Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

Background:Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler's group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during human investigations and animal self-administration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking.Hypothesis:The hypothesis is that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression.Discussion:Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, and results in histone H3 glutamine 5 dopaminylation (H3Q5dop) and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase signaling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a "homeostatic brake."Conclusion:The decrease in Src signaling in NAc D2-MSNs, (like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD) normalizes the NAc dopamine expression and decreases cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

Alcohol and other substance use disorders share comorbidity with other RDS disorders, i.e., a reduction in dopamine signaling within the reward pathway. RDS is a term that connects addictive, obsessive, compulsive, and impulsive behavioral disorders. An estimated 2 million individuals in the United States have opioid use disorder related to prescription opioids. It is estimated that the overall cost of the illegal and legally prescribed opioid crisis exceeds one trillion dollars. Opioid Replacement Therapy is the most common treatment for addictions and other RDS disorders. Even after repeated relapses, patients are repeatedly prescribed the same opioid replacement treatments. A recent JAMA report indicates that non-opioid treatments fare better than chronic opioid treatments. Research demonstrates that over 50 percent of all suicides are related to alcohol or other drug use. In addition to effective fellowship programs and spirituality acceptance, nutrigenomic therapies (e.g., KB220Z) optimize gene expression, rebalance neurotransmitters, and restore neurotransmitter functional connectivity. KB220Z was shown to increase functional connectivity across specific brain regions involved in dopaminergic function. KB220/Z significantly reduces RDS behavioral disorders and relapse in human DUI offenders. Taking a Genetic Addiction Risk Severity (GARS) test combined with a the KB220Z semi-customized nutrigenomic supplement effectively restores dopamine homeostasis (WC 199).

Pioneering work reported by Anton, et al. [1] in this journal may be an important step in the treatment algorithm of patients with alcohol use disorder (AUD). Identifying patients who need and would benefit from treatment with naltrexone [2] might help to change clinicians’ hesitancy to utilize these medications in AUD where twelve step treatment programs have renewed interest and support [3]. Modern therapeutics and personalized medication are predicated on the basis of tests or measures that can provide potential matching of safe and effective medications with the population of patients who are most likely to benefit from these therapeutic interventions. Anton’s work might help to improve the utilization of medications in not only in classical AUD but also in a wider spectrum of alcohol misusing patients. The importance of genetic testing to predict Medical Assistance Treatment (MAT) response came to prominence by the initial discovery of the DRD2 Taq A1 allele and its relationship to alcoholism [4]. In addition, it also seems essential to analyze genetic polymorphisms related to opioid and dopaminergic genes as antecedent polymorphic predictors of clinical responses to naltrexone [5]. We also applaud the efforts of Anton’s team in evaluating whether response to naltrexone depends on or is predicted by potential interactions of the OPRM1 SNP rs1799971 with the dopamine transporter gene DAT1/SLC6A3

The consensus of the current literature strongly supports the concept that brain neurotransmitters, and second messengers involved in the net release of dopamine in the mesolimbic region, especially the Nucleus Accumbens (NAc), is directly linked to motivation, anti-stress, incentive salience (wanting), and well-being. The role of dopamine in terms of alcohol withdrawal symptomology, cocaine craving behavior, dopamine -condensation products (TIQs), and more recently, the genetic aspects of drug-seeking and pro-dopamine regulation, provide compelling evidence of the relevant molecular neurological correlates of dopaminergic /endorphinergic mechanisms in reward circuitry due to genetic polymorphisms and epigenetic insults. In the face of an Americans opioid epidemic, the clinical consensus is to treat Opioid Use Disorder (OUD) with life-long opioid substitution therapy. However, the authors suggest a paradigm shift involving novel modalities like targeting the endorphinergic system linked to dopamine release at the NAc, in terms of the induction of required "dopamine homeostasis." Utilizing the known genetic - environmental interaction theorem P = G + E, the authors provide a clear rationale for the adoption of genetic risk testing coupled with endorphinergic/dopamine regulation to address dysfunction across the brain reward circuitry. The goal of altering resting-state, functional connectivity may require a gentle "neurotransmitter fix" vis enkephalinase inhibition to overcome or combat - self-induction of acute dopamine release via psychoactive substance misuse resulting in chronic dopamine down-regulation. As subsets of reward deficiency, we are poised to provide novel, genetically guided therapy for endorphinergic, opioidergic, and dopaminergic deficiencies and related syndromes, utilizing "Precision Addiction Management.

A recent analysis from Stanford University suggested that without any changes in currently available treatment, prevention, and public health approaches, we should expect to have 510,000 deaths from prescription opioids and street heroin from 2016 to 2025 in the US. In a recent review, Mayo Clinic Proceedings (October 2019), Gold and colleagues at Mayo Clinic reviewed the available medications used in opioid use disorders and concluded that in private and community practice adherence is more important as a limiting factor to retention, relapse, and repeat overdose. It is agreed that the primary utilization of known opioid agonists like methadone, buprenorphine and naloxone combinations, while useful as a way of reducing societal harm, is limited by 50% of more discontinuing treatment within 6 months, their diversion, and addiction liability. Opioid agonists may have other unintended consequences, like continuing the down regulation of dopamine systems. While naltrexone would be expected to have opposite effects, adherence is also low even after detoxification and long acting naltrexone injections. Recent studies have shown Naltrexone is beneficial by attenuation of craving via "psychological extinction" and reducing relapse. Buprenorphine is the MAT of choice currently but injectable Naltrexone plus an agent to improve dopaminergic function and tone may renew interest amongst addiction physicians and patients. Understanding this dilemma there is increasing movement to opt for the non-addicting narcotic antagonist Naltrexone. Even with extended injectable option there is still poor compliance. As such, we describe an open label investigation in humans showing improvement of naltrexone compliance and outcomes with dopamine augmentation with the pro- dopamine regulator KB220 (262 days) compared to naltrexone alone (37days). This well studied complex consists of amino-acid neurotransmitter precursors and enkephalinase inhibitor therapy compared to treatment as usual. Consideration of this novel paradigm shift may assist in not only addressing the current opioid epidemic but the broader question of reward deficiency in general.

Opioids have been used to treat pain and invoke pleasure for centuries. Modern scientific advancements have led to more potent, synthetic opioids. While certainly more effective in treating pain, they can also be much more addictive. Over the years the scientific community has developed a clearer understanding of the role opioid receptors play in causing and treating opioid use disorders (OUD) and we now know that OUD can develop in individuals taking opioids for "legitimate" pain. Current guidelines suggest that all prescribers (especially those prescribing opioids) be capable treating OUD. Pharmacological advances have led to a wide array of safe and effective treatment options to address OUDs. This paper will discuss the history of opioid development, what is known about the transition from analgesic uses to addiction and modern evidenced based treatment strategies to address OUDs.

The extant literature confirms that an array of polymorphic genes related to- neurotransmitters and second messengers govern the net release of dopamine in the Nucleus Accumbens (NAc) in the mesolimbic region of the brain. They are linked predominantly to motivation, anti-stress, incentive salience (wanting), and wellbeing. Notably, in 2000 the Nobel Prize was awarded to Carlsson, Greengard, and Kandel for their work on the molecular and cellular function of dopaminergic activity at neurons. This historical psychopharmacological work involved neurotransmission of serotonin, endorphins, glutamate, and dopamine, and the seminal work of Blum, Gold, Volkow, Nestler, and others related to neurotransmitter function and related behaviors. Currently, Americans are facing their second and worst opioid epidemic, prescribed opioids, and easy access drive this epidemic of overdoses, and opioid use disorders (OUDs). Presently the clinical consensus is to treat OUD, as if it were an opioid deficiency syndrome, with long-term to life-long opioid substitution therapy. Opioid agonist administration is seen as necessary to replace missing opioids, treat OUD, and prevent overdoses, like insulin is used to treat diabetes. Treatment of OUD and addiction, in general, is similar to the endocrinopathy conceptualization in that it views opioid agonist MATs as an essential core to therapy. Is this approach logical? Other than as harm reduction, is using opioids to treat OUD therapeutic or harmful in the long term? This historical Trieste provides a molecular framework to understand the current underpinnings of endorphinergic/dopaminergic mechanisms related to opioid deficiency syndrome and generalized reward processing depletion.

Background: Opioid dependence and death in America have reached epidemic proportions. Since 2000, we have seen an increase of over 3,000 percent in patients seeking treatment for substance use disorders. The “gold standard” for medically –assisted treatment, that is, Buprenorphine (a partial opioid agonist), combined with Naloxone, an opioid antagonist. Unfortunately, the relapse rates for Buprenorphine programs are high, and withdrawal reactions are common when Buprenorphine is precipitously discontinued. We must find approaches to treating substance use disorders that are more effective. Objectives: This report reviews the neuropharmacology of neurotransmitters involved in brain reward circuitry to increase understanding of the effect of Buprenorphine/Naloxone treatment on patients with substance use disorders. Discussion: We provide evidence, from animal and human models, regarding the acute and chronic effects of Buprenorphine on Dopaminergic reward processing. Microdialysis in animal models reveals that acute Buprenorphine tends to increase mesolimbic dopamine release. However, longterm use tends to decrease dopamine release. Cessation of Buprenorphine combination treatment increases drug reinstatement and relapse. Conclusions: This review of both the acute and chronic effects of Buprenorphine naloxone combination therapy on neurotransmission and behavior suggests new treatment targets and clinical options. “Pro-Dopamine Regulation” to induce dopaminergic homeostasis, via new options, other than the current, underutilized FDA approved Medication Assisted Treatments, which favor dopamine antagonism is proposed. We hypothesize that dopamine homeostasis is a crucial process that suppresses withdrawal symptoms, drug seeking and relapse in abstinent individuals. Keywords: Buprenorphine, dopamine, dopaminergic homeostasis, Naloxone, nucleus accumbens, opioid addiction, pro-dopamine regulation.

Blum's laboratory first showed the benefits of naloxone or narcotic antagonists in the treatment of alcohol dependence. This seminal work published in Nature in the early 70's, in conjunction with many other studies, later served as the basis for the development of the narcotic antagonist (NTX) now used to treat both alcohol and opioid dependence. In 2006 an extended-release injectable of Naltrexone (XR-NTX) was approved by the FDA. Naltrexone is a relatively weak antagonist of κ- and δ-receptors and is also a potent μ-receptor antagonist. Dosages of naltrexone that effectively reduce opioid and alcohol consumption also actively block μ-receptors, but chronically down-regulate mesolimbic dopamine release. While studies show benefit especially in the short term, there is ongoing evidence that the retention and compliance with NTX are not sufficient to characterize adherence as high. However, extended-release NTX opioid treatment is associated with superior outcomes including less likely relapse (defined as daily use), and much longer time to relapse despite higher rates of concurrent non-opioid substance use like cocaine. Regarding long-term extended-release injectable (XR-NTX) for opioid dependence; there was higher compliance with Opioid Use Disorder (OUD) than for Alcohol Use Disorder (AUD.). Consideration of modalities in combination with XR-NTX is imperative. Research by Blum., et al. showed that a combination of Naltrexone and a pro-dopamine regulator neuro-nutrient (KB220) significantly prevented opioid relapse. Thus, early identification of addiction vulnerability with the Genetic Addiction Risk Score (GARS™) a panel of polymorphic risk alleles from ten reward circuitry genes will provide valuable information especially as it relates to genetically guided therapy with the KB220 neuro nutrient termed 'Precision Addiction Management".

The brain regions tied to pleasure can be triggered by engaging in sex, eating tasty food, watching a movie, accomplishments at school and athletics, consuming drugs, and noble efforts to help the community, the country, and the world. It is noteworthy that research suggests that the latter type of satisfaction, supporting the community, may result in the most substantial positive effects on our immune system. However, these pathways for these effects are not understood. Berridge and Kringelbach have suggested that pleasure is mediated by well-developed mesocorticolimbic circuitry and serves adaptive functions. In affective disorders, anhedonia (lack of pleasure) or dysphoria (negative affect) can result from a breakdown of that hedonic system. Most importantly, human neuroimaging investigations indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural pathway shared by all rewarding stimuli and behaviors. Over many years the controversy of dopamine involvement in pleasure/reward has led to confusion in terms, such as trying to separate motivation from pure pleasure (i.e., wanting versus liking). We take the position that animal studies cannot provide real clinical information that is described by self-reports in humans. On November 23rd, 2017, evidence for our concerns was revealed. A brain system involved in everything from addiction to autism appears to have evolved differently in humans than in apes, as reported by a large research team in the journal Science. To reiterate, the new findings by Sousa et al., also suggest the importance of not over-relying on rodent and even non-human primate studies. Extrapolations, when it comes to the concept of pleasure, dopamine, and reinforcement, are not supported by these data. Human experience and study are now much more critical and important. Extrapolations from non-humans to humans may be more fiction than fact. While this statement is bold it should not at all suggest that animal date is unimportant, that is not the case. It is extremely valuable in many aspects and we must encourage the development of animal models for disease. However, we must be cautious in our interpretation of results without leaping to conclusions that may be explained by follow-up human experiments and subsequent data. We are further proposing that in terms of overcoming a never -ending battle related to the current drug epidemic, the scientific community should realize that disturbing dopamine homeostasis by taking drugs or having a system compromised by genes or other epigenetic experiences, should be treated by alternative therapeutic modalities, expressed in this article as a realistic key goal. Application of genetic addiction risk (GARS™) testing and pro-dopamine regulation (KB220) should be considered along with other promising technologies including cognitive behavioral therapy, mind fullness, brain spotting and trauma therapy. Basic scientists have worked very hard to dis-entangle pleasure from incentive salience and learning signals in brain reward circuitry, but this work may be limited to animal models and rodents. A different consideration regarding the human reward systems is required.

Addiction is a public health crisis in the United States. Understanding the cause and providing effective treatment for patients-in particular, those with substance use disorders-is challenging. Research has demonstrated that addiction is not a flaw in one's moral fiber or a disease of choice; rather, it is driven by alterations in neuronal mechanisms, especially those that involve the neurotransmitter dopamine, which plays a critical role in the brain's reward pathway. Much of osteopathic philosophy is based on the concept of total body homeostasis and allostasis. This article discusses the role of achieving dopamine homeostasis as part of a comprehensive biopsychosocial treatment strategy in the effective management of addiction. The authors aim to motivate osteopathic primary care physicians to incorporate osteopathic philosophy into the treatment of patients with substance use disorders.

Background: In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed “Brain Reward Cascade.” These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed “Reward Deficiency Syndrome” (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. Objective: In this review article, we attempt to clarify these terms and provide a working model to accurately diagnose and treat these unwanted behaviors. Method: We are hereby proposing the development of a translational model we term "Reward Deficiency Solution System™" that incorporates neurogenetic testing and meso-limbic manipulation of a "hypodopaminergic" trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced "dopamine resistance," while embracing "dopamine homeostasis." Result: The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184.

This commentary is to inform clinicians challenged with an increase in people seeking treatment for Substance Use Disorder (SUD), that the ninety percent revolving door, is, in part, due to post-withdrawal, untreated neurotoxicity. This impairment attenuates neurotransmitter signaling and compromises resting state functional connectivity, leading to unwanted sequelae including depression, sleep disturbances, sensation seeking, lack of satisfaction and impulsivity. Neuroimaging studies indicate that neurobiological recovery can take years. Like a "double edge sword" SUD has a biological bi -directional (bio-directional) effect on the brain reward circuitry. The acute intake of psychoactive drugs results in heightened dopaminergic activity, while, the opposite, hypodopaminergia occurs following chronic abuse. Individuals with SUD can have a genetic predisposition, compounded by stress and neurotoxically induced, epigenetic insults that impact recovery from protracted abstinence. Follow-up post -short-term recovery usually includes supportive therapies and programs like 12 -steps and other fellowships. However, relapse will usually occur if post -short-term recovery hypodopaminergia is not treated with attempts at epigenetic manipulation of compromised brain neurochemistry using some manner of pro-dopamine regulation.