Sex Differences in the Endocannabinoid System: Implications for Stress-Related Psychiatric Disorders

Abstract

Stress-related psychiatric disorders including post-traumatic stress disorder (PTSD), depression, and anxiety are among the most prevalent conditions in the world, and their incidence continues to rise each year. These patient populations are comprised of more women than men and are difficult to treat as the underlying neurobiology is complex, and a diverse array of symptoms present clinically, often in a sex-dependent manner. The dysregulation of the stress-responsive locus coeruleus–norepinephrine (LC-NE) system has been implicated in the onset and progression of many psychiatric diseases, and restoration of LC-NE function is associated with resolved symptoms in cases of successful treatment. Brain endocannabinoids (eCBs) are ubiquitously expressed neurotransmitters involved in the regulation of many physiological processes, including modulating behavioral responses to stress. The LC is a target of eCB action and exerts its influence via the cannabinoid type 1 receptor (CB1r). The eCB system is capable of enhancing or reducing LC responsivity to various physiological and environmental stimuli. Thus, targeting the eCB system may have therapeutic potential in treating stress-related psychiatric disorders, in part, by modulating the LC-NE system. Conventional pharmacological approaches are often only successful in a subpopulation of afflicted individuals. Therefore, the purpose of the present study is to characterize compensatory mechanisms in the eCB system under conditions of NE depletion, a model of symptoms that arise in patient subpopulations that are difficult to treat such as atypical depression. Protein expression levels of a key enzyme in the biosynthesis of the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol lipase-[alpha] (DGL-[alpha]), as well as two eCB degrading enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) were examined in the LC of mice that lack the NE-synthesizing enzyme, dopamine [beta]-hydroxylase (D[beta]H-knockout, KO) and in rats treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), an LC-specific neurotoxin. In D[beta]H-KO mice, DGL-[alpha] expression was significantly increased in both sexes when compared to wildtype (WT). While MGL expression was not altered in either D[beta]H-KO, FAAH expression was significantly reduced in female D[beta]H-KO groups compared to WT. In DSP-4 male rats, DGL-[alpha] expression was significantly increased compared to saline-treated controls, and a similar trend was observed in DSP-4 treated female rats. There were no observed differences in either groups for MGL expression. Meanwhile, FAAH was found to be significantly decreased in DSP-4 treated males and significantly increased in DSP-4 treated females. Thus, the results of these findings suggest increased eCB tone in DSP-4 treated male rats and overall increased turnover in female DSP-4 treated rats. The results indicate that sex-specific strategies may be advantageous for stress-related therapeutics which are aimed at modifying the LC-NE system via the eCB system.M.S., Drug Discovery and Development -- Drexel University, 201