Potential Link Between Exercise and N-Methyl-D-Aspartate Glutamate Receptors in Alcohol Use Disorder: Implications for Therapeutic Strategies.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

Exercise Influences the Brain's Metabolic Response to Chronic Cocaine Exposure in Male Rats.

Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors.

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy.

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

Summary Document Research on RDS Anti-addiction Modeling: Annotated Bibliography.

Annotated bibliography of genetic addiction risk severity (GARS) publications, pro-dopamine regulation in nutraceuticals (KB220 nutraceutical variants), and policy documents. Further research is required to encourage the field to consider "Reward Deficiency Syndrome (RDS) Anti-addiction Modeling" which involves early risk identification by means of genetic assessment similar to GARS, followed by induction of dopamine homeostasis by means of genetically guided pro-dopamine regulation similar to KB220. These results suggest that genetically based treatments may be a missing piece in the treatment of substance use disorder (SUD).

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."

Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review.

Methylphenidate (MP) is a psychostimulant commonly prescribed for individuals with attention deficit hyperactivity disorder (ADHD) but it is also taken with and without a prescription for performance enhancement. Prior research has characterized the effects of MP on behavior, cognition, and neurochemistry. This exploratory review covers the uses of MP and examined the effects of MP on gene expression in the brain following exposure. Overall, MP causes a wide-spread potentiation of genes, in a region-specific manner; consequently, inducing neuronal alterations, such as synaptic plasticity and transmission, resulting in observed behaviors and affects. Monoamine neurotransmitters and post-synaptic density protein genes generally had a potentiating effect in gene expression after exposure to MP.

The Role of Estrogen Signaling and Exercise in Drug Abuse: A Review.

BACKGROUND: Discovering how sex differences impact the efficacy of exercise regimens used for treating drug addiction is becoming increasingly important. Estrogen is a hormone believed to explain a large portion of sex differences observed during drug addiction, and why certain exercise regimens are not equally effective between sexes in treatment. Addiction is currently a global hindrance to millions, many of whom are suffering under the influence of their brain's intrinsic reward system coupled with external environmental factors. Substance abuse disorders in the U.S. alone cost billions of dollars annually. REVIEW SUMMARY: Studies involving the manipulation of estrogen levels in female rodents, primarily via ovariectomy, highlight its impact regarding drug addiction. More specifically, female rodents with higher estrogen levels during the estrus phase increase cocaine consumption, whereas those in the non-estrus phase (low estrogen levels) decrease cocaine consumption. If estrogen is reintroduced, self-administration increases once again. Exercise has been proven to decrease relapse tendency, but its effect on estrogen levels is not fully understood. CONCLUSIONS: Such findings and results discussed in this review suggest that estrogen influences the susceptibility of females to relapse. Therefore, to improve drug-abuse-related treatment, exercise regimens for females should be generated based on key sex differences with respect to males.

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.

Exercise Modifies the Brain Metabolic Response to Chronic Cocaine Exposure Inhibiting the Stria Terminalis.

It is well known that exercise promotes health and wellness, both mentally and physiologically. It has been shown to play a protective role in many diseases, including cardiovascular, neurological, and psychiatric diseases. The present study examined the effects of aerobic exercise on brain glucose metabolic activity in response to chronic cocaine exposure in female Lewis rats. Rats were divided into exercise and sedentary groups. Exercised rats underwent treadmill running for six weeks and were compared to the sedentary rats. Using positron emission tomography (PET) and [18F]-Fluorodeoxyglucose (FDG), metabolic changes in distinct brain regions were observed when comparing cocaine-exposed exercised rats to cocaine-exposed sedentary rats. This included activation of the secondary visual cortex and inhibition in the cerebellum, stria terminalis, thalamus, caudate putamen, and primary somatosensory cortex. The functional network of this brain circuit is involved in sensory processing, fear and stress responses, reward/addiction, and movement. These results show that chronic exercise can alter the brain metabolic response to cocaine treatment in regions associated with emotion, behavior, and the brain reward cascade. This supports previous findings of the potential for aerobic exercise to alter the brain's response to drugs of abuse, providing targets for future investigation. These results can provide insights into the fields of exercise neuroscience, psychiatry, and addiction research.

EPIC Spinal Procedure with Sound Wave Technology Induces Biomechanical Alignment Putatively Influencing Pain Response.

Spinal biomechanical alignment is now able to be altered through the use of unique sound wave technology. This methodological commentary will correlate recent studies demonstrating the ability of sound waves to carry mass, how the EPIC technique spinal procedure uses a sound wave impulse to create measurable changes in spinal alignment, and the clinical safety and efficacy of this approach. The EPIC technique is a direct genealogical descendant of the technique originally developed by the founding family of chiropractic. With sound wave therapies currently being used to break up kidney stones, called lithotripsy, in physical therapy for the treatment of soft tissue injuries, in the treatment of prostate cancer, and in the treatment of Alzheimer's disease, it is possible that the use of sound wave therapies may enter into the realm of altering joint biomechanics. Through a neurovascular examination, the EPIC technique spinal procedure can ascertain the presence of craniocervical subluxation, followed by acquiring multi-dimensional radiographic images for structural analysis. Currently using digital radiographic analysis, the EPIC technique acquires an epigenetic profile of structural asymmetries as well as a multi-directional biomechanical malposition profile of the spine, combining both profiles to ascertain the exact degrees for realignment. EPIC clinics have successfully utilized EPIC on over 20,000 cases. Comparison of pre-treatment biomechanical lateral displacement of the C1 vertebra around the Z-axis measured on digital radiographs, and post-treatment biomechanical lateral displacement of the C1 vertebra measured on digital radiographs immediately following the procedure, demonstrated an average 52% reduction in lateral biomechanical displacement around the Z-axis in a select group of over 2,000 cases. While more research is required, we are encouraged by these preliminary results. WC 265.

"TO BE OR NOT TO BE" GWAS Ends the Controversy about the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS).

Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.

Genetic Correlates as a Predictor of Bariatric Surgery Outcomes after 1 Year.

This study analyzed genetic risk assessments in patients undergoing bariatric surgery to serve as a predictive factor for weight loss parameters 1 year after the operation. Thirty (30) patients were assessed for Genetic Addiction Risk Severity (GARS), which analyzes neurogenetic polymorphisms involved in addiction and reward deficiency. Genetic and psychosocial data collected before the operation were correlated with weight loss data, including changes in weight, body mass index (BMI), and percent of expected weight loss (%EWL). Results examined correlations between individual gene risk alleles, 1-year body weight data, and psychosocial trait scores. Spearman's correlations revealed that the OPRM1 (rs1799971) gene polymorphism had significant negative correlation with 1-year weight (rs = -0.4477, p < 0.01) and BMI (rs = -0.4477, p < 0.05). In addition, the DRD2 risk allele (rs1800497) was correlated negatively with BMI at 1 year (rs = -0.4927, p < 0.05), indicating that one risk allele copy was associated with lower BMI. However, this allele was positively correlated with both ∆Weight (rs = 0.4077, p < 0.05) and %EWL (rs = 0.5521, p < 0.05) at 1 year post-surgery. Moreover, the overall GARS score was correlated with %EWL (rs = 0.4236, p < 0.05), ∆Weight (rs = 0.3971, p < 0.05) and ∆BMI (rs = 0.3778, p < 0.05). Lastly, Food Cravings Questionnaire (FCQ) scores were negatively correlated with %EWL (rs = -0.4320, p < 0.05) and ∆Weight at 1 year post-surgery (rs = -0.4294, p < 0.05). This suggests that individuals with a higher genetic addiction risk are more responsive to weight loss treatment, especially in the case of the DRD2 polymorphism. These results should translate clinically to improve positivity and attitude related to weight management by those individuals born with the risk alleles (rs1800497; rs1799971).

Dopaminergic dysfunction: Role for genetic & epigenetic testing in the new psychiatry.

Reward Deficiency Syndrome (RDS), particularly linked to addictive disorders, costs billions of dollars globally and has resulted in over one million deaths in the United States (US). Illicit substance use has been steadily rising and in 2021 approximately 21.9% (61.2 million) of individuals living in the US aged 12 or older had used illicit drugs in the past year. However, only 1.5% (4.1 million) of these individuals had received any substance use treatment. This increase in use and failure to adequately treat or provide treatment to these individuals resulted in 106,699 overdose deaths in 2021 and increased in 2022. This article presents an alternative non-pharmaceutical treatment approach tied to gene-guided therapy, the subject of many decades of research. The cornerstone of this paradigm shift is the brain reward circuitry, brain stem physiology, and neurotransmitter deficits due to the effects of genetic and epigenetic insults on the interrelated cascade of neurotransmission and the net release of dopamine at the Ventral Tegmental Area -Nucleus Accumbens (VTA-NAc) reward site. The Genetic Addiction Risk Severity (GARS) test and pro-dopamine regulator nutraceutical KB220 were combined to induce "dopamine homeostasis" across the brain reward circuitry. This article aims to encourage four future actionable items: 1) the neurophysiologically accurate designation of, for example, "Hyperdopameism /Hyperdopameism" to replace the blaming nomenclature like alcoholism; 2) encouraging continued research into the nature of dysfunctional brainstem neurotransmitters across the brain reward circuitry; 3) early identification of people at risk for all RDS behaviors as a brain check (cognitive testing); 4) induction of dopamine homeostasis using "precision behavioral management" along with the coupling of GARS and precision Kb220 variants; 5) utilization of promising potential treatments include neuromodulating modalities such as Transmagnetic stimulation (TMS) and Deep Brain Stimulation(DBS), which target different areas of the neural circuitry involved in addiction and even neuroimmune agents like N-acetyl-cysteine.

Psychostimulants prescribed to children for ADHD following distal radius fractures significantly reduce bone density as a function of duration.

Methylphenidate and mixed amphetamine salts (MAS) are psychostimulant medications widely prescribed for various psychiatric disorders. Although these medications are known to adversely impact bone mineral content and density, as well as biomechanical integrity during skeletal development in rats, their effect on bone density in children remains largely unknown. The primary aim of this work was to investigate the effects of methylphenidate and MAS on bone density following distal radius fractures in pediatric populations, and secondarily assess any impact on healing. The retrospective case-control study was designed to assess fracture healing in patients treated with stimulant drugs and matched controls. For the primary outcome, X-rays (n = 188) were evaluated using an optical density image analysis technique to compare bone density throughout the bone healing process. Results showed that methylphenidate and MAS significantly reduced bone healing by approximately 20% following distal radius fractures in these children. The data also suggested that duration of psychostimulant use played a role in bone healing; the longer the treatment (1-5 years), the lower the bone density was observed (by approximately 52%) as compared to controls (no medication). However, subjects taking these drugs for longer than 5 years did not show a significant difference. Our results suggested that children taking psychostimulants for up to 5 years had slower bone healing following distal radius fractures. Orthopedic surgeons planning elective surgeries should be cognizant of this as a potential issue in recovery after any elective bone procedures and preoperatively optimize bone health as well as counsel patients and their families.

Personalized repetitive transcranial magnetic stimulation (prtms®) for post-traumatic stress disorder (ptsd) in military combat veterans.

Emerging data suggest that post-traumatic stress disorder (PTSD) arises from disrupted brain default mode network (DMN) activity manifested by dysregulated encephalogram (EEG) alpha oscillations. Hence, we pursued the treatment of combat veterans with PTSD (n = 185) using an expanded form of repetitive transcranial magnetic stimulation (rTMS) termed personalized-rTMS (PrTMS). In this treatment methodology spectral EEG based guidance is used to iteratively optimize symptom resolution via (1) stimulation of multiple motor sensory and frontal cortical sites at reduced power, and (2) adjustments of cortical treatment loci and stimulus frequency during treatment progression based on a proprietary frequency algorithm (PeakLogic, Inc. San Diego) identifying stimulation frequency in the DMN elements of the alpha oscillatory band. Following 4 - 6 weeks of PrTMS® therapy in addition to routine PTSD therapy, veterans exhibited significant clinical improvement accompanied by increased cortical alpha center frequency and alpha oscillatory synchronization. Full resolution of PTSD symptoms was attained in over 50% of patients. These data support DMN involvement in PTSD pathophysiology and suggest a role in therapeutic outcomes. Prospective, sham controlled PrTMS® trials may be warranted to validate our clinical findings and to examine the contribution of DMN targeting for novel preventive, diagnostic, and therapeutic strategies tailored to the unique needs of individual patients with both combat and non-combat PTSD.