SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress

Stress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

Systematic review of Pharmacogenomics Knowledgebase evidence for pharmacogenomic links to the dopamine reward pathway for heroin dependence

Genetics play an important role in opioid use disorder (OUD); however, few specific gene variants have been identified. Therefore, there is a need to further understand the pharmacogenomics influences on the pharmacodynamics of opioids. The Pharmacogenomics Knowledgebase (PharmGKB), a database that links genetic variation and drug interaction in the body, was queried to identify polymorphisms associated with heroin dependence in the context of opioid related disorders/OUD. Eight genes with 22 variants were identified as linked to increased risk of heroin dependence, with three genes and variants linked to decreased risk, although the level of evidence was moderate to low. Therefore, continued exploration of biomarker influences on OUD, reward pathways and other contributing circuitries is necessary to understand the true impact of genetics on OUD before integration into clinical guidelines.

Genetic variation in alcoholism and opioid addiction susceptibility and treatment: a pharmacogenomic approach

<abstract> <p>Alcohol and opioid abuse have pervasive and detrimental consequences from the individual to societal level. The extent of genetic contribution to alcoholism has been studied for decades, yielding speculative and often inconsistent results since the previous discovery of two pharmacokinetic variants strongly protective against alcoholism. The neurobiology of addiction involves innumerate genes with combinatorial and epistatic interactions, creating a difficult landscape for concrete conclusions. In contrast, pharmacogenomic variation in the treatment of alcoholism yields more immediate clinical utility, while also emphasizing pathways crucial to the progression of addiction. An improved understanding of genetic predisposition to alcohol abuse has inherent significance for opioid addiction and treatment, as the two drugs induce the same reward pathway. This review outlines current knowledge, treatments, and research regarding genetic predisposition to alcoholism, focusing on pharmacodynamic variation within the dopaminergic system and shared implications for opioid abuse. Multifaceted and highly polygenic, the phenotype of addiction seems to grow more complex as new research extends the scope of its impact on the brain, body, and progeny.</p> </abstract>

Effects of systemic glycine on accumbal glycine and dopamine levels and ethanol intake in male Wistar rats

Approved medications for alcohol use disorder (AUD) display modest effect sizes. Pharmacotherapy aimed at the mechanism(s) by which ethanol activates the dopamine reward pathway may offer improved outcomes. Basal and ethanol-induced accumbal dopamine release in the rat involve glycine receptors (GlyR) in the nucleus accumbens (nAc). Glycine transporter 1 (GlyT-1) inhibitors, which raise extracellular glycine levels, have repeatedly been shown to decrease ethanol intake in the rat. To further explore the rational for elevating glycine levels in the treatment of AUD, this study examined accumbal extracellular glycine and dopamine levels and voluntary ethanol intake and preference in the rat, after systemic treatment with glycine. The effects of three different doses of glycine i.p. on accumbal glycine and dopamine levels were examined using in vivo microdialysis in Wistar rats. In addition, the effects of the intermediate dose of glycine on voluntary ethanol intake and preference were examined in a limited access two-bottle ethanol/water model in the rat. Systemic glycine treatment increased accumbal glycine levels in a dose-related manner, whereas accumbal dopamine levels were elevated in a subpopulation of animals, defined as dopamine responders. Ethanol intake and preference decreased after systemic glycine treatment. These results give further support to the concept of elevating central glycine levels to reduce ethanol intake and indicate that targeting the glycinergic system may represent a pharmacologic treatment principle for AUD.

Naltrexone Treatment for Prolonged Grief Disorder: Study Protocol for a Randomized, Triple-Blinded, Placebo-Controlled Trial

BACKGROUNDThere is a lack of effective pharmacotherapy for prolonged grief disorder (PGD). Evidence suggests that the neurobiology of PGD involves the same circuitry as the reward pathway. Based upon this evidence, we hypothesize that PGD can be conceptualized as a disorder of addiction, and therefore could benefit from being treated with medications that are currently used to treat such disorders. One such medication is naltrexone, which is currently used to treat alcohol and opioid dependence. Oral naltrexone was chosen for its mechanism of action, safety, and convenience. The primary aim of this study is to establish the efficacy of using oral naltrexone as a pharmacological treatment for PGD. Specifically, we hypothesize that participants receiving naltrexone will demonstrate reduced PGD symptoms when compared to placebo.METHODS/DESIGNThis is a randomized, placebo-controlled, triple-blinded (to healthcare professionals, participants, and data analysts) in which we propose to enroll 46 participants who meet criteria for Prolonged Grief Disorder (PGD). Participants will be randomly assigned to the naltrexone 50 mg oral arm or placebo arm; medications will be over-encapsulated to appear identical. Participants will take their assigned medication for 8 weeks, with monthly clinic visits to assess symptom severity, social closeness, and adverse reactions. Weekly surveys of Prolonged Grief-13-Revised (PG-13-R) will be used to relate naltrexone use to changes in PGD symptom severity. Follow-up 4 weeks after their last visit will assess the longevity of treatment, as well as any lingering adverse reactions.DISCUSSIONThis study is the first to investigate the use of oral naltrexone as pharmacological treatment for PGD. The acute and debilitating nature of the disorder, in addition to the evidence demonstrating the increased risk of comorbidities, highlights the need for pharmacological treatment like naltrexone that can act more rapidly, may help those for whom psychotherapy may not be effective, and/or may augment psychotherapy to promote PGD symptom grief resolution.TRIAL REGISTRATIONClinicalTrials.gov, NCT04547985. Registered on 8/31/2020, https://clinicaltrials.gov/ct2/show/NCT04547985.

Histone Glutamine Modification by Neurotransmitters: Paradigm Shift in the Epigenetics of Neuronal Gene Activation and Dopaminergic VTA Reward Pathway

Normal brain function means fine-tuned neuronal circuitry with optimum neurotransmitter signaling. The classical views and experimental demonstrations established neurotransmitters release-uptake through synaptic vesicles. Current research highlighted that neurotransmitters not merely influence electrical impulses; however, contribute to gene expression, now we know, by posttranslational modifications of chromatinised histones. Epigenetic modifications of chromatin, like DNA methylation, histone methylation, acetylation, ubiquitilation etc., influence gene expression during neuronal development, differentiation and functions. Protein glutamine (Q) modification by tissue transglutaminase (TGM2) controls a wide array of metabolic and signaling activities, including neuronal functions. Dopamine neurons are central element in the brain reward system that controls the learning of numerous behaviours. The ventral tegmental area (VTA) consists of dopamine, GABA, or glutamate neurons. The VTA and adjacent substantia nigra are the two major dopaminergic areas in the brain. In view of this, and to focus insight into the neuronal functions caused by TGM2 mediated histone modifications at the Q residues, either serotonylation (for example, H3K4me3Q5 to H3K4me3Q5ser) in the context of cellular differentiation and signaling, or dopaminylation (for example, H3Q5 to H3Q5dop) in the dopaminergic VTA reward pathway and the precise role of cocaine withdrawal in this scenario are summarized and discussed in this contribution.