Molecular neuro-biological and systemic health benefits of achieving dopamine homeostasis in the face of a catastrophic pandemic (COVID- 19): A mechanistic exploration.

In the face of the global pandemic of COVID 19, approaching 1.75 Million infected worldwide (4/12/2020) and associated mortality (over 108, 000 as of 4/12/2020) as well-as other catastrophic events including the opioid crisis, a focus on brain health seems prudent [1] (https://www.coronavirus.gov). This manuscript reports on the systemic benefits of restoring and achieving dopamine homeostasis to reverse and normalize thoughts and behaviors of Reward Deficiency Syndrome (RDS) dysfunctional conditions and their effects on behavioral physiology; function of reward genes; and focuses on digestive, immune, eye health, and the constellation of symptomatic behaviors. The role of nutrigenomic interventions on restoring normal brain functions and its benefits on these systems will be discussed. We demonstrate that modulation of dopamine homeostasis using nutrigenomic dopamine agonists, instead of pharmaceutical interventions, is achievable. The allied interlinking with diverse chronic diseases and disorders, roles of free radicals and incidence of anaerobic events have been extensively highlighted. In conjunction, the role of dopamine in aspects of sleep, rapid eye movement and waking are extensively discussed. The integral aspects of food indulgence, the influence of taste sensations, and gut-brain signaling are also discussed along with a special emphasis on ocular health. The detailed mechanistic insight of dopamine, immune competence and the allied aspects of autoimmune disorders are also highlighted. Finally, the integration of dopamine homeostasis utilizing a patented gene test and a research-validated nutrigenomic intervention are presented. Overall, a cutting-edge nutrigenomic intervention could prove to be a technological paradigm shift in our understanding of the extent to which achieving dopamine homeostasis will benefit overall health.

Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic.

The United States are amid an opioid overdose epidemic; we are challenged to provide non-addicting/non-pharmacological alternatives to assist in pain attenuation. There are proven strategies available to manage chronic pain effectively without opioids. Utilization review providers for insurance companies often ignore medicine based scientific peer-reviewed studies that warn against the chronic use of opioid medications, as well as the lack of evidence to support long-term use of opioids for pain. This paradigm must change if we are to indeed change the drug-embracing culture in American chronic pain management. A barrier to treatment is pushback on the part of insurance companies especially as it relates to fighting against pain relief alternatives compared to classical analgesic agents. Pain specialists in the U.S., are compelled to find alternative solutions to help pain victims without promoting unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain." It is noteworthy that reward center of the brain plays a crucial role in the modulation of nociception, and that adaptations in dopaminergic circuitry may affect several sensory and affective components of chronic pain syndromes. Possibly knowing a patient's genetic addiction risk score (GARS™) could eliminate guessing as it relates to becoming addicted.

Would induction of dopamine homeostasis via coupling genetic addiction risk score (GARS®) and pro-dopamine regulation benefit benzodiazepine use disorder (BUD)?

Prescriptions for Benzodiazepines (BZDs) have risen continually. According to national statistics, the combination of BZDs with opioids has increased since 1999. BZDs (sometimes called "benzos") work to calm or sedate a person by raising the level of the inhibitory neurotransmitter GABA in the brain. In terms of neurochemistry, BZDs act at the GABAA receptors to inhibit excitatory neurons, reducing VTA glutaminergic drive to reduce dopamine release at the Nucleus accumbens. Benzodiazepine Use Disorder (BUD) is very difficult to treat, partly because BZDs are used to reduce anxiety which paradoxically induces hypodopaminergia. Considering this, we are proposing a paradigm shift. Instead of simply targeting chloride channel direct GABAA receptors for replacement or substitution therapy, we propose the induction of dopamine homeostasis. Our rationale is supported by the well-established notion that the root cause of drug and non-drug addictions (i.e. Reward Deficiency Syndrome [RDS]), at least in adults, involve dopaminergic dysfunction and heightened stress. This proposition involves coupling the Genetic Addiction Risk Score (GARS) with a subsequent polymorphic matched genetic customized Pro-Dopamine Regulator known as KB220ZPBM (Precision Behavioral Management). Induction of dopamine homeostasis will be clinically beneficial in attempts to combat BUD for at least three reasons: 1) During detoxification of alcoholism, the potential induction of dopamine regulation reduces the need for BZDs; 2) A major reason for BZD abuse is because people want to achieve stress reduction and subsequently, the potential induction of dopamine regulation acts as an anti-stress factor; and 3) BUD and OUD are known to reduce resting state functional connectivity, and as such, potential induction of dopamine regulation enhances resting state functional connectivity. Future randomized placebo-controlled studies will investigate this forward thinking proposed novel modality.

Intracerebral administration of neuronal nitric oxide synthase antiserum attenuates traumatic brain injury-induced blood-brain barrier permeability, brain edema formation, and sensory motor disturbances in the rat.

The role of nitric oxide (NO) in traumatic brain injury (TBI)-induced sensory motor function and brain pathology was examined using intracerebral administration of neuronal nitric oxide synthase (nNOS) antiserum in a rat model. TBI was produced by a making a longitudinal incision into the right parietal cerebral cortex limited to the dorsal surface of the hippocampus. Focal TBI induces profound edematous swelling, extravasation of Evans blue dye, and up-regulation of nNOS in the injured cerebral cortex and the underlying subcortical areas at 5 hours. The traumatized animals exhibited pronounced sensory motor deficit, as seen using Rota-Rod and grid-walking tests. Intracerebral administration of nNOS antiserum (1 : 20) 5 minutes and 1 hour after TBI significantly attenuated brain edema formation, Evans blue leakage, and nNOS expression in the injured cortex and the underlying subcortical regions. The nNOS antiserum-treated rats showed improved sensory motor functions. However, administration of nNOS antiserum 2 hours after TBI did not influence these parameters significantly. These novel observations suggest that NO participates in blood-brain barrier disruption, edema formation, and sensory motor disturbances in the early phase of TBI, and that nNOS antiserum has some potential therapeutic value requiring additional investigation.

Fifty Years in the Development of a Glutaminergic-Dopaminergic Optimization Complex (KB220) to Balance Brain Reward Circuitry in Reward Deficiency Syndrome: A Pictorial.

Dopamine along with other chemical messengers like serotonin, cannabinoids, endorphins and glutamine, play significant roles in brain reward processing. There is a devastating opiate/opioid epidemicin the United States. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day due to narcotic overdose and alarmingly heroin overdose is on the rise. The Food and Drug Administration (FDA) has approved some Medication-Assisted Treatments (MATs) for alcoholism, opiate and nicotine dependence, but nothing for psychostimulant and cannabis abuse. While these pharmaceuticals are essential for the short-term induction of "psychological extinction," in the long-term caution is necessary because their use favors blocking dopaminergic function indispensable for achieving normal satisfaction in life. The two institutions devoted to alcoholism and drug dependence (NIAAA & NIDA) realize that MATs are not optimal and continue to seek better treatment options. We review, herein, the history of the development of a glutaminergic-dopaminergic optimization complex called KB220 to provide for the possible eventual balancing of the brain reward system and the induction of "dopamine homeostasis." This complex may provide substantial clinical benefit to the victims of Reward Deficiency Syndrome (RDS) and assist in recovery from iatrogenically induced addiction to unwanted opiates/opioids and other addictive behaviors.

Hypothesizing Molecular Genetics of the Holocaust: Were Dopaminergic Genes Involved or Brain Wash?

Numerous studies indicated that the prevalence of certain alleles of the dopamine D2 receptor gene (DRD2) vary across different ethnic groups. Under adverse environmental conditions, these alleles can increase the risk of developing psychiatric symptoms. Thus, we hypothesized that the prevalence of the DRD2 gene Taq IA allele may serve to explain the horrific behaviours practiced by the Nazi regime. Hitler's 'Brain Washing' methods goaded his followers to carry out genocide at a time when carriers of the DRD2 TaqIA allele (the so called 'aggressive--genotype') were significantly higher among the Aryan Germans compared to resident German Jews. It would be of interest, to genotype the Jewish Holocaust survivors, to determine whether those with the Taq AI allele survived in greater numbers. The hypothesis being that, greater survival may result in enhanced frequency of not only the DRD2 AI allele but other reward gene polymorphisms among survivors. Understanding the molecular genetics of any population in terms of reward dependence and subsequent behaviours will be most beneficial in future human interaction whether negative (war) or positive (peace) in nature.

"Pro-dopamine regulation (KB220Z™)" as a long-term therapeutic modality to overcome reduced resting state dopamine tone in opiate/opioid epidemic in America.

Since it is known that relapse, morality, and hospitalizations have been tied to the presence of the Dopamine D2 Receptor A1 allele, as one example, and carriers of this gene variant have a proclivity to favor amino-acid therapy, it seems intuitive that the incorporation of modalities to provide a balance and or restoration of hypodopaminergia should be considered as a front-line tactic to overcome the current American opiate/opioid epidemic, saving millions from death and unwanted locked-in-addiction. If we continue down the prim road path of fighting addiction to narcotics with narcotics, we are doomed to fail. This lesson can also have global interest.

Priming reduces input activity in right posterior cortex during stem completion.

A recent positron emission tomography (PET) study showed reduced blood flow in the right posterior cortex for primed words during a stem completion task, suggesting reduction in processing demand in this area for primed tasks. The time course of this attenuation was studied using event-related potentials (ERPs) in 40 normal subjects. As compared to the unprimed stems, primed stems elicited significantly less positive ERP in the right posterior channels between 60 and 200 ms after presentation of the stem. The results, while confirming the PET findings, implicate involvement of right posterior cortex in bottom-up processing of primed stimuli. In addition to right posterior channels, the primed stems also had attenuated positivity in the right frontal channels after 250 ms of stem presentation, indicating reduced requirement for explicit recall process.

Visual word stem completion priming within and across modalities: a PET study.

Using positron emission tomography, we studied changes in the regional cerebral blood flow (rCBF) associated with cross modality (auditory to visual) and within modality visual priming in a word stem completion task. Compared to baseline completion performance and to within modality visual priming, cross modality priming was associated with increased rCBF in prefrontal cortex and decreased rCBF in the left angular gyrus. The results confirm and complement trends observed in a previous study concerning visual to auditory cross modality priming, and suggest that distinct cortical mechanisms may mediate within- and cross modality priming on the stem completion task. The findings are consistent with the neuropsychological data concerning auditory to visual cross modality priming, and indicate involvement of aspects of explicit retrieval and lexical processes in cross modality priming.

Centrally infused anions alter body temperature in conscious rats.

Central anionic influences on the regulation of body temperature were studied in 42 conscious male rats. The animals were divided into seven equal groups and were given intraventricular infusions of either chloride or bicarbonate solution of sodium, calcium, or potassium. Infusions were made in the unanesthetized and unrestrained animals through stainless steel cannulae, chronically implanted into the anteroventral part of third ventricle. Control rats received intraventricular infusions of artificial cerebrospinal fluid. All of the chloride solutions, irrespective of the associated cations, elicited hyperthermia, whereas bicarbonates had hypothermic effect. Responses of chloride and bicarbonate solutions varied significantly (p < 0.001). There was, however, cationic modification of the anionic responses. Thus, sodium ions manifested hyperthermic modifications, accentuating hyperthermia of chloride and attenuating hypothermic effect of bicarbonate. Calcium and potassium ions exerted hypothermic modulation. The results suggest that anionic concentration of intraventricular CSF is crucial for central regulation of body temperature in unanesthetized conscious rats. The cations probably have only modulatory influences.

Intracerebroventricular chloride infusion enhances water intake in rats.

Central anionic influences on dipsogenic response was studied in 54 euhydrated rats. Quantity of water consumed following third ventricular infusions of equimolar hypertonic chloride and bicarbonate solutions of sodium, potassium, calcium, and barium was compared. Control group (n = 6) was given artificial cerebrospinal fluid infusion while rats of the remaining 8 groups (n = 6 each) received one of the test solutions. All the chloride solutions, irrespective of the cations to which they were associated, elicited significantly greater dipsogenic response as compared to the control, or the bicarbonate solutions. Response of the bicarbonate solutions was more than the control only in the observation taken 30 min after the infusions. In the later observations, there was no significant difference. Drinking was not affected significantly by the cationic composition of the infusion fluids. Anionic concentration of the solutions has predominantly influenced the dipsogenic response. Enhancement of drinking following infusions of chloride solutions suggests the possibility of the CSF anions exerting active physiological influences over the juxtacerebroventricular sensors.

Third ventricular chloride infusions enhance drinking in water deprived rats.

The influence of intraventricularly infused anions on drinking was studied in 54 water deprived male rats, divided in 9 equal groups. Stainless steel cannulae were chronically implanted into the anteroventral part of the third ventricle (AV3V) and the animals were water deprived for 24 hr prior to the infusions. Control group (n = 6) was given 10 microliters of artificial cerebrospinal fluid. The rats of the remaining 8 groups received similar quantity of equiosmolar chloride or bicarbonate solution of either sodium, potassium, calcium or barium. Cumulative quantity of water consumed in 30 min, 1 hr, and 24 hr after the infusion was recorded. All the chloride solutions, irrespective of the associated cation, enhanced drinking. Effects of the bicarbonates were relatively weak and transient. Dipsogenic effects of the solutions depended on their anionic composition. Thus, chlorides of all the cations elicited greater drinking than their bicarbonates. Responses of the similar anionic solutions were comparable. It appears that intraventricularly infused chloride ions stimulate drinking in water deprived rats.

Influence of intracerebroventricularly infused anions on feeding response.

Chloride and bicarbonate solutions of potassium, calcium, sodium, and barium were infused into the third ventricle of the rats to observe the influence of anions on feeding response. Stainless steel cannulae were chronically implanted into the anteroventral part of the third ventricle of 54 rats, which were divided in 9 equal groups. While the control group was given 10 microliters of artificial cerebrospinal fluid intraventricularly, the remaining 8 groups received the equal quantity (10 microliters) of one of the hypertonic equimolar test solutions. Chloride solutions of potassium, calcium, and barium evoked significantly (p less than 0.05) higher feeding than the control group, while none of the bicarbonate solutions influenced feeding significantly. Chloride solutions of all the 4 cations elicited significantly (p less than 0.05) higher feeding than the corresponding bicarbonate solutions in 24 hr. It was observed that though the cations differed, there was no significant difference in the responses elicited by the different chloride solutions. Similarly, various bicarbonate solutions elicited similar responses. Osmolality and pH of the infusion solution have not influenced feeding significantly. It is concluded that the anionic, but not the cationic concentration of the fluid bathing juxtacerebroventricular sensors, predominantly influence the feeding response.

Alterations of ventricular pH alter water intake and food consumption in rats.

The pH of third ventricular CSF was altered by infusing acidic or alkaline solution of artificial cerebrospinal fluid (aCSF) through chronically implanted stainless steel cannula. In two separate group of rats (n = 18 each) water and food consumptions were recorded 30 min, 1 hr, and 24 hr after intraventricular infusions of the modified aCSF solutions having pH 6.0, 8.0 and 7.4 (control). On raising the CSF pH, water intake increased in all three observations. Feeding was not affected in the observations taken after 30 min and 1 hr, but significantly reduced food consumption was observed 24 hr after the infusions. Lowering of pH had no effect either on dipsogenic or feeding response. The CSF pH correlated positively with drinking in all three observations. Since dipsogenic and feeding responses are centrally regulated by ion sensitive cells, it may be presumed that altered CSF pH influenced the activities of the sensors by altering ionic conductance across their membranes.

Dipsogenic and feeding influences of intraventricularly infused anionic choline solutions.

Chloride and bicarbonate solutions of choline were infused into the anteroventral part of the third ventricle of two different groups of rats through chronically implanted stainless steel cannulae. Dipsogenic and feeding responses elicited by these solutions were studied by observations taken at half hour intervals up to two h and then, after 24 h of infusions. Results were compared with the control response evoked by similar infusion of artificial cerebrospinal fluid (aCSF). Food and water intakes were recorded in different groups (n = 18 each) of rats. Dipsogenic response elicited by choline chloride solution in the observation taken 24 h after infusion, however, was higher only as compared to the control. Dipsogenic effect of bicarbonate solution was not significantly different from the control in the first two observations (30 and 60 min), but in the later observations (90, 120 min and 24 h), it was significantly higher. None of the choline solutions significantly alter feeding response within 2 h of infusions. However, in the observation taken 24 h after infusion, the response evoked by choline chloride was greater than that elicited by aCSF. The results support our earlier observation that chloride concentration of third ventricular CSF significantly influences water and food consumption. Intraventricularly administered choline also appears to have positive influence on these behaviors.

Lithium chloride SCN injection alters the circadian rhythm of food intake.

Effect of lithium injections through chronically implanted cannulae into the bilateral suprachiasmatic nuclei (SCN) on the circadian rhythm of food intake was investigated in the rat. It was observed that the circadian rhythm was disrupted by injections of lithium at the beginning of the light as well as the dark phase of the LD cycle. In either case the percentage of the food consumed during the 12-hr light period increased while that during the dark period decreased without any significant change in the total daily intake. Disruptions in the circadian rhythm of food intake failed to show any dose-response relation. Injections of saline into the SCN or lithium into the nearby SCN area did not produce a disruption of the circadian rhythm of food intake.

Neurotrophic factors attenuate alterations in spinal cord evoked potentials and edema formation following trauma to the rat spinal cord.

Influence of brain derived neurotrophic factor (BDNF) and insulin like growth factor-1 (IGF-1) on spinal cord injury induced disturbances in spinal cord conduction, edema formation and cellular stress response was examined in a rat model. Pretreatment with BDNF or IGF-1 significantly attenuated the loss of SCEP negative amplitude seen immediately after spinal cord injury. In these neurotrophins treated rats, upregulation of heat shock protein (HSP 72 kD) immunoreactivity, a measure of cellular stress response and spinal cord edema formation were considerably reduced 5 h after injury. These results suggest that neurotrophic factors improve spinal cord conduction after trauma and this beneficial effect of growth factors may be related with their ability to attenuate trauma induced cellular stress response, not reported earlier.

An L-type calcium channel blocker, nimodipine influences trauma induced spinal cord conduction and axonal injury in the rat.

The influence of the potent L-type Ca[2+] channel antagonist Nimodipine on spinal cord evoked potentials (SCEP) and axonal injury following trauma to the spinal cord was examined in a rat model. Spinal cord injury (SCI) was produced by an incision into the right dorsal horn of the T10-11 segments under urethane anaesthesia (1.5 g/kg, i.p.). SCEPs were recorded by epidural electrodes placed over the T9 (rostral) and T12 (caudal) segments after stimulation of the right tibial and sural nerves. SCI induced a pronounced decrease of the SCEP negative amplitude in the rostral (T9) recordings immediately after trauma. Axonal injury seen as degradation of myelin basic protein (MBP) immunostaining and myelin vesiculation at the ultrastructural level was most pronounced at 5 h. Continuous administration of Nimodipine (2 microg/kg/min, i.v.) from 30 min prior to injury until sacrifice markedly attenuated the changes in SCEP amplitude and latency. Axonal damage, loss of MBP, and myelin vesiculation were much less evident in the nimodipine treated traumatised rats. These observations suggest that Ca[2+] channels play an important role in the trauma induced alterations in SCEP and axonal injury, and indicate a therapeutic value of Ca[2+] blockers in SCI.