Regulation of Basal and Ethanol Abstinence-Induced Affective Behaviors by GluN2B-containin NMDA Receptors in the Bed Nucleus of the Stria Terminalis and Endocannabinoids

Abstract

Major depressive disorder (MDD) represents an enormous societal burden that will directly affect nearly one fifth of Americans within their lifetime. Despite its high prevalence and contribution to disability, current treatment strategies – primarily SSRIs – have low efficacy and take weeks to months of treatment before alleviation of symptoms occurs. Recently, the noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist ketamine was shown to induce rapid and long lasting antidepressant effects in both rodent models of depression and MDD patients. However, the mechanism underlying ketamine’s effects are not completely known. The bed nucleus of the stria terminalis (BNST) is a part of the extended amygdala and sits at the nexus of higher order processing, reward circuitry, and stress circuitry and has been implicated in depression-like behavior. We found that antagonism of the GluN2B subunit of the NMDAR, through both global pharmacology as well as genetically restricted to the BNST, resulted in reduced depression-like behavior in the Novelty-Induced Hypophagia task (NIH). We also found that ketamine was able to reduce depression-like behavior induced by forced abstinence from a six week two bottle choice ethanol (EtOH) drinking paradigm. Female singly housed mice displayed high preference for EtOH, and drinking seemed to become habit-driven over the course of the paradigm. Protracted forced abstinence was required to induce long-lasting depression-like behaviors, which were ameliorated by ketamine, but not another NMDAR antagonist memantine. Additionally, we found that amelioration of depression-like behaviors could also be achieved by augmenting the endocannabinoid (eCB) 2-AG through inhibition of its degradation enzyme monacylglycerol (MAG) lipase by JZL-184. Antidepressant-like effects of JZL-184 were completely blocked by low dose rimonabant, a cannabinoid receptor 1 (CB1) antagonist. We found that eCB levels were altered during EtOH drinking and abstinence in the basolateral amygdala. Future studies will aim to examine the mechanisms underlying antidepressant effects eCBs and ketamine within the BNST both basally and following EtOH administration.