Role of Cannabinoid Type 1 Receptor in Locus Coeruleus Activity: Implications for Therapeutic Intervention in Stress-Induced Psychiatric Disorders

Cannabinoids have profound effects on mood and behavior, in part through their modulation of the stress-integrative locus coeruleus (LC)-noradrenergic system. Cannabinoid type 1 receptor (CB1r) agonists are capable of increasing noradrenergic activity and anxiety-like behaviors; however, they can also decrease stress-induced anxiety. In order to more closely examine the role of CB1r in regulating LC-norepinephrine (NE) activity, whole-cell patch clamp electrophysiology was performed on LC-NE neurons from CB1r-knockout (KO) mice. Since sex differences are found within the endocannabinoid (eCB) system, stress signaling, and the prevalence of psychiatric disorders, both males and females were examined. CB1r deletion caused an increase in LC-NE excitability, input resistance, and NE levels in the prefrontal cortex in male mice, but not females. Additionally, stress peptide corticotropin releasing factor (CRF)-induced increases in LC-NE excitability are lost in CB1r-KO mice. Western blot analysis revealed an increase in CRF and tyrosine hydroxylase expression levels, and decrease in norepinephrine transporter expression in male CB1r-KO compared to WT in the LC, and an increase in [alpha]2-adrenoceptor expression in female CB1r-KO compared to WT. Next, immunoelectron and immunofluorescence microscopy determined the cellular localization of CB1r with respect to the CRF in the LC, showing co-localization of CB1r to CRF-containing amygdalar afferents. Finally social stress, which leads to anxiety-like behaviors, differentially alters eCB system protein levels in the LC in resilient and non-resilient populations of rats across sexes. These results expand the understanding of cannabinoid-CRF-adrenergic interactions, and how targeting CB1r could provide therapeutic relief for anxiety disorders.Ph.D., Pharmacology and Physiology -- Drexel University, 201

The endocannabinoid system in mental disorders: Evidence from human brain studies

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CB1 receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders.This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-67457-R, MINECO/FEDER), the Plan Estatal de I+D+i 2013-2016, the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Spanish Ministry of Economy, FEDER (PI13/01529) and the Basque Government (IT616/13). I I-L is a recipient of a Predoctoral Fellowship from the Basque Government. E F-Z is a recipient of a Predoctoral Fellowship from the University of Cantabria. CM is a recipient of a Postdoctoral Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, ID 747487)