Addressing cortex dysregulation in youth through brain health check coaching and prophylactic brain development.

The Carter Center has estimated that the addiction crisis in the United States (US), if continues to worsen at the same rate, may cost the country approximately 16 trillion dollars by 2030. In recent years, the well-being of youth has been compromised by not only the coronavirus disease 2019 pandemic but also the alarming global opioid crisis, particularly in the US. Each year, deadly opioid drugs claim hundreds of thousands of lives, contributing to an ever-rising death toll. In addition, maternal usage of opioids and other drugs during pregnancy could compromise the neurodevelopment of children. A high rate of DNA polymorphic antecedents compounds the occurrence of epigenetic insults involving methylation of specific essential genes related to normal brain function. These genetic antecedent insults affect healthy DNA and mRNA transcription, leading to a loss of proteins required for normal brain development and function in youth. Myelination in the frontal cortex, a process known to extend until the late 20s, delays the development of proficient executive function and decision-making abilities. Understanding this delay in brain development, along with the presence of potential high-risk antecedent polymorphic variants or alleles and generational epigenetics, provides a clear rationale for embracing the Brain Research Commission's suggestion to mimic fitness programs with an adaptable brain health check (BHC). Implementing the BHC within the educational systems in the US and other countries could serve as an effective initiative for proactive therapies aimed at reducing juvenile mental health problems and eventually criminal activities, addiction, and other behaviors associated with reward deficiency syndrome.

Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

Neurogenetics and Epigenetics of Loneliness.

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.

The Opioid Epidemic: a Crisis Disproportionately Impacting Black Americans and Urban Communities.

The heroin epidemic has existed for decades, but a sharp rise in opioid overdose deaths (OODs) jolted the nation in the mid-twenty-teens and continues as a major health crisis to this day. Although the new wave of OODs was initially approached as a rural problem impacting a White/Caucasian demographic, surveillance records suggest severe impacts on African Americans and urban-dwelling individuals, which have been largely underreported. The focus of this report is on specific trends in OOD rates in Black and White residents in states with a significant Black urban population and declared as hotspots for OOD: (Maryland (MD), Illinois (IL), Michigan (MI), and Pennsylvania (PA)), and Washington District of Columbia (DC). We compare OODs by type of opioid, across ethnicities, across city/rural demographics, and to homicide rates using 2013-2020 data acquired from official Chief Medical Examiners' or Departments of Health (DOH) reports. With 2013 or 2014 as baseline, the OOD rate in major cities (Baltimore, Chicago, Detroit, Philadelphia) were elevated two-fold over all other regions of their respective state. In DC, Wards 7 and 8 OODs were consistently greater than other jurisdictions, until 2020 when the rate of change of OODs increased for the entire city. Ethnicity-wise, Black OOD rates exceeded White rates by four- to six-fold, with fentanyl and heroin having a disproportionate impact on Black opioid deaths. This disparity was aggravated by its intersection with the COVID-19 pandemic in 2020. African Americans and America's urban dwellers are vulnerable populations in need of social and political resources to address the ongoing opioid epidemic in under-resourced communities.

Are We Getting High Cause the Thrill is Gone?

In the USA alone, opioid use disorder (OUD) affects approximately 27 million people. While the number of prescriptions may be declining due to increased CDC guidance and prescriber education, fatalities due to fentanyl-laced street heroin are still rising. Our laboratory has extended the overall concept of both substance and non-substance addictive behaviors, calling it "Reward Deficiency Syndrome (RDS)." Who are its victims, and how do we get this unwanted disorder? Is RDS caused by genes (Nature), environment (Neuro-epigenetics, Nurture), or both? Recent research identifies resting-state functional connectivity in the brain reward circuitry as a crucial factor. Analogously, it is of importance to acknowledge that the cumulative discharge of dopamine, governed by the nucleus accumbens (NAc) and modulated by an array of additional neurotransmitters, constitutes a cornerstone of an individual's overall well-being. Neuroimaging reveals that high-risk individuals exhibit a blunted response to stimuli, potentially due to DNA polymorphisms or epigenetic alterations. This discovery has given rise to the idea of a diminished 'thrill,' though we must consider whether this 'thrill' may have been absent from birth due to high-risk genetic predispositions for addiction. This article reviews this issue and suggests the general concept of the importance of "induction of dopamine homeostasis." We suggest coupling a validated genetic assessment (e.g., GARS) with pro-dopamine regulation (KB220) as one possible frontline modality in place of prescribing potent addictive opioids for OUD except for short time harm reduction. Could gene editing offer a 'cure' for this undesirable genetic modification at birth, influenced by the environment and carried over generations, leading to impaired dopamine and other neurotransmitter imbalances, as seen in RDS? Through dedicated global scientific exploration, we hope for a future where individuals are liberated from pain and disease, achieving an optimal state of well-being akin to the proverbial 'Garden of Eden'.

Dopaminylation in Psychostimulant Use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression.

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.

Nicotinamide Adenine Dinucleotide (NAD+) and Enkephalinase Inhibition (IV1114589NAD) Infusions Significantly Attenuate Psychiatric Burden Sequalae in Substance Use Disorder (SUD) in Fifty Cases.

Background: There is a shortage of clinical studies examining the efficacy of Nicotinamide Adenine Dinucleotide and Enkephalinase infusions (IV1114589NAD) in treating Substance Use Disorder (SUD). Objective: This study aims to provide evidence that IV1114589NAD infusions significantly attenuate substance craving behavior. Methods: The study cohort consisted of addicted poly-drug, mixed gender, multi-ethnic individuals resistant to standard treatment. The investigation utilized Likert-Scales to assess behavioral outcomes. Results: Using Wilcoxon signed-rank tests and sign tests, our team detected significant results by comparing baseline to post outcome scores after IV1114589NAD injections: craving scores (P=1.063E-9); anxiety (P=5.487E-7); and depression (P=1.763E-4). A significant reduction in cravings, anxiety, and depression followed a dose-dependent linear trend. Linear trend analyses showed a significant relationship between NAD infusions and decreasing scores for cravings (P=0.015), anxiety (P=0.003), and depression (P=8.74E-5). A urine analysis was conducted on a subset of 40 patients midway through the study to assess relapse; 100% of the urine samples analyzed failed to detect illicit substance use. Discussion: The opioid crisis in America has claimed close to 800,000 lives since 2004; daily deaths are estimated to stand at 127, and in 2021, over 107,000 deaths were due to overdose. There is an urgency to find safe, side-effect-free solutions. Current interventions, such as Naltrexone implants, are invasive and may interfere with dopamine homeostasis leading to an anti-reward phenomenon. Larger randomized double-blinded placebo-controlled studies are needed to elucidate further the significance of the results presented in this study. The current pilot study provides useful preliminary data regarding the effectiveness of IV1114589NAD infusions in SUD treatment. Conclusion: This pilot study provides significant evidence that NAD infusions are beneficial in the treatment of SUD. This investigation serves as a rationale to extend these findings onto future research investigating the use of NAD/NADH as a stand-alone treatment, especially in patients showing high genetic risk as measured in the Genetic Addiction Risk Severity (GARS) test. Utilizing GARS will help provide a real personalized therapeutic approach to treat Reward Deficiency Syndrome (RDS).

Statistical Validation of Risk Alleles in Genetic Addiction Risk Severity (GARS) Test: Early Identification of Risk for Alcohol Use Disorder (AUD) in 74,566 Case-Control Subjects.

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least Alcohol Use Disorder (AUD), Blum's group developed the Genetic Addiction Risk Severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions published from 1990 until 2021. This analysis calculated the Hardy-Weinberg Equilibrium of each polymorphism in cases and controls. If available, the Pearson's χ2 test or Fisher's exact test was applied to comparisons of the gender, genotype, and allele distribution. The statistical analyses found the OR, 95% CI for OR, and a post-risk for 8% estimation of the population's alcoholism prevalence revealed a significant detection. The OR results showed significance for DRD2, DRD3, DRD4, DAT1, COMT, OPRM1, and 5HTT at 5%. While most of the research related to GARS is derived from our laboratory, we are encouraging more independent research to confirm our findings.

Researching Mitigation of Alcohol Binge Drinking in Polydrug Abuse: KCNK13 and RASGRF2 Gene(s) Risk Polymorphisms Coupled with Genetic Addiction Risk Severity (GARS) Guiding Precision Pro-Dopamine Regulation.

Excessive alcohol intake, e.g., binge drinking, is a serious and mounting public health problem in the United States and throughout the world. Hence the need for novel insights into the underlying neurobiology that may help improve prevention and therapeutic strategies. Therefore, our group employed a darkness-induced alcohol intake protocol to define the reward deficiency domains of alcohol and other substance use disorders in terms of reward pathways' reduced dopamine signaling and its restoration via specifically-designed therapeutic compounds. It has been determined that KCNK13 and RASGRF2 genes, respectively, code for potassium two pore domain channel subfamily K member 13 and Ras-specific guanine nucleotide-releasing factor 2, and both genes have important dopamine-related functions pertaining to alcohol binge drinking. We present a hypothesis that identification of KCNK13 and RASGRF2 genes' risk polymorphism, coupled with genetic addiction risk score (GARS)-guided precision pro-dopamine regulation, will mitigate binge alcohol drinking. Accordingly, we review published reports on the benefits of this unique approach and provide data on favorable outcomes for both binge-drinking animals and drunk drivers, including reductions in alcohol intake and prevention of relapse to drinking behavior. Since driving under the influence of alcohol often leads to incarceration rather than rehabilitation, there is converging evidence to support the utilization of GARS with or without KCNK13 and RASGRF2 risk polymorphism in the legal arena, whereby the argument that "determinism" overrides the "free will" account may be a plausible defense strategy. Obviously, this type of research is tantamount to helping resolve a major problem related to polydrug abuse.

Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor µ1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms?

While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic alterations across dopaminergic reward systems lead to uncontrollable self-administration of opioids and other drugs. For instance, diminished availability via knockout of dopamine D3 receptor (DRD3) increases vulnerability to opioids. Building upon this concept via the use of a sophisticated polymorphic risk analysis in a human cohort of chronic opioid users, we found evidence for a higher frequency of polymorphic DRD3 risk allele (rs6280) than opioid receptor µ1 (rs1799971). In conclusion, while opioidergic mechanisms are involved in OUD, dopamine-related receptors may have primary influence on opioid-seeking behavior in African Americans. These findings suggest OUD-targeted novel and improved neuropharmacological therapies may require focus on DRD3-mediated regulation of dopaminergic homeostasis.

A Review of DNA Risk Alleles to Determine Epigenetic Repair of mRNA Expression to Prove Therapeutic Effectiveness in Reward Deficiency Syndrome (RDS): Embracing "Precision Behavioral Management".

This is a review of research on "Precision Behavioral Management" of substance use disorder (SUD). America is experiencing a high prevalence of substance use disorder, primarily involving legal and illegal opioid use. A 3000% increase in treatment for substance abuse has occurred between 2000 and 2016. Unfortunately, present day treatment of opioid abuse involves providing replacement therapy with powerful opioids to, at best, induce harm reduction, not prophylaxis. These interventions do not enhance gene expression and restore the balance of the brain reward system's neurotransmitters. We are proposing a generalized approach called "Precision Behavioral Management". This approach includes 1) using the Genetic Addiction Risk Severity (GARS, a 10 candidate polymorphic gene panel shown to predict ASI-alcohol and drug severity) to assess early pre-disposition to substance use disorder; 2) using a validated reward deficiency syndrome (RDS) questionnaire; 3) utilization of the Comprehensive Analysis of Reported Drugs (CARD™) to assess treatment compliance and abstinence from illicit drugs during treatment, and, importantly; 4) utilization of a "Pro-dopamine regulator (KB220)" (via IV or oral [KB220Z] delivery systems) to optimize gene expression, restore the balance of the Brain Reward Cascade's neurotransmitter systems and prevent relapse by induction of dopamine homeostasis, and; 5) utilization of targeted DNA polymorphic reward genes to direct mRNA genetic expression profiling during the treatment process. Incorporation of these events can be applied to not only the under-considered African-American RDS community, but all victims of RDS, as a demonstration of a paradigm shift that uniquely provides a novel putative "standard of care" based on DNA guided precision nutrition therapy to induce "dopamine homeostasis" and rebalance neurotransmitters in the Brain Reward Cascade. We are also developing a Reward Deficiency Syndrome Diagnostic Criteria (RDSDC) to assist in potential tertiary treatment.

Exploration of Epigenetic State Hyperdopaminergia (Surfeit) and Genetic Trait Hypodopaminergia (Deficit) During Adolescent Brain Development.

BACKGROUND: The risk for all addictive drug and non-drug behaviors, especially, in the unmyelinated Prefrontal Cortex (PFC) of adolescents, is important and complex. Many animal and human studies show the epigenetic impact on the developing brain in adolescents, compared to adults. Some reveal an underlying hyperdopaminergia that seems to set our youth up for risky behaviors by inducing high quanta pre-synaptic dopamine release at reward site neurons. In addition, altered reward gene expression in adolescents caused epigenetically by social defeat, like bullying, can continue into adulthood. In contrast, there is also evidence that epigenetic events can elicit adolescent hypodopaminergia. This complexity suggests that neuroscience cannot make a definitive claim that all adolescents carry a hyperdopaminergia trait. OBJECTIVE: The primary issue involves the question of whether there exists a mixed hypo or hyper-dopaminergia in this population. METHOD: Genetic Addiction Risk Score (GARS®) testing was carried out of 24 Caucasians of ages 12-19, derived from families with RDS. RESULTS: We have found that adolescents from this cohort, derived from RDS parents, displayed a high risk for any addictive behavior (a hypodopaminergia), especially, drug-seeking (95%) and alcohol-seeking (64%). CONCLUSION: The adolescents in our study, although more work is required, show a hypodopaminergic trait, derived from a family with Reward Deficiency Syndrome (RDS). Certainly, in future studies, we will analyze GARS in non-RDS Caucasians between the ages of 12-19. The suggestion is first to identify risk alleles with the GARS test and, then, use well-researched precision, pro-dopamine neutraceutical regulation. This "two-hit" approach might prevent tragic fatalities among adolescents, in the face of the American opioid/psychostimulant epidemic.

Selective screening for lysosomal storage disorders in a large cohort of minorities of African descent shows high prevalence rates and novel variants.

Population studies point to regional and ethnicity-specific differences in genetic predisposition for some lysosomal storage disorders (LSDs). The aim of the study was to determine the prevalence of the three treatable forms of lysosomal storage disorders (Gaucher disease [GD], Pompe disease [PD], and Fabry disease [FD]) in a cohort of mostly urban-dwelling individuals of African ancestry, a previously unknown genetic landscape for LSDs. Large-scale selective multistep biochemical and genetic screening was performed in patients seeking healthcare for various health concerns. Fluorimetric enzyme assays for GD, PD, and FD were performed on dried blood spots. Targeted gene sequencing was performed on samples that showed significantly lower enzyme activities (<10% of control mean) after two tiers of enzymatic screening. A total of 5287 unique samples representing a cross section of patients who visited Howard University Hospital and College of Medicine from 2015 to 2017 were included in the study. Study samples were obtained from a population where ~90% reported as African-American, ~5% Hispanic, and <5% Caucasian or other. Regarding GD, three subjects had either homozygous or heterozygous mutations in the GBA gene. As to PD, eight subjects were either homozygous or compound heterozygous for GAA mutations, including three novel mutations: (a) c.472 A > G; p.T158A, (b) c.503G > T; p.R168L, (c) c.1985del. Regarding FD, two subjects had pathogenic GLA mutations, and four had single nucleotide polymorphisms in the 5'UTR, previously implicated in modulating gene expression. The findings highlight a higher incidence of abnormal enzyme levels and pathogenic mutations in the target population reflecting ancestry-based specific genotype and phenotype variations.

High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial.

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30-600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.

Pre-clinical models of reward deficiency syndrome: A behavioral octopus.

Individuals with mood disorders or with addiction, impulsivity and some personality disorders can share in common a dysfunction in how the brain perceives reward, where processing of natural endorphins or the response to exogenous dopamine stimulants is impaired. Reward Deficiency Syndrome (RDS) is a polygenic trait with implications that suggest cross-talk between different neurological systems that include the known reward pathway, neuroendocrine systems, and motivational systems. In this review we evaluate well-characterized animal models for their construct validity and as potential models for RDS. Animal models used to study substance use disorder, major depressive disorder (MDD), early life stress, immune dysregulation, attention deficit hyperactivity disorder (ADHD), post traumatic stress disorder (PTSD), compulsive gambling and compulsive eating disorders are discussed. These disorders recruit underlying reward deficiency mechanisms in multiple brain centers. Because of the widespread and remarkable array of associated/overlapping behavioral manifestations with a common root of hypodopaminergia, the basic endophenotype recognized as RDS is indeed likened to a behavioral octopus. We conclude this review with a look ahead on how these models can be used to investigate potential therapeutics that target the underlying common deficiency.

Administration of a putative pro-dopamine regulator, a neuronutrient, mitigates alcohol intake in alcohol-preferring rats.

BACKGROUND: Excessive alcohol intake is a serious but preventable public health problem in the United States and worldwide. Alcohol and other substance use disorders occur co-morbid with more generalized reward deficiency disorders, characterized by a reduction in dopamine (DA) signaling within the reward pathway, and classically associated with increased impulsivity, risk taking and subsequent drug seeking behavior. It is postulated that increasing dopamine availability and thus restoring DA homeostasis in the mesocorticolimbic system could reduce the motivation to seek and consume ethanol. Here, we treated animals with a neuro-nutrient, KB220Z also known as Synaptamine, designed to augment DA signaling. METHOD: KB220Z was administered to genetically alcohol-preferring (P) adult male and female rats by oral gavage (PO), intraperioneally (IP), or subcutaneously (SQ) for 4 consecutive days at a 3.4 mL/Kg rat equivalent dose and compared to saline (SQ, IP) or water (PO) controls. Subsequent to treatment, lever pressing and consumption of 10 % ethanol or control 3% sucrose during operant responding was assessed using a drinking in the dark multiple scheduled access (DIDMSA) binge drinking protocol. Locomotor and elevated zero maze activity, and DRD2 mRNA expression via in situ hybridization (ISH) were assessed independently following 4 days of a SQ regimen of KB220Z. RESULTS: KB220Z administered via IP and SQ markedly and immediately reduced binge drinking of 10 % ethanol in both male and female rats whereas PO administration took at least 3 days to decrease lever pressing for ethanol in both male and female rats. There was no effect of SQ KB220Z on 3% sucrose drinking. Elevated activity in the open field was significantly decreased, and time spent in the open arm of the EZM was moderately reduced. The regimen of SQ KB220Z did not impact the number of DRD2 punctae in neurons of the NAc, but the NAc shell expressed more DRD2 mRNA/cell than NAc core independent of KB220Z. CONCLUSION: KB220Z attenuates ethanol drinking and other RDS behaviors in P rats possibly by acting on the dopaminergic system, but not by effecting an increase in NAc DRD2 mRNA expression.

Hypodopaminergia and "Precision Behavioral Management" (PBM): It is a Generational Family Affair.

BACKGROUND/AIMS: This case series presents the novel Genetic Addiction Risk Score (GARS®) coupled with a customized pro-dopamine regulator matched to polymorphic reward genes having a hypodopaminergic risk. METHODS: The proband is a female with a history of drug abuse and alcoholism. She experienced a car accident under the influence and voluntarily entered treatment. Following an assessment, she was genotyped using the GARS, and started a neuronutrient with a KB220 base indicated by the identified polymorphisms. She began taking it in April 2018 and continues. RESULTS: She had success in recovery from Substance Use Disorder (SUD) and improvement in socialization, family, economic status, well-being, and attenuation of Major Depression. She tested negative over the first two months in treatment and a recent screening. After approximately two months, her parents also decided to take the GARS and started taking the recommended variants. The proband's father (a binge drinker) and mother (no SUD) both showed improvement in various behavioral issues. Finally, the proband's biological children were also GARS tested, showing a high risk for SUD. CONCLUSION: This three-generation case series represents an example of the impact of genetic information coupled with an appropriate DNA guided "Pro-Dopamine Regulator" in recovery and enhancement of life.

Neuropharmacological and Neurogenetic Correlates of Opioid Use Disorder (OUD) As a Function of Ethnicity: Relevance to Precision Addiction Medicine.

BACKGROUND: Over 100 people die daily from opioid overdose and $78.5B per year is spent on treatment efforts, however, the real societal cost is multifold greater. Alternative strategies to eradicate/manage drug misuse and addiction need consideration. The perception of opioid addiction as a social/criminal problem has evolved to evidence-based considerations of them as clinical disorders with a genetic basis. We present evaluations of the genetics of addiction with ancestryspecific risk profiles for consideration. OBJECTIVE: Studies of gene variants associated with predisposition to substance use disorders (SUDs) are monolithic, and exclude many ethnic groups, especially Hispanics and African Americans. We evaluate gene polymorphisms that impact brain reward and predispose individuals to opioid addictions, with a focus on the disparity of research which includes individuals of African and Hispanic descent. METHODOLOGY: PubMed and Google Scholar were searched for: Opioid Use Disorder (OUD), Genome- wide association studies (GWAS); genetic variants; polymorphisms, restriction fragment length polymorphisms (RFLP); genomics, epigenetics, race, ethnic group, ethnicity, ancestry, Caucasian/ White, African American/Black, Hispanic, Asian, addictive behaviors, reward deficiency syndrome (RDS), mutation, insertion/deletion, and promotor region. RESULTS: Many studies exclude non-White individuals. Studies that include diverse populations report ethnicity-specific frequencies of risk genes, with certain polymorphisms specifically associated with Caucasian and not African-American or Hispanic susceptibility to OUD or SUDs, and vice versa. CONCLUSION: To adapt precision medicine-based addiction management in a blended society, we propose that ethnicity/ancestry-informed genetic variations must be analyzed to provide real precision- guided therapeutics with the intent to attenuate this uncontrollable fatal epidemic.