrahydrocannabinol (THC). The aim of this study was to compare the protracted effects of adolescent versus late-adolescent chronic exposure to THC on short-term memory and plasticity and to examine whether rapamycin, a blocker of the mammalian target of rapamycin (mTOR) pathway, can restore THC-induced deficits in memory and plasticity. Male rats were injected with ascending doses of THC [2.5, 5, 10 mg/kg; intraperitoneally (i.p.)] during adolescence and late-adolescence (post-natal days 30-41 and 45-56, respectively), followed by daily injections of rapamycin (1 mg/kg, i.p.) during the first 10 days of cessation from THC. Thirty days after the last injection, rats were tested for short-term and working memory, anxiety-like behaviour, and plasticity in the pathways projecting from the ventral subiculum (vSub) of the hippocampus to the prefrontal cortex (PFC) and nucleus accumbens (NAc). THC exposure in adolescence, but not late-adolescence, was found to induce long-term deficits in object recognition short-term memory and synaptic plasticity in the hippocampal-accumbens pathway. Importantly, rapamycin rescued these persistent effects of THC administered during adolescence. Our findings show that some forms of memory and plasticity are sensitive to chronic THC administration during adolescence and that rapamycin administered during THC cessation may restore cognitive function and plasticity, thus potentially protecting against the possible long-term harmful effects of THC.