Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses.

The central amygdala (CeA) is a key structure at the limbic-motor interface regulating stress responses and emotional learning. Endocannabinoid (eCB) signaling is heavily implicated in the regulation of stress-response physiology and emotional learning processes; however, the role of eCBs in the modulation of synaptic efficacy in the CeA is not well understood. Here we describe the subcellular localization of CB1 cannabinoid receptors and eCB synthetic machinery at glutamatergic synapses in the CeA and find that CeA neurons exhibit multiple mechanistically and temporally distinct modes of postsynaptic eCB mobilization. These data identify a prominent role for eCBs in the modulation of excitatory drive to CeA neurons and provide insight into the mechanisms by which eCB signaling and exogenous cannabinoids could regulate stress responses and emotional learning

Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

Summary: Endocannabinoid (eCB) signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG) in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα) in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. : The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy et al. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels

Core Data Elements for Pregnancy Pharmacovigilance Studies Using Primary Source Data Collection Methods:Recommendations from the IMI ConcePTION Project

The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised nor systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this manuscript is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies which can be used to standardise data collection procedures, and thereby improve data harmonisation and evidence synthesis capabilities. This CDE reference framework was developed within the IMI ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition and derivation of each data item identified from these systems. With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy