Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia.

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects.

The role of BDNF in mediating the prophylactic effects of (R,S)-ketamine on fear generalization and extinction.

Fear generalization is a conserved survival mechanism that can become maladaptive in the face of traumatic situations, a feature central to certain anxiety disorders including posttraumatic stress disorder (PTSD). However, the neural circuitry and molecular mechanisms underlying fear generalization remain unclear. Recent studies have shown that prophylactic treatment with (R,S)-ketamine confers protective effects in stress-induced depressive behaviors and enhances contextual fear discrimination, but the extent to which these effects extend to fear generalization after auditory fear conditioning remains unclear.

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAH) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CBR) levels at inhibitory and excitatory terminals in the VTA.

Ventral hippocampus interacts with prelimbic cortex during inhibition of threat response via learned safety in both mice and humans.

Heightened fear and inefficient safety learning are key features of fear and anxiety disorders. Evidence-based interventions for anxiety disorders, such as cognitive behavioral therapy, primarily rely on mechanisms of fear extinction. However, up to 50% of clinically anxious individuals do not respond to current evidence-based treatment, suggesting a critical need for new interventions based on alternative neurobiological pathways.

The microbiota regulate neuronal function and fear extinction learning.

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders.

Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human.

Social deficits are common in many psychiatric disorders. However, due to inadequate tools for manipulating circuit activity in humans and unspecific paradigms for modeling social behaviors in rodents, our understanding of the molecular and circuit mechanisms mediating social behaviors remains relatively limited. Using human functional neuroimaging and rodent fiber photometry, we identified a mOFC-BLA projection that modulates social approach behavior and influences susceptibility to social anxiety.

FAAH genetic variation enhances fronto-amygdala function in mouse and human.

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels.

Immune function in PTSD.

Disturbed regulation of both the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenomedullary system in posttraumatic stress disorder (PTSD) suggests that immune function, which is modulated by these systems, may also be dysregulated. Two dermatologic, in vivo measures of immune function, delayed-type hypersensitivity (DTH) and skin barrier function recovery, were examined in female subjects with PTSD and compared to measures in healthy female comparison subjects. In addition, at the time of DTH test placement, circulating numbers of lymphocyte subtypes were assessed.

Changes in cerebrospinal fluid neurochemistry during pregnancy.

Background: Little is known about changes in brain function that may occur during pregnancy. Studies in rodents and sheep suggest that several brain neurotransmitter and neurohormonal systems known to modulate anxiety may be altered during pregnancy.

Methods: Cerebrospinal fluid (CSF) and plasma samples were obtained from 21 women (during weeks 38-39 of pregnancy) who were undergoing elective cesarean section and from 22 healthy nonpregnant women.