Postgrad Med. 2009 Nov;121(6):176-96.

Neurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing "deprivation-amplification relapse therapy" (DART).

BACKGROUND AND HYPOTHESIS: It is well known that after prolonged abstinence, individuals who use their drug of choice experience a powerful euphoria that often precipitates relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed "supersensitivity" might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared with DRD2 A2 allele carriers. Because carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine D2 agonist bromocriptine. Moreover, under chronic or long-term therapy with D2 agonists, such as bromocriptine, it has been shown in vitro that there is a proliferation of D2 receptors. One explanation for this relates to the demonstration that the A1 allele of the DRD2 gene is associated with increased striatal activity of L-amino acid decarboxylase, the final step in the biosynthesis of dopamine. This appears to be a protective mechanism against low receptor density and would favor the utilization of an amino acid neurotransmitter precursor like L-tyrosine for preferential synthesis of dopamine. This seems to lead to receptor proliferation to normal levels and results in significantly better treatment compliance only in A1 carriers. PROPOSAL AND CONCLUSION: We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse, including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: "denervation supersensitivity." Rats with unilateral depletions of neostriatal dopamine display increased sensitivity to dopamine agonists estimated to be 30 to 100 x in the 6-hydroxydopamine (6-OHDA) rotational model. Given that mild striatal dopamine D2 receptor proliferation occurs (20%-40%), it is difficult to explain the extent of behavioral supersensitivity by a simple increase in receptor density. Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing amino acid neurotransmitter precursors, enkephalinase, and catechol-O-methyltransferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in reward deficiency syndrome (RDS) probands. If future translational research reveals that dopamine agonist therapy reduces relapse in RDS, it would support the proposed concept, which we term "deprivation-amplification relapse therapy" (DART). This term couples the mechanism for relapse, which is "deprivation-amplification," especially in DRD2 A1 allele carriers with natural D2 agonist therapy utilizing amino acid precursors and COMT and enkepalinase inhibition therapy.
Med Hypotheses. 2009 Nov 13. [Epub ahead of print]

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

Department of Psychiatry, University of Florida, College of Medicine and McKnight Brain Institute, Gainesville, Florida, USA; Department of Nutrigenomics, LifeGen Inc., San Diego, California, USA; Department of Clinical Neurology, Path Research and Medical Foundation, New York, USA; Department of Holistic Medicine, G&G Holistic Treatment Center, North Miami Beach, FL, USA.
Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction.
Med Hypotheses. 2009 Sep;73(3):427-34. Epub 2009 May 17.

Nutrigenomic targeting of carbohydrate craving behavior: can we manage obesity and aberrant craving behaviors with neurochemical pathway manipulation by Immunological Compatible Substances (nutrients) using a Genetic Positioning System (GPS) Map?

Department of Nutrigenomics and Personalized Medicine, LifeGen, Inc., La Jolla, CA, USA.
Genetic mediated physiological processes that rely on both pharmacological and nutritional principles hold great promise for the successful therapeutic targeting of reduced carbohydrate craving, body-friendly fat loss, healthy body recomposition, and overall wellness. By integrating an assembly of scientific knowledge on inheritable characteristics and environmental mediators of gene expression, we review the relationship of genes, hormones, neurotransmitters, and nutrients as they correct unwanted weight gain coupled with unhappiness. In contrast to a simple one-locus, one-mechanism focus on pharmaceuticals alone, we hypothesize that the use of nutrigenomic treatment targeting multi-physiological neurological, immunological, and metabolic pathways will enable clinicians to intercede in the process of lipogenesis by promoting lipolysis while attenuating aberrant glucose cravings. In turn, this approach will enhance wellness in a safe and predictable manner through the use of a Genetic Positioning System (GPS) Map. The GPS Map, while presently incomplete, ultimately will serve not only as a blueprint for personalized medicine in the treatment of obesity, but also for the development of strategies for reducing many harmful addictive behaviors and promoting optimal health by using substances compatible with the body's immune system.
Neuropsychiatr Dis Treat. 2008 Oct;4(5):893-918.

Attention-deficit-hyperactivity disorder and reward deficiency syndrome.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC.
Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the "brain reward cascade," especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD(2) A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other "reward genes" are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.
PMID: 19183781 [PubMed - in process]
Lipids Health Dis. 2008 Nov 13;7:44.

Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene.

BACKGROUND: Endeavors to manage obesity have been heavily reliant on controlling energy intake and expenditure equilibrium, but have failed to curtail the overweight and obesity epidemic. This dynamic equilibrium is more complex than originally postulated and is influenced by lifestyle, calorie and nutrient intake, reward cravings and satiation, energy metabolism, stress response capabilities, immune metabolism and genetics. Fat metabolism is an important indicator of how efficiently and to what extent these factors are competently integrating. We investigated whether an Irvingia gabonensis seed extract (IGOB131) would provide a more beneficial comprehensive approach influencing multiple mechanisms and specifically PPAR gamma, leptin and adiponectin gene expressions, important in anti-obesity strategies. METHODS: Using murine 3T3-L1 adipocytes as a model for adipose cell biology research, the effects of IGOB131 were investigated on PPAR gamma, adiponectin, and leptin. These adipocytes were harvested 8 days after the initiation of differentiation and treated with 0 to 250 microM of IGOB131 for 12 and 24 h at 37 degree C in a humidified 5 percent CO2 incubator. The relative expression of PPAR gamma, adiponectin, and leptin in 3T3-L1 adipocytes was quantified densitometrically using the software LabWorks 4.5, and calculated according to the reference bands of beta-actin. RESULTS: The IGOB131 significantly inhibited adipogenesis in adipocytes. The effect appears to be mediated through the down-regulated expression of adipogenic transcription factors (PPAR gamma) [P less than 0.05] and adipocyte-specific proteins (leptin) [P less than 0.05], and by up-regulated expression of adiponectin [P less than 0.05]. CONCLUSION: IGOB131 may play an important multifaceted role in the control of adipogenesis and have further implications in in-vivo anti obesity effects by targeting the PPAR gamma gene, a known contributory factor to obesity in humans.
Theor Biol Med Model. 2008 Nov 12;5:24.

Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary.

BACKGROUND AND HYPOTHESIS: Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors. PROPOSAL AND CONCLUSION: The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.
J Psychoactive Drugs. 2008 Sep;40(3):263-72.

Hypothesizing that marijuana smokers are at a significantly lower risk of carcinogenicity relative to tobacco-non-marijuana smokers: evidenced based on statistical reevaluation of current literature.

Department of Engineering and Management of Advanced Technology, Chang Jung Christian University, Tainan, Taiwan.
A hypothetical link between marijuana smoking and cancer has been established based on a number of misleading assumptions. However, recent studies tend to suggest, if anything, an inverse association between marijuana use and cancers. To test the hypothesis that marijuana smoking significantly lowers the risk of developing cancer in humans, we analyzed published data from a prospective cohort study on cancer incidence among nonsmokers (NS), marijuana-only smokers (MS), tobacco-only smokers (TS), and marijuana and tobacco smokers (MTS). Using the log linear model to calculate the probability of developing each cancer form as a function of the interaction between marijuana and tobacco smoking, as well as functions of marijuana and tobacco smoking main effects whereby chi square statistics were calculated for the interaction and main effect estimates, we found that in all cases tested there was a significantly lower risk for MS compared to TS. Male and female TS had a greater probability of developing lung cancer than did MS. Males and females TS had a greater probability of developing lung cancer compared with NS. Males and female MTS had a slightly higher probability of developing lung cancer than did MS. This difference was statistically significant: chi2 = 30.51, p < .00001, with a correlation coefficient of -0.75, Z = -7.84, p < .05. Male and female MTS had a lower probability of developing lung cancer than did TS. This difference was statistically significant: chi2 = 71.61, p = .00003, with a correlation coefficient of 0.61, Z = 5.06, p < .05.
Med Hypotheses. 2009 Jan;72(1):14-22. Epub 2008 Oct 31.

Hypothesizing that brain reward circuitry genes are genetic antecedents of pain sensitivity and critical diagnostic and pharmacogenomic treatment targets for chronic pain conditions.

Chang Jung Christian University, Tainan, Taiwan, ROC.
While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.
PMID: 18951726 [PubMed - indexed for MEDLINE]
Adv Ther. 2008 Sep;25(9):894-913.

LG839: anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome.

INTRODUCTION: This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical, LG839 (LifeGen, Inc., La Jolla, CA, USA). METHODS: A total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes. A subset of 27 self-identified obese subjects of Dutch descent, having the same DNA pattern of four out of the five candidate genes tested (chi-square analysis) as the entire data set, was subsequently evaluated. Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed. RESULTS: Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating (all P<0.01), increased perception of overeating, enhanced quality of sleep, increased happiness (all P<0.05), and increased energy (P<0.001). Polymorphic correlates were obtained for a number of genes (LEP, PPAR-gamma2, MTHFR, 5-HT2A, and DRD2 genes) with positive clinical parameters tested in this study. Of all the outcomes and gene polymorphisms, only the DRD2 gene polymorphism (A1 allele) had a significant Pearson correlation with days on treatment (r=0.42, P=0.045). CONCLUSION: If these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality to combat obesity.
PMID: 18781289 [PubMed - indexed for MEDLINE]
Age (Dordr). 2007 Sep;29(2-3):55-67. Epub 2007 May 12.

Plasma growth hormones, P300 event-related potential and test of variables of attention (TOVA) are important neuroendocrinological predictors of early cognitive decline in a clinical setting: evidence supported by structural equation modeling (SEM) parameter estimates.

PATH Research Foundation, New York, NY, USA.
A review of the literature in both animals and humans reveals that changes in sex hormone have often been associated with changes in behavioral and mental abilities. Previously published research from our laboratory, and others, provides strong evidence that P300 (latency) event-related potential (ERP), a marker of neuronal processing speed, is an accurate predictor of early memory impairment in both males and females across a wide age range. It is our hypothesis, given the vast literature on the subject, that coupling growth hormones (insulin-like growth factor-I, (IGF-I) and insulin-like growth factor binding protein 3 (IGF-BP3)), P300 event-related potential and test of variables of attention (TOVA) are important neuroendocrinological predictors of early cognitive decline in a clinical setting. To support this hypothesis, we utilized structural equation modeling (SEM) parameter estimates to determine the relationship between aging and memory, as mediated by growth hormone (GH) levels (indirectly measured through the insulin-like growth factor system), P300 latency and TOVA, putative neurocognitive predictors tested in this study. An SEM was developed hypothesizing a causal directive path, leading from age to memory, mediated by IGF-1 and IGF-BP3, P300 latency (speed), and TOVA decrements. An increase in age was accompanied by a decrease in IGF-1 and IGF-BP3, an increase in P300 latency, a prolongation in TOVA response time, and a decrease in memory functioning. Moreover, independent of age, decreases in IGF-1 and IGF-BP3, were accompanied by increases in P300 latency, and were accompanied by increases in TOVA response time. Finally, increases in P300 latency were accompanied by decreased memory function, both directly and indirectly through mediation of TOVA response time. In summary, this is the first report utilizing SEM to reveal the finding that aging affects memory function negatively through mediation of decreased IGF-1 and IGF-BP3, and increased P300 latency (delayed attention and processing speed).
PMID: 19424831 [PubMed]
Adv Ther. 2007 Mar-Apr;24(2):402-14.

Gene \Narcotic Attenuation Program attenuates substance use disorder, a clinical subtype of reward deficiency syndrome.

Chang Jung Christian University, Tainan, Taiwan, Republic of China.
This study evaluated the effects of a putative activator of brain reward circuitry on outcomes in a 1-y prospective comprehensive outpatient clinical program. As part of the Gene Narcotic Attenuation Program, Haveos (Synaptamine)(TM) was administered for the treatment of substance use disorder. Seventy-six patients (45 males and 31 females; mean age, 33 y [standard deviation, 7.0]) who had been given a diagnosis of serious substance use disorder were recruited. After exclusion of 15 patients who dropped out before the end of the study, self-reported craving decreased from program entrance to 12 wk (visual analog scale whereby 0 represents no craving and 5, the strongest craving) for 61 compliant patients (mean decrease, 2.85, 95% confidence interval [CI], 2.65, 3.05); this improvement was significant (P<.001). Building up to relapse scores (each of 5 individual items and summary value) showed similar improvement after 1 y of treatment; the mean decrease in scores was significant for stress (t=3.3; P=.002), depression (t=4.0; P<.001), anger (t=4.4; P<.001), anxiety (t=4.5, P<.001), drug craving (t=5.4, P<.001), and summary building up to relapse (t=4.1; P<.001). Also, recovery score measures of energy level (t=8.4; P<.001) and ability to refrain from drug-seeking behavior (t=7.4; P<.001) showed significant mean increases from entry to 1 y. During the study, the alcoholic dropout rate was only 7% (4 of 57), which was significantly (Fisher's exact test, P<.001) lower than the 73% (11 of 15) dropout rate reported for psychostimulant users. Although these results are significant, any interpretation must await the performance of rigorous double-blind studies.
PMID: 17565932 [PubMed - indexed for MEDLINE]
Med Hypotheses. 2007;69(5):1054-60. Epub 2007 Apr 30.

Manipulation of catechol-O-methyl-transferase (COMT) activity to influence the attenuation of substance seeking behavior, a subtype of Reward Deficiency Syndrome (RDS), is dependent upon gene polymorphisms: a hypothesis.

There are common genetic mechanisms responsible for both drug effects and subsequent seeking behavior. In 1996, we coined the term Reward Deficiency Syndrome (RDS). Past and current treatment of substance seeking behavior, a subtype of Reward Deficiency Syndrome (RDS), is considered by most to be inadequate. Recently, we evaluated a complex named Synaptamine [Haveos (SG8839R)]. The main difference with an older studied variant and the latest variant is the inclusion of a proprietary form of Rhodiola rosea, a known catechol-O-methyl-transferase inhibitor (COMT) to potentially enhance the activity of presynaptic released dopamine. In this regard, based on the current literature we hypothesize that manipulation of catechol-O-methyl-transferase (COMT) activity to influence the attenuation of substance seeking behavior, is dependent upon gene polymorphisms. In this regard we hypothesize that carrying the LL genotype with low COMT activity should as theorized, increase the reward induced by substance-induced dopamine release and may indeed increase the propensity to type 1 alcoholism and possibly other drugs that activate the dopaminergic system. Thus when alcohol is present in low COMT LL genotype, increasing COMT activity, not inhibiting it should assist in the reduction of social consumption or abuse. Alternatively, under physiological conditions (no psychoactive substances present (e.g. alcohol) carrying the DRD2 A1 allele with associated low D2 receptors should, as theorized, increase craving behavior because of a low or hypodopaminergic state causing the individual to seek out substances that increase the release of dopamine for subsequent activation of unbound D2 sites in the nucleus accumbens. Thus, in the absence of alcohol or other psychoactive drugs (dopamine releasers), especially during recovery or rehabilitation, decreasing, not increasing COMT activity, should result in enhanced synaptic dopamine as physiologically released, thereby proliferating D2 receptors while reducing stress, increasing well-being, reducing craving behavior and preventing relapse. Based on this hypothesis, we believe that adding the COMT inhibitor R. rosea (as Rhodimin) to our amino-acid and chromium combination in DUI offenders and other illegal drug-related crimes, increases the potential for more targeted neurochemical rebalancing and enhanced relapse prevention. Finally, we hypothesize that these data coupled together provide evidence that the combination of enkephalinase inhibition, neurotransmitter precursor loading, brain tryptophan enhancing and COMT inhibition as well as DNA analysis of the individual's genome, may be useful as an adjunct to therapy when used in outpatient recovery, specifically to assist in reducing craving behavior and preventing relapse.
Adv Ther. 2006 Nov-Dec;23(6):1040-51.

Reward deficiency syndrome in obesity: a preliminary cross-sectional trial with a Genotrim variant.

Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083, USA.
Obesity is the second largest preventable cause of death in the United States. Even though it was classified as a disease in 1985, traditionally, obesity has been treated primarily as a behavioral problem that requires only modifications in diet and exercise. Similar to research on obesity, clinical studies have elucidated the role of biologic and genetic factors in alcoholism and other conditions previously classified as behavioral. These studies showed that behavioral adjustments alone may not address underlying genetic causes. We hypothesize that biologic and genetic factors must be addressed synergistically while behavioral modifications are implemented to adequately treat obese patients. We hypothesize that a predisposition to glucose craving and obesity is due to inadequate dopaminergic activity in the reward center of the brain. This defect drives individuals to engage in activities of behavioral excess, which, in turn, enhance brain dopamine function. Consumption of large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates production and usage of dopamine within the brain; the term reward deficiency syndrome (RDS) may be used to categorize such biologic influences on behavior. We propose that a novel approach to nutritional supplementation may be required to target the role of RDS in obesity. In this regard, GenoTrim, a DNA-customized nutritional solution, has been developed and is currently under investigation in several clinical studies. Through its mechanism of action, GenoTrim addresses the genetic influence of RDS on obesity. In this cross-sectional study, 24 subjects were studied after they had completed a case report format questionnaire. For this assessment, we used a novel assessment tool-a path analysis. This statistical regression model is used to (1) examine the effectual relationships between various systems within a multisystem matrix, and (2) measure the contributory roles of those relationships in obesity, enabling the development of targeted and effective therapeutic interventions
Drug Metab Lett. 2007 Jan;1(1):55-60.

Folate nutrigenetics: a convergence of dietary folate metabolism, folic acid supplementation, and folate antagonist pharmacogenetics.

Department of Molecular Nutrition and Nutrigenomics, Salugen, Inc., San Diego, California, USA.
Folate (Vitamin B9, Folic acid, folinic acid, folacin, pteroyglutamic acid) is essential for life-sustaining processes of DNA synthesis, replication, and repair which are naturally present in common foods such as peas, oranges, broccoli, and whole-wheat products. Folate levels have been associated with birth defects, cardiovascular disease, and many other important healthcare issues, which has resulted in government-mandated food fortification to deliver minimum levels of intake. Despite this one-size-fits-all recommendation by governmental regulatory bodies, studies suggest that a genetic predisposition may exist within as much as 67% (combining both the CT and TT alleles) of the population that causes a metabolic folate deficiency. Thus, genetic factors may play an important role in folate levels and metabolism. A substantial body of scientific evidence supports the importance of folate, genes associated with folate, genes associated with anti-folate therapeutics, and thereby a convergence in nutritional genetics or nutrigenetics. This review will comment on the substantial body of scientific evidence demonstrating the relevance for nutrigenetic measurements to guide dietary folate intake and nutritional supplementation with folic acid.
Med Hypotheses. 2007;68(4):844-52. Epub 2006 Oct 27.

Genotrim, a DNA-customized nutrigenomic product, targets genetic factors of obesity: hypothesizing a dopamine-glucose correlation demonstrating reward deficiency syndrome (RDS).

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, United States. This e-mail address is being protected from spambots. You need JavaScript enabled to view it < This e-mail address is being protected from spambots. You need JavaScript enabled to view it >
Obesity is the second largest cause of preventable death in the United States. Historically, obesity was considered a behavioral problem that could be simply addressed with behavioral modifications in diet and exercise. As scientific advancements have demonstrated in other neurological healthcare conditions such as alcoholism, there are important biological and genetic components that limit the efficacy of behavioral adjustments alone. In light of data suggesting frequent co-morbidities to obesity, including diabetes mellitus, atherosclerosis, osteoporosis, and potentially others, we hypothesize that the biologic and genetic factors, synergistically with behavioral modifications, must be addressed to adequately treat this disease. We hypothesize that one such genetic factor that influences behavior and thus obesity is a predisposition to glucose craving and the overall effect of dopaminergic activity in the reward center of the brain. This defect drives individuals to engage in activities of behavioral excess, which will increase brain dopamine function, for which we have created the term reward deficiency syndrome (RDS) to categorize such biological influences on behavior. Consuming large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates the brain's production of and utilization of dopamine. So too does the intake of crack/cocaine and the abuse of nicotine. We are proposing that a novel approach to nutritional supplementation may be required to target the RDS role in obesity. In this regard, Genotrim, a DNA based customized nutraceutical has been designed and is currently under investigation in several clinical studies. This is the first hypothesis paper whereby this new paradigm shift in thinking about obesity is presented.
Adv Ther. 2006 Jul-Aug;23(4):582-600.

Delayed P300 latency correlates with abnormal Test of Variables of Attention (TOVA) in adults and predicts early cognitive decline in a clinical setting.

PATH Research Foundation, New York, NY, USA.
Delayed P300 latency identifies dementia better than the Mini-Mental Status Exam and, in some cases, the Wechsler Memory Scale (WMS-III). The purpose of this study was to determine whether the outcome of an objective Test of Variables of Attention (TOVA) correlates with the findings of an electrophysiologic test-P300 latency-in patients 40 y of age or older. Adult attention deficit disorder may be an important premorbid marker of memory dysfunction or dementia. In males, the means for P300 latency and age-adjusted P300 latency were significantly greater for patients classified as SD-BL (significantly deviant or borderline: TOVA<-1.0) than for those categorized as normal (TOVA(3)0) for attention failure (ie, omissions [P<.010] and commissions [P<.005]) but not for response time or for variability. Males with >2 SD-BL quarters had significantly delayed P300 latency and age-adjusted P300 latency compared with males who had 0 SD-BL quarters (P<.020) and 1 SD-BL quarter (P<.005). In females, the means for P300 latency and age-adjusted P300 latency were significantly delayed for those grouped as SD-BL than for those labeled normal for response time (P<.001) and variability (P<.010), but not for omissions or for commissions. Females with >2 SD-BL quarters had significantly delayed P300 latency and age-adjusted P300 latency compared with females who had 0 SD-BL quarters (P<.005) and 1 SD-BL quarter (P<.010). Results suggest that TOVA abnormalities may be an indicator of delayed P300 and attention disorder. Recent research correlates TOVA abnormalities with impaired WMS scores of early dementia. Coupling of TOVA assessment findings with results of P300, Mini-Mental Status Exam, and WMS-III may allow for enhanced accuracy in the diagnosis and evaluation of the complex pathway of failing attention, memory, and cognition that leads to dementia.
Med Hypotheses. 2006;66(5):1008-18. Epub 2006 Jan 5.

DNA based customized nutraceutical "gene therapy" utilizing a genoscore: a hypothesized paradigm shift of a novel approach to the diagnosis, stratification, prognosis and treatment of inflammatory processes in the human.

We hypothesize that using a multi-variant nutrigenomic index for the purposes of customizing or adjusting the formulation of nutritional supplements will result in an improved and novel approach to the diagnosis, stratification, prognosis, and treatment of inflammatory processes in the human. This multi-variant genetic index, or Genoscore, is derived by analyzing genotype and/or phenotype through measuring multiple genetic mutations of single nucleotide polymorphisms, gene expression, or other forms of genetic and phenotypic measurements. We also propose that manipulation of neurochemical reward circuitry in the mesolimbic brain region providing dopamine release at the nucleus accumbens (NAc), will have both pain and stress relief benefists, which are a cornerstone to the human inflammatory process. This hypothesis, applies to all genes currently discovered or which will be discovered and any nutritional or dietary supplement ingredient currently available or which will become available. For example, if a DNA test was measuring two genes through single nucleotide polymorphisms (Gene A and Gene B), the index scores (Genoscore) that would be reported to the clinician and patient would be based upon the number of mutations. An index score of 0 would mean no mutation. An index score of 1 may mean a mutation in Gene A. An Index Score of 2 may mean a mutation in Gene B. An Index Score of 3 may mean a mutation in Gene A and Gene B, resulting in a simple report, easily understandable to both the clinician and patient that provides insights into disease diagnosis, stratification, prognosis, as well as the metabolism, efficacy and/or toxicity associated with specific vitamins, minerals, herbal supplements, homeopathic ingredients and other ingredients in the nutritional and/or dietary supplement regimen. Furthermore, we have provided support that evidence shows the importance of the dopaminergic connection as an anti-pain and anti-stress molecule, working at the mesocorticolimbic region of the brain, specifically at the NAc. Additionally, we have provided support that clinical evidence demonstrates the effectiveness and safety of natural substances for joint health, such as glucosamine sulfate , chondroitin sulfate, and Ganoderma lucidum.
Theor Biol Med Model. 2005 Dec 23;2:50.

Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths.

BACKGROUND: Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie? RESULTS: We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered. CONCLUSION: The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.
Med Hypotheses. 2005;65(4):703-7.

Are dopaminergic genes involved in a predisposition to pathological aggression? Hypothesizing the importance of "super normal controls" in psychiatricgenetic research of complex behavioral disorders.

Chang Jung Christian University, Taiwan, ROC.
Comment in:
We hypothesize that pathological aggression, a complex behavioral disorder, in adolescents may in part involve polymorphisms of the dopaminergic system. While a number of neurotransmitter systems must be involved, due to polygenic inheritance, one major pathway should involve the dopaminergic system. Advances in our knowledge of the neurobiology of aggression and violence have given rise to rational pharmacological treatments for these behaviors. The main biological systems that are known to be involved are certain reward neurotransmitters including: serotonin, opioid peptides, gamma-aminobutyric acid, and the catecholamines (dopamine and norepinephrine). It is our notion that pathological aggressive behavior is in part similar mechanistically to other forms of impulsive behaviors such as pathological gambling. By analogy to drug dependence, it has been speculated that the underlying pathology in pathological gambling is a reduction in the sensitivity of the reward system. While studying pathological gamblers and controls during a guessing game using functional Magnetic Resonance Imaging, Reuter et al. observed a reduction of ventral striatal and ventromedial prefrontal activation in the pathological gamblers that were negatively correlated with gambling severity. Subsequently, linking hypo activation of these areas to disease severity. A positive correlation of both the dopamine D2 receptor gene (DRD2) and the dopamine transporter gene (DAT1) polymorphisms were observed with pathological violence in adolescents in a blinded clinical trial. Thus, this and other cited work preliminary suggest a role for both the DRD2 and DAT genes in pathological aggressive behavior. We further hypothesize that follow-up gene research in this area, albeit premature, resulting in confirmation of positive correlations with dopaminergic polymorphisms, and utilizing highly screened controls (eliminating any addictive, compulsive and impulsive behaviors in both proband and family) may have important ramifications in our young population
Med Hypotheses. 2004;63(3):538-48.

Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy.

Chang Jung Christian University, Tainan, Taiwan, ROC.
We decided to test the hypothesis that possibly by combining a narcotic antagonist and amino-acid therapy consisting of an enkephalinase inhibitor (D-phenylalanine) and neurotransmitter precursors (L-amino- acids) to promote neuronal dopamine release might enhance compliance in methadone patients rapidly detoxified with the narcotic antagonist Trexan (Dupont, Delaware). In this regard, Thanos et al. [J. Neurochem. 78 (2001) 1094] and associates found increases in the dopamine D2 receptors (DRD2) via adenoviral vector delivery of the DRD2 gene into the nucleus accumbens, significantly reduced both ethanol preference (43%) and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. This DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This work further suggests that high levels of DRD2 may be protective against alcohol abuse [JAMA 263 (1990) 2055; Arch, Gen. Psychiatr. 48 (1991) 648]. The DRD2 A1 allele has also been shown to associate with heroin addicts in a number of studies. In addition, other dopaminergic receptor gene polymorphisms have also associated with opioid dependence. For example, Kotler et al. [Mol. Phychiatr. 3 (1997) 251] showed that the 7 repeat allele of the DRD4 receptor is significantly overpresented in the opioid-dependent cohort and confers a relative risk of 2.46. This has been confirmed by Li et al. [Mol. Psychiatry 2 (1997) 413] for both the 5 and 7 repeat alleles in Han Chinese case control sample of heroin addicts. Similarly Duaux et al. [Mol. Psychiatry 3 (1998) 333] in French Heroin addicts, found a significant association with homozygotes alleles of the DRD3-Bal 1. A study from NIAAA, provided evidence which strongly suggests that DRD2 is a susceptibility gene for substance abusers across multiple populations (2003). Moreover, there are a number of studies utilizing amino-acid and enkephalinase inhibition therapy showing reduction of alcohol, opiate, cocaine and sugar craving behavior in human trials (see Table 1). Over the last decade, a new rapid method to detoxify either methadone or heroin addicts utilizing Trexan sparked interest in many treatment centers throughout the United States, Canada, as well as many countries on a worldwide basis. In using the combination of Trexan and amino-acids, results were dramatic in terms of significantly enhancing compliance to continue taking Trexan. The average number of days of compliance calculated on 1000 patients, without amino-acid therapy, using this rapid detoxification method is only 37 days. In contrast, the 12 subjects tested, receiving both the Trexan and amino-acid therapy was relapse-free or reported taking the combination for an average of 262 days (p < 0.0001F). Thus coupling amino-acid therapy and enkephalinase inhibition while blocking the delta-receptors with a pure narcotic antagonist may be quite promising as a novel method to induce rapid detox in chronic methadone patients. This may also have important ramifications in the treatment of both opiate and alcohol-dependent individuals, especially as a relapse prevention tool. It may also be interesting too further test this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphrine.
PMID: 15288384 [PubMed - indexed for MEDLINE]
Clin Electroencephalogr. 2003 Jul;34(3):124-39.

P300 (latency) event-related potential: an accurate predictor of memory impairment.

To determine if P300 latency changes precede and correlate with memory and mental status, patients (N=1506 aged 20-100 years) who received medical and psychiatric diagnoses (from 1997 to 2002), were assessed for P300 (N=1496), WMS-III (N=694), and MMSE (N=456). Patient and control groups included, a) normal WMS-III on all 4 subscales (N=36), b) normal WMS-III and MMSE (N=189) with subjective memory/mental status complaints, and c) medical patients with normal WMS-III and no memory complaints (N=205), and d) P300 control group without medical, psychiatric or memory problems for ROC. Patients with impaired/borderline memory had a prolonged P300 latency (P<0.02) compared to age matched non-impaired controls; in patients with normal WMS-III/MMSE, with subjective mild memory/mental status impairment, P300 latency was prolonged compared to controls (P=0.0004). The P300 latency increased by 0.72ms per year (P=7.9x10(-65)) and voltage decreased by 0.03dV per year (P=6.7x10(-10)), and both parameters were linearly correlated with the age of the subjects. Male subjects had an average voltage of 6.1dV and female 6.8dV (P=0.00009). Statistically, prolonged latency began at age range 41-50 (P=0.0002); reduced P300 voltage began at age range 51-60 (P=0.003). WMS-III memory decline for all measures began in females at age range 61-70 (P value at least=0.02) and for males at age range 61-80 (P=0.02). Prolonged P300 latency (P<0.0001) and memory impairment (at least <0.02) were greater for females than males. MMSE memory decline, male and female, began at age range 81-90 (P value of at least 0.00007). In our logistic regression model P300 latency was more predictive of WMS-III impairment than MMSE > 24. In patients whose WMS-III score is impaired < or = 69, or borderline < or = 79 (P at least=0.004), a P300 latency more prolonged than the norm (> or = 300 + 30 + Age) identifies these patients, whereas a MMSE > 24 failed. With the ROC curve, we confirmed that P300 latency could accurately identify borderline/impaired memory.
J Psychoactive Drugs. 2000 Nov;32 Suppl:i-iv, 1-112.

Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.

Department of Biological Sciences, University of North Texas, Denton, Texas, USA.
The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces "reward" when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. "The reward cascade" involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or "reward site." It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the "pleasure molecule" and/or the "antistress molecule." When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor A1 allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette's Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome.
Prog Brain Res. 2000;126:325-41.

Reward deficiency syndrome: genetic aspects of behavioral disorders.

The dopaminergic and opioidergic reward pathways of the brain are critical for survival since they provide the pleasure drives for eating, love and reproduction; these are called 'natural rewards' and involve the release of dopamine in the nucleus accumbens and frontal lobes. However, the same release of dopamine and production of sensations of pleasure can be produced by 'unnatural rewards' such as alcohol, cocaine, methamphetamine, heroin, nicotine, marijuana, and other drugs, and by compulsive activities such as gambling, eating, and sex, and by risk taking behaviors. Since only a minority of individuals become addicted to these compounds or behaviors, it is reasonable to ask what factors distinguish those who do become addicted from those who do not. It has usually been assumed that these behaviors are entirely voluntary and that environmental factors play the major role; however, since all of these behaviors have a significant genetic component, the presence of one or more variant genes presumably act as risk factors for these behaviors. Since the primary neurotransmitter of the reward pathway is dopamine, genes for dopamine synthesis, degradation, receptors, and transporters are reasonable candidates. However, serotonin, norepinephrine, GABA, opioid, and cannabinoid neurons all modify dopamine metabolism and dopamine neurons. We have proposed that defects in various combinations of the genes for these neurotransmitters result in a Reward Deficiency Syndrome (RDS) and that such individuals are at risk for abuse of the unnatural rewards. Because of its importance, the gene for the [figure: see text] dopamine D2 receptor was a major candidate gene. Studies in the past decade have shown that in various subject groups the Taq I A1 allele of the DRD2 gene is associated with alcoholism, drug abuse, smoking, obesity, compulsive gambling, and several personality traits. A range of other dopamine, opioid, cannabinoid, norepinephrine, and related genes have since been added to the list. Like other behavioral disorders, these are polygenically inherited and each gene accounts for only a small per cent of the variance. Techniques such as the Multivariate Analysis of Associations, which simultaneously examine the contribution of multiple genes, hold promise for understanding the genetic make up of polygenic disorders.
Mol Psychiatry. 1997 May;2(3):239-46.

Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB).

UTHSC School of Public Health at Houston, Department of Behavioral Sciences, San Antonio 78284-7976, USA.
The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms in the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance-seeking behaviors (ethanol, drugs, tobacco, and food) and other related behaviors (pathological gambling, Tourette's disorder, attention-deficit/hyperactivity disorder). This is the first study supporting a strong association between the dopamine D2 receptor Taq A1 allele with schizoid/avoidant behavior (SAB). Additionally, an albeit weaker association between the 480-bp VNTR 10/10 allele of the dopamine transporter (DAT1) gene with SAB was similarly found.
Clin Electroencephalogr. 1997 Apr;28(2):68-75.

Enhancement of attention processing by Kantroll in healthy humans: a pilot study.

University of Texas Health Science Center, Houston 77025, USA.
This is the first report in humans of the effects of daily ingestion of a specific amino acid mixture, Kantroll, on cognitive event-related potentials (ERPs) associated with performance. Cognitive ERPs were generated by two computerized visual attention tasks, the Spatial Orientation Task (SOT) and Contingent Continuous Performance Task (CCPT), in normal young adult volunteers, where each subject acted as his own control for testing before and after 28-30 days of amino acid ingestion. A statistically significant amplitude enhancement of the P300 component of the ERPs was seen after Kantroll for both tasks, as well as improvement with respect to cognitive processing speeds. The enhancement of neurophysiologic function observed in this study on normal controls is consistent with the facilitation of recovery of individuals with RDS (i.e., substance use disorder, ADHD, carbohydrate bingeing) following the ingestion of the amino acid supplement, Kantroll, and warrants additional placebo-controlled, double-blind, studies to confirm and extend these results.
Pharmacogenetics. 1996 Aug;6(4):297-305.

Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report.

Department of Behavioural Sciences, University of Texas-Houston, School of Public Health, San Antonio, USA.
In order to investigate the prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with and without comorbid substance use disorder, a total of 40 patients, from an outpatient neuropsychiatric clinic in Princeton, New Jersey, were genotyped for presence or absence of the Taq I DRD2 A1 allele. The primary inclusion criterion for 40 obese subjects was a body mass index (BMI) equal to or over 25 (uncharacterized); 11 obese subjects had severe substance use disorder; 20 controls had a BMI below 25; and, 33 substance use disorder (less severe) patients had a BMI below 25. The data were statistically compared with three different sets of controls divided into three separate groups (Group I, n = 20; Group II, n = 286; Group III, n = 714). They differed according to screening criteria (drug, alcohol, nicotine abuse/dependence, BMI below 25 and other related behaviours including parental history of alcoholism or drug abuse and DSM IV, Axis I and Axis II diagnoses). Groups II and III were population controls derived from the literature. The prevalence of the Taq I A1D2 dopamine receptor (DRD2) alleles was determined in 40 Caucasian obese females and males. In this sample with a mean BMI of 32.35 +/- 1.02, the A1 allele of the DRD2 gene was present in 52.5% of these obese subjects. Furthermore, we found that in the 23 obese subjects possessing comorbid substance use disorder, the prevalence of the DRD2 A1 allele significantly increased compared to the 17 obese subjects without comorbid substance use disorder. The DRD2 A1 allele was present in 73.9% of the obese subjects with comorbid substance use disorder compared to 23.5% in obese subjects without comorbid substance use disorder. Moreover, when we assessed severity of substance usage (alcoholism, cocaine dependence, etc.) increasing severity of drug use increased the prevalence of the Taq I DRD2 A1 allele; where 66.67% (8/12) of less severe probands possessed the A1 allele compared to 82% (9/11) of the most severe cases. Linear trend analyses showed that increasing use of drugs was positively and significantly associated with A1 allelic classification (p < 0.00001). These preliminary data suggest that the presence of the DRD2 A1 allele confirms increased risk not only for obesity, but also for other related addictive behaviours (previously referred to as the Reward Deficiency Syndrome) and that a BMI over 25 by itself (without characterization of macroselection or comorbid substance use disorders) is not a sufficient criterion for association with the DRD2 A1 allele.
J R Soc Med. 1996 Jul;89(7):396-400.

The D2 dopamine receptor gene as a determinant of reward deficiency syndrome.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284, USA.
The dopaminergic system, and in particular the dopamine D2 receptor, has been profoundly implicated in reward mechanisms in the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance seeking behaviour (alcohol, drug, tobacco, and food) and other related behaviours (pathological gambling, Tourette's syndrome, and attention deficit hyperactivity disorder). We propose that variants of the D2 dopamine receptor gene are important common genetic determinants of the 'reward deficiency syndrome'.
Clin Electroencephalogr. 1996;27(4 Suppl):5-27.

Substance use disorder exacerbates brain electrophysiological abnormalities in a psychiatrically-ill population.

Department of Psychiatry, New York University School of Medicine, New York, New York, USA.
Erratum in:
  • Clin Electroencephalogr 1997 Jan;28(1):63.
OBJECTIVE: To assess by brain electrical activity mapping whether cocaine and alcohol abuse and dependence would exacerbate electro-physiological abnormalities in a psychiatrically-ill population. DESIGN, SETTING, AND PARTICIPANTS: Utilizing a brain mapping system, we assessed EEG, Spectral Analysis (Quantitative EEG[QEEG]). Evoked Potentials (Auditory and Visual), and P300 (cognitive evoked potential), in a total of 111 probands divided into three groups: controls (N = 16), psychiatrically-ill without comorbid substance use disorder (N = 34), and psychiatrically-ill with comorbid substance use disorder (cocaine and alcohol abuse and dependence) (N = 61), at an outpatient neuropsychiatric clinic. With regard to demographic data, the group participating in this study did not differ significantly. A comparison was made among the groups to assist in differentiating the effects of substance use disorder compared to psychiatric disease on brain electrical activity. MAIN OUTCOME MEASURES: An assessment of electrophysiological abnormalities and their brain location in psychiatric and substance use disorder patients was done with a brain electrical activity mapping test. MAIN RESULTS: Among the non-substance use disorder, psychiatrically-ill (PI) and substance use disorder, psychiatrically-ill (PI/SD) groups, significantly different brain map abnormalities were observed relative to an assessed normal population MANOVA (P = .017). Moreover, with regard to Spectral Analysis, ANOVA was significant at a P = .038, and we found a weighted linear trend of increased abnormal total spectral analysis (P = .0113), whereby substance use was significantly worse than controls. Moreover among the PI and PI/SD groups, significantly greater total evoked potential (EP) brain trap abnormalities were observed when compared with a characterized normal population (P = .0023) with increasing abnormalities as a function of substance use disorder as measured by a weighted linear trend (P = .0022). In order to determine the site of the EPS abnormalities, we evaluated these abnormalities by location. In this regard, we found all temporal abnormalities (AVBITA, see Table 2) among the PI and PI/SD groups to be significantly greater relative to an assessed normal population (P = .0026). Furthermore, we observed a linear trend of increased temporal abnormalities with increasing substance use disorder (P < .0008). In terms of bitemporal abnormalities (AVBIT) among the PI and PI/SD groups, we also found significantly more bitemporal lobe abnormalities in the PI/SD group compared to our control population (P = .009). Additionally, a weighted linear trend of increased abnormal bitemporal lobe abnormalities was observed with increasing substance use disorder (P = .0022). In the frontal lobe similar findings were observed. With AVBIFA the ANOVA was P < .011, with a weighted linear trend of P < .005 and the PI/SD group were significantly more abnormal than PI or CS on a Duncan Range test. It is noteworthy that in a selected group of depressed (Major Depressive Disorder Recurrent, 296.3) patients, we found profound abnormalities in the various brain map parameters tested. MANOVA and Univariate ANOVA's revealed significantly greater abnormalities in the PI and PI/SD groups compared to assessed controls. A MANOVA for total brain abnormalities was significant at P = .043 and univariate ANOVA's for composite measurements of TSA (P = .017), EPS (P = .0002), AVBITA (P = .000015), and AVBIT (P < .00002) are also significant. With regard to EPS and AVBITA a weighted linear trend was observed where there were increasing abnormalities with increasing substance use disorder, P = .0001 and P = .000003, respectively. Most importantly we found that in addition to increased abnormalities with increasing substance use disorder the PI/SD group had significantly more abnormalities compared to the PI group with regard to both the TSA (P < .05) and AVBIT (P < .05) composite parameters as meas
Am J Med Genet. 1995 Dec 18;60(6):529-31.

Lack of association between alcohol-dependence and D3 dopamine receptor gene in three independent samples.

Laboratoire d'Epidémiologie Génétique, INSERM Unité 155, Université Paris, VII, France.
Numerous studies on the involvement of dopamine receptors in the genetics of alcoholism focused on associations between a polymorphism of the D2 dopamine receptor (DRD2) gene and alcohol dependence. However, the results of these studies are conflicting. Another receptor, the D3 dopamine receptor (DRD3), may be of additional interest since it is specifically located in the limbic area, and in particular in the nucleus accumbens which plays a significant role in the reward process of addiction behavior. We thus tested the association in three independent samples of alcoholic patients, with different origins and various inclusion criteria. No difference in the DRD3 gene polymorphism emerged between controls and alcoholic patients, regardless of their origin, inclusion criteria, or presence or absence of the DRD2 TaqI A1-allele. Despite the fact that more information could have been considered and that association studies provide limited information, there is good evidence that this DRD3 polymorphism does not play a major role in the genetic component of alcoholism.
Pharmacogenetics. 1995 Jun;5(3):121-41.

Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284, USA.
Drug and alcohol seeking behaviour has become a great global problem affecting millions of inhabitants with a cost to society in the billions. Dopaminergic reward pathways have frequently been implicated in the etiology of addictive behaviour. While other neurotransmitters have also been implicated, to date the only molecular genetic defect which has been found to associate with alcoholism, drug dependency, obesity, smoking, pathological gambling, attention-deficit-hyperactivity disorder (ADHD), Tourette syndrome, as well as other related compulsive behaviours, are the variants of the dopamine D2 receptor gene (DRD2). In this review of the available data on the subject, we report a number of independent meta-analyses that confirm an association of DRD2 polymorphisms and impulsive-additive-compulsive behaviour (IACB), which we have termed "Reward Deficiency Syndrome". While we agree that Meta-analyses of all exant studies support an association of variants of DRD2 and IACB, correct negative findings with alcoholism may be due to differences in assessing controls and inclusion/exclusion criteria for selection of diseased probands.
PMID: 7550364 [PubMed - indexed for MEDLINE]
Funct Neurol. 1995 Jan-Feb;10(1):37-44.

The D2 dopamine receptor gene as a predictor of compulsive disease: Bayes' theorem.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284, USA.
The dopaminergic system, and in particular the dopamine D2 receptor, has been profoundly implicated in reward mechanisms in the meso-limbic circuitry of the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance (alcohol, drug, tobacco and food) seeking behavior. Decades of research indicate that genetics play an important role in vulnerability to severe substance seeking behavior. We propose that variants of the D2 dopamine receptor gene are important common genetic determinants in predicting compulsive disease.
Pharmacogenetics. 1994 Dec;4(6):313-22.

Prolonged P300 latency in a neuropsychiatric population with the D2 dopamine receptor A1 allele.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284.
The role of the dopaminergic system in P300 has been implicated and previous studies have suggested the presence of a heritable component in the genesis of P300 or P3, a late positive component of the event-related potential. In the present investigation, 155 Caucasian male and female diagnosed neuropsychiatrically-ill patients with and without comorbid drug and alcohol abuse/dependence were genotyped for the presence or absence of the A1 allele of the D2 dopamine receptor gene (DRD2). The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between all groups studied with A1 and A2 allele carriers. However, we now report prolonged P3 latency in neuropsychiatrically-ill patients (with or without polysubstance abuse) with those carrying two copies of the A1 allele (homozygote) of the DRD2 gene (quadratic trend, p = 0.01). Moreover, the age-adjusted mean P3 latency in the D2A2/A2 allele group was 327.8 +/- 3.08 ms compared by ANOVA, to 360.04 +/- 4.86 ms in the D2A1/A1 group. Our work suggests an association of polymorphisms of the DRD2 gene and a biological marker previously indicated to have predictive value in vulnerability to substance abuse.
JAMA. 1994 Jan 19;271(3):204-8.

No structural mutation in the dopamine D2 receptor gene in alcoholism or schizophrenia. Analysis using denaturing gradient gel electrophoresis.

Clinical Neurogenetics Branch, National Institute of Mental Health, Bethesda, Md. 20892.
OBJECTIVE--To examine the dopamine D2 receptor (DRD2) gene coding sequences for abnormalities associated with schizophrenia or alcoholism and thereby help to resolve the controversy surrounding the reported association of alcoholism with a restriction fragment length polymorphism located close to the DRD2 gene. DESIGN--Mutational analysis of complete DRD2 gene coding sequences by denaturing gradient gel electrophoresis followed by direct nucleotide sequencing of detected variants. SETTING--Patients and controls from clinical and epidemiologic collections in the United States and Europe. PATIENTS--A total of 253 unrelated individuals, including 106 patients with schizophrenia, 113 with alcoholism, and 34 controls. For alcoholism we included patients from previously published series in which an association of illness with allele A1 was reported (Taql site 3' to the DRD2 gene) and from other published series in which nonconfirmations of this association were reported. Nearly all persons examined were white. MAIN OUTCOME MEASURES--Frequency of nonsilent variations in DRD2 gene DNA sequences in the different diagnostic groups. RESULTS--We found three infrequent DNA variants that predict altered amino acid sequence of the receptor. None of these is associated with either alcoholism or schizophrenia. CONCLUSION--No structural coding abnormalities in the DRD2 gene are present in alcoholism or schizophrenia.
PMID: 8277546 [PubMed - indexed for MEDLINE]
Drug Alcohol Depend. 1993 Oct;33(3):271-85.

Allelic association of the D2 dopamine receptor gene with cocaine dependence.

Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
Erratum in:
  • Drug Alcohol Depend 1993 Dec;34(1):83-4.
The objective of the present study was to examine allelic prevalence of the D2 dopamine receptor (DRD2) gene in male cocaine-dependent (CD) Caucasian (non-Hispanic) subjects and to determine the relationship of DRD2 alleles to family history and selected behavioral measures. The prevalence of the A1 allele in CD subjects (n = 53) was 50.9%. It was significantly higher than either the 16.0% prevalence (P < 10(-4)) in non-substance abusing controls (n = 100) or the 30.9% prevalence (P < 10(-2)) in population controls (n = 265) wherein substance abusers were not excluded. Similarly, a significantly higher prevalence (P < 10(-2)) of the B1 allele was found in CD subjects (n = 52) compared with non-substance abusing controls (n = 53); 38.5% vs. 13.2%. Logistic regression analysis of CD subjects identified potent routes of cocaine use and the interaction of early deviant behaviors and parental alcoholism as significant risk factors associated with the A1 allele. The cumulative number of these three risk factors in CD subjects was positively and significantly (P < 10(-3)) related to A1 allelic prevalence. The data showing a strong association of the minor alleles (A1 and B1) of the DRD2 with cocaine dependence suggest that a gene, located on the q22-q23 region of chromosome 11, confers susceptibility to this drug disorder.
Trends Neurosci. 1993 Mar;16(3):83-8.

Substance abuse vulnerability and D2 receptor genes.

Laboratory of Molecular Neurobiology, National Institute on Drug Abuse, Baltimore, MD 21224.
Comment in:
Dopamine systems are key to the actions of several substances. Inter-individual differences in genes encoding proteins involved in dopaminergic neurotransmission could plausibly explain some of the genetic bases for inter-individual differences in vulnerability to substance abuse. The restriction fragment length polymorphism (RFLP) markers TaqIA1 and B1 at the dopamine D2 receptor (DRD2) gene locus in Caucasians are associated with substance abuse behaviors. In most, but not all, studies of alcoholics and polysubstance abusers, these TaqIA1 and B1 gene markers are present more often in substance abusers than in control individuals. No study has identified substance abusers or controls by sampling randomly from the general population; allelic association findings could thus conceivably be confounded by RFLP differences based on ethnicity or other factors. However, meta-analyses of the data from controlled studies available to date are consistent with the proposal that DRD2 gene variants contribute to inter-individual differences in vulnerability to alcoholism and polysubstance abuse.
PMID: 7681236 [PubMed - indexed for MEDLINE]
Alcohol. 1993 Jan-Feb;10(1):59-67.

Genetic predisposition in alcoholism: association of the D2 dopamine receptor TaqI B1 RFLP with severe alcoholics.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
Previous studies have shown an association of the 3' Taq1 A1 allele of the D2 dopamine receptor (DRD2) gene with severe alcoholism. The recent demonstration of a new polymorphism located closer to the regulatory regions of this gene, permits an associational analysis of these 5' Taq1 B alleles with alcoholism and a comparison with the 3' Taq1 A alleles. Restriction fragment length polymorphism methodology was used to analyze a total of 133 blood samples of nonalcoholics, less severe alcoholics, and severe alcoholics. In white subjects (n = 115), no significant difference in the prevalence of the B1 allele is found between nonalcoholics (n = 30) and less severe alcoholics (n = 36). However, the prevalence of this allele is significantly higher in severe alcoholics (n = 49) when compared to either nonalcoholics (p = 0.008) or less severe alcoholics (p = 0.005). When Taq1 B and Taq1 A alleles of the DRD2 gene are compared in whites, the prevalence of the A1 allele is significantly higher than the B1 allele only in the severe alcoholic group. In conclusion, alleles in both the 5' and 3' region of the DRD2 gene associate with severe alcoholism. This suggests that the DRD2 gene may have an etiological role in some severe alcoholics.
Alcohol. 1991 Sep-Oct;8(5):409-16.

Association of the A1 allele of the D2 dopamine receptor gene with severe alcoholism.

Laboratory of Pharmacogenetics, University of Texas Health Science Center, San Antonio 78284.
In a blinded study, 159 subjects composed of nonalcoholics (N = 43), less severe alcoholics (N = 44), severe alcoholics (N = 52) and young children of alcoholics (CoAs, N = 20) were studied for their allelic association with the D2 dopamine receptor (D2DR) gene utilizing peripheral lymphocytes as the DNA source. The combined alcoholic group compared to the nonalcoholic group showed a significantly greater association with the A1 allele of the D2DR gene. Furthermore, an even more robust association was found when severe alcoholics were compared to nonalcoholics. CoAs also showed a significantly greater association with the A1 allele than nonalcoholics but not when compared to alcoholics. Analysis of risk of alcoholism severity suggests that it comprises of two independent components: family history of alcoholism and presence of the A1 allele. Genotype and allelic frequency of the D2DR gene were also analyzed with respect to race. A higher percentage of blacks compared to whites had the A1/A1 genotype, and A1 allelic frequency in the total sample of blacks was significantly greater than in the total sample of whites. Moreover, frequency of the A1 allele was significantly greater in severe alcoholics compared to nonalcoholics in both whites and blacks. However, due to the small sample size of blacks, these racial differences need to be further studied. This study, of the largest sample of alcoholics to date, strongly affirms association of severe alcoholism with the A1 allele of the D2DR gene.
Arch Gen Psychiatry. 1991 Jul;48(7):648-54.

Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism.

Neuropsychiatric Institute, UCLA 90024.
The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd [binding affinity] and Bmax [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.
JAMA. 1990 Apr 18;263(15):2055-60.

Allelic association of human dopamine D2 receptor gene in alcoholism.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284.
Comment in:
In a blinded experiment, we report the first allelic association of the dopamine D2 receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3' coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3' sequence of the human dopamine D2 receptor gene (lambda hD2G1). In the present samples, the presence of A1 allele of the dopamine D2 receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.
J Psychoactive Drugs. 1990 Apr-Jun;22(2):173-87.

Neurodynamics of relapse prevention: a neuronutrient approach to outpatient DUI offenders.

Cambridge Institute, San Francisco, California.
The central nervous system rewarding properties of ethanol, cocaine, and heroin may activate a common catecholaminergic reward system in the mesolimbic circuitry of the brain. Driving-under-the-influence (DUI) offenders with either alcohol- or cocaine-related problems were studied. The neuronutrients SAAVE and Tropamine significantly reduced relapse rates and enhanced recovery in these DUI outpatient offenders over a 10-week period. Follow-up on both the SAAVE and Tropamine groups after 10 months revealed a 73% and a 53% overall recovery rate, respectively. These clinical results favor the use of these neuronutrients as adjuncts to psychological therapeutic modalities.
Experientia. 1989 May 15;45(5):444-52.

Ethanol ingestive behavior as a function of central neurotransmission.

Department of Pharmacology, University of Texas, San Antonio 78484-7764.
Uncontrollable alcohol ingestive behavior has been linked to deficits of central neurotransmission. The pineal gland plays an important role in modulating ethanol intake in numerous animal species. The opioidergic (i.e. beta-endorphin, enkephalin, and dynorphin) system is involved in both the actions of alcohol and opiates, as well as craving and/or genetic predisposition towards abuse of these two agents. Furthermore, there is significant evidence to link ingestive behaviors with the ventral tegmental accumbens-hypothalamic axis, whereby the biogenic amines dopamine and serotonin are reciprocally involved. Evidence is presented which implicates the striatum and the hypothalamus as possible specific loci for regional differences between alcohol-preferring and alcohol-nonpreferring mice. We believe that photoperiod-induced alcohol ingestive behavior may involve alterations in both pineal and hypothalamic opioid peptides.
Alcohol. 1988 Nov-Dec;5(6):481-93.

Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers: double-blind placebo-controlled study of the nutritional adjunct SAAVE.

University of Texas Health Sciences Center, Department of Pharmacology, San Antonio.
We investigated the effects of the amino acid and vitamin mixture SAAVE in inpatient, chemically-dependent subjects to evaluate the role of neurotransmitters in facilitating recovery and adjustment to a detoxified, sober state. SAAVE is formulated from amino acids that are precursors for neurotransmitters and neuromodulators thought to be involved in alcohol and drug seeking behavior. In a double-blind, placebo-controlled, randomized study of 62 alcoholics and polydrug abusers, SAAVE patients had a significantly reduced stress response as measured by the skin conductance level (SCL), and significantly improved Physical Scores and BESS Scores (behavioral, emotional, social and spiritual). After detoxification there was a six-fold decrease in AMA rates when comparing SAAVE vs. placebo groups. In this inpatient treatment experience SAAVE facilitated the rate of recovery and allowed patients to respond more fully and more quickly to the behavioral goals of the program, for example as measured by the BESS Score. The use of SAAVE to achieve enkephalinase inhibition and precursor amino acid loading in the acute inpatient treatment environment provides the practitioner with the potential ability to restore the neurochemical changes inherent to alcoholism and drug abuse. These findings increase our understanding of the clinically relevant neurobiological mechanisms which underlie compulsive disease.
PMID: 3072969 [PubMed - indexed for MEDLINE]
Experientia. 1988 Sep 15;44(9):751-3.

Narcotic antagonism of seizures induced by a dopamine-derived tetrahydroisoquinoline alkaloid.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
This paper describes experiments designed to evaluate whether the narcotic antagonist naloxone significantly interferes with seizures induced by tetrahydroisoquinolines (TIQs). In these experiments we found that naloxone significantly reduced seizure scores induced by intra-cranially infusing mice with 50 micrograms of the dopamine-derived tetrahydroisoquinoline (TIQ) alkaloid, 6,7-dihydroxy TIQ. These findings support an opioid involvement in the actions of TIQs and may lead to further understanding of opioid-mediated novel excitatory receptors
Int J Addict. 1988 Sep;23(9):991-8.

Improvement of inpatient treatment of the alcoholic as a function of neurotransmitter restoration: a pilot study.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284.
We report results of a double-blind evaluation of the nutritional supplement SAAVE for facilitating improvement in a 30-day inpatient alcohol and drug rehabilitation center. SAAVE is uniquely designed to elevate levels of enkephalin(s), serotonin, catecholamines, and GABA, which are believed to be functionally deficient in alcoholics. Twenty-two patients were studied. The SAAVE patients, as compared to the control group (a) had a lower BUD (building up to drink) score, 1 vs 2; (b) required no PRN benzodiazepines, 0% vs 94%; (c) ceased tremoring at 72 h, as compared to 96 h; and (d) had no severe depression on the MMPI, in contrast to 24% of control group. These preliminary data suggest that SAAVE is a valuable adjunct to therapy by aiding the patient's physical adjustment to a detoxified state while facilitating a more positive response to behavioral therapy.
Int J Addict. 1988 Aug;23(8):781-96.

Alcoholism: scientific basis of a neuropsychogenetic disease.

Department of Pharmacology, University of Texas Health Sciences Center, San Antonio 78284.
Until recently alcoholism was regarded as being an incurable psychological problem. During the last decade a chain of research has led to a new insight into the causes and potential alleviation of alcohol craving: Recent discoveries indicate that the brain has receptor sites for naturally occurring opiate-like substances (endorphins and enkephalins) which are produced by the nervous system. Opiates such as morphine or heroin, and some of the metabolic products of alcohol (tetrahydroisoquinolines), can also attach themselves to these receptors. It has been further discovered that the craving for alcohol is related to a deficiency of the naturally occurring opiate-like substances as well as other neurotransmitter substances. This deficiency can occur genetically or as a result of prolonged stress or long-term heavy drinking. The neurochemical imbalance may be treated chemically, leading to a possible alleviation of the craving for alcohol, especially in conjunction with psychotherapeutic and counseling regimens.
Alcohol. 1987 Nov-Dec;4(6):449-56.

Enkephalinase inhibition: regulation of ethanol intake in genetically predisposed mice.

Department of Pharmacology, University of Texas Health Science Center, San Antonio 78234.
This is the first report of alteration in alcohol intake in mice with a genetic predisposition to alcohol preference and known to have innate brain enkephalin deficiencies. We have been able to significantly attenuate both volitional and forced ethanol intake respectively by acute and chronic treatment with hydrocinnamic acid and D-phenylalanine, known carboxypeptidase (enkephalinase) inhibitors. Since these agents, through their enkephalinase inhibitory activity, raise brain enkephalin levels, we propose that excessive alcohol intake can be regulated by alteration of endogenous brain opioid peptides.
Experientia. 1987 Apr 15;43(4):408-10.

Regional brain [Met]-enkephalin in alcohol-preferring and non-alcohol-preferring inbred strains of mice.

Scrutiny of the data from these studies reveals that the C58/J alcohol-preferring mice have significantly lower baseline methionine-enkephalin levels in both the corpus striatum and hypothalamus compared to C3H/CHRGL/2 non-alcohol-preferring mice. In other brain regions in these two strains, specifically, pituitary, amygdala, midbrain, and hippocampus, analysis of methionine-enkephalin levels did not show any significant differences. This suggests that the hypothalamus may indeed be a specific locus involved in the regulation of alcohol intake, via the molecular interaction between neuroamines, opioid peptides, as they are influenced by genetics and environment.
PMID: 3569490 [PubMed - indexed for MEDLINE]
Am J Drug Alcohol Abuse. 1987;13(3):365-72.

Alcohol and opioid peptides: neuropharmacological rationale for physical craving of alcohol.

Matrix Technologies, Inc., Houston, Texas 77058.
Until recently alcoholism was regarded as an incurable psychological problem. During the last decade a chain of research has led to important hypotheses about the etiology of the physical craving of alcohol. Recent discoveries indicate that the brain has receptor sites for naturally occurring opiatelike substances (endorphins, enkephalins, and dynorphins) which are produced by the nervous system. Opiates such as morphine or heroin and some of the metabolic products of alcohol (tetrahydroisoquinolines) can also attach themselves to these receptors. It has been further discovered that the physiological craving for alcohol may be the result of a deficiency of the naturally occurring opiatelike substances as well as other neurochemical deficits (i.e., dopaminergic, GABAergic, and serotonergic). These neurochemical deficits can occur genetically or as a result of long-term heavy drinking.
Funct Neurol. 1986 Apr-Jun;1(2):156-64.

Enkephalinase inhibition by thiorphan and subsequent response of ethanol, normorphine and enkephalins on mouse vas deferens.

In this study, a comparison was made between ethanol, normorphine methionine-enkephalin and [D-ala2] enkephalinamide and the ability of thiorphan, an enkephalinase inhibitor, to potentiate their in vitro activity to inhibit the electrically induced contractions of mouse vas deferens. Thiorphan did not significantly alter the response of either ethanol or normorphine on mouse vas deferens, whereas it significantly potentiated the response of methionine enkephalin.
PMID: 3301556 [PubMed - indexed for MEDLINE]
Experientia. 1985 Jul 15;41(7):932-3.

Methionine enkephalin as a possible neuromodulator of regional cerebral blood flow.

In swine, cerebral blood flow was documented by a left ventricular injection of radiolabeled 15-micron spheres. Utilizing this procedure, the effect of the putative neurotransmitter methionine-enkephalin on regional cerebral blood flow was systemically evaluated. Our results revealed that a peripheral infusion of methionine enkephalin into miniature swine significantly increased cerebral blood flow in the basal ganglia, cerebellum, pons, inferior parietal cortex and frontal cortex. Non-significant increases were observed in the hippocampus, occipital cortex and medulla oblongata while no effect on blood flow was observed in the pituitary gland. Significance of these results in the potential role of methionine enkephalin as a modulator of blood flow to the brain.
Alcohol Drug Res. 1985-1986;6(6):455-61.

Evidence for the importance of the "genotype" theory in alcohol seeking behavior: a commentary.

Consensus of the literature points towards a neuropsychogenetic model of alcoholism. Evidence in both animals and humans tends to support the proposed "genotype" theory of alcohol-seeking behavior, whereby a predisposition to alcohol preference may be mediated in part by either innate (genetic) or environmentally (stress and/or alcohol) induced brain opioid peptide dysfunction. Potential therapeutic rationale involving the utilization of novel inhibitors of carboxypeptidase A (enkephalinase) which raise endogenous enkephalin levels and possess anti-alcohol seeking effects is emphasized.
Eur J Pharmacol. 1984 Nov 13;106(2):415-7.

Supersensitivity to norepinephrine induced by prenatal exposure to ethanol.

Pregnant random bred mice were treated with ethanol (ETOH) (0.33 g/kg) for 1 or 2 days prior to parturition. When compared to saline controls, ETOH-treated adult males had vasa deferentia that were supersensitive to norepinephrine (NE). Tissues from mice prenatally treated for 1 day with ETOH showed a decreased response to electrical stimulation whereas vas deferens obtained from 2-day-treated ethanol showed no significant difference in the response compared to that of controls. These findings indicate that prenatal exposure to ETOH can influence the subsequent sensitivity of the vas deferens to adrenergic stimulation. These changes appear to reflect effects of ETOH during critical periods.
Proc Natl Acad Sci U S A. 1983 Nov;80(21):6510-2.

Ethanol acceptance as a function of genotype amounts of brain [Met]enkephalin.

Our results indicate a negative correlation between the amount of ethanol (10%) consumed and endogenous levels of brain [Met]enkephalin in C57BL/6J (alcohol-preferring) and DBA/2J (alcohol-nonpreferring) inbred mice strains. Additionally, it was found that 8 wk after 1-day starved groups of both C57BL/6J and DBA/2J mice were challenged with ethanol (10%) for 1-day acceptance, they had significantly lower levels of brain [Met]enkephalin compared with their nonalcohol-treated controls. These results suggest that the brain endogenous peptidyl opiates may play a crucial role in alcohol-seeking behavior.
Experientia. 1982 Dec 15;38(12):1469-70.

Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring c57BL mice.

These experiments systematically investigated ethanol preference in both the C57Bl/6N and C57Bl/6J mice utilizing three-choice 2-bottle preference test. In addition, these sublines were evaluated for whole brain methionine-enkephalin levels, which were significantly lower in C57Bl/6J mice (alcohol preferring) compared to C57Bl/6N mice (alcohol non-preferring). This finding supports the involvement of the peptidyl opiates in ethanol seeking behavior.
Science. 1982 Jun 25;216(4553):1425-7.

Reduced leucine-enkephalin--like immunoreactive substance in hamster basal ganglia after long-term ethanol exposure.

Golden Syrian hamsters were placed individually in cages with three drinking bottles--one empty, one containing water, and the third containing water and ethanol. Control hamsters received water only. After 1 year the experimental hamsters showed a significantly lower concentration of leucine-enkephalin-like immunoreactive substance in the basal ganglia than the control hamsters. This finding indicates that the action of ethanol involves endogenous peptidyl opiates.
Pharmacol Biochem Behav. 1982 Jan;16(1):13-5.

Ethanol intoxication as a function of genotype dependent responses in three inbred mice strains.

Three strains of mice, ICR Swiss, DBA/2J and C57Bl/6J were compared for initial sensitivity, recovery from intoxication, and acute tolerance development to ethanol. The The C57Bl/6J mice were found to be less sensitive and to recover more rapidly from the effects of the same dose of ethanol than the other two strains treated. None of the strains tested demonstrated acute tolerance to ethanol when given the same dose 3 hours later.
Alcohol Clin Exp Res. 1978 Apr;2(2):133-7.

Identification of an isoquinoline alkaloid after chronic exposure to ethanol.

A rapid and simple method for extraction of biogenic amines from small tissue samples was used to examine striata from ethanol-treated mice for TIQs. The results indicate that chronic ethanol administration can induce the formation of MSAL in striatal tissue.
Alcohol Clin Exp Res. 1978 Apr;2(2):113-20.

Putative role of isoquinoline alkaloids in alcoholism: a link to opiates.

Although the isoquinoline hypothesis has stimulated and even tantalized the scientific inquiry of a small number of investigators, it has been an area of widespread controversy. For the most part, until recently, alcohol researchers would ascribe very little importance to the role played by insoquinolines in alcohol actions or in the disease state known as alcoholism. To most, there was adequate evidence that these condensation amines had potent pharmacologic properties but little was known about their biochemical and behavioral interaction with ethanol or opiates. As pointed out here, there is an increasing amount of evidence that indicates the putative role of isoquinolines as regulators of alcohol dependence. There is even evidence that suggests a possible "link" to opiates. If this turns out to be the case, then it is rational to consider the possibility that when one imbibes alcohol a central opiate-like substance is, in essence, produced. It would appear that the sum total of evidence to date supports the notion that there are common territories between the two highly addictive classes of drugs--alcohol and opiates. Although still not definite, future studies may well confirm the intermediacy of the TIQ compounds.
Aviat Space Environ Med. 1977 Aug;48(8):705-7.

Alterations in brain electrolytes during acceleration in mice.

Calcium, magnesium, sodium, and potassium levels were determined in brain tissues of mice subjected to gravitational acceleration in the longitudinal direction. Although no significant changes occur in calcium and magnesium levels, potassium levels markedly increase while sodium levels decrease following exposure to 5 and 10 Gz for 5 min. The electrolyte changes are of long duration and remain for periods greater than 5 h.
PMID: 889543 [PubMed - indexed for MEDLINE]
Experientia. 1977 Jun 15;33(6):754-5.

Analgesic effects of 3-carboxysalsolinol alone and in combination with morphine.

A biphasic dose-response pattern is generated by the isoquinoline, 3-carboxysalsolinol, in analgesia tests conducted in mice. Carbidopa pretreatment enhances this effect, as well as the morphine-induced analgesic increase by 3-carboxysalsolinol. Naloxone blockade of all of these responses suggests an interaction of the alcohol-based isoquinoline with central opiate receptors.
Experientia. 1977 Feb 15;33(2):213-5.

Intensification of amphetamine-induced excitation by methysergide, a serotonergic receptor blocker.

Methysergide, a serotonergic receptor blocker, was studied to determine its effects against d-amphetamine-induced excitation as measured by convulsions elicited by handling in mice. Significant intensification (p less than 0.01) of the action of d-amphetamine was observed in mice. These results indicate that reduction in serotonergic activity in the central nervous system enhances excitation induced by d-amphetamine.
PMID: 844561 [PubMed - indexed for MEDLINE]
Clin Toxicol. 1977;11(4):459-72.

Peyote, a potential ethnopharmacologic agent for alcoholism and other drug dependencies: possible biochemical rationale.

The authors examine folk psychiatry among Native American Church members from an enthnopharmacologic viewpoint. Alcohol and opiate abuse among Indian and non-Indian are presented in case histories proving to be asymptomatic under Indian guidance and through participation in the peyote ritual. The biochemical alkaloids common in the peyote cactus, rather than just the psychoactive substances (mescaline), are purported to be pharmacologically similar to the neuroamine-derived alkaloids found in the brain during alcohol intoxification. Evidence is reviewed that points out possible common features of alcohol and opiate dependence leading to the speculation for a common mode of treatment may reside in plants rich in isoquinoline alkaloids.
J Pharm Pharmacol. 1976 Nov;28(11):832-5.

Enhancement of ethonol-induced withdrawal convulsions by blockade of 5-hydroxytryptamine receptors.

Male Swiss-Webster mice were made physically dependent on ethanol using the ethanol vapour inhalation technique. Animals pretreated with methysergide, a known 5-hydroxytryptamine receptor blocking agent, had significantly greater alcohol-induced withdrawal convulsions than saline pretreated controls. These findings suggest that the reduction of 5-HT at receptor sites may result in the augmentation of the withdrawal convulsions.
Experientia. 1976 Apr 15;32(4):493-5.

Suppression of ethanol withdrawal by dopamine.

An ethanol-inhalation technique was used to determine a potential relationship between dopamine and central nervous effects produced by alcohol. Both L-DOPA and intracranially injected dopamine resulted in attenuation of ethanol-induced withdrawal convulsion scores, whereas, haloperidol, a known dopaminergic blocker was found to significantly increase convulsion scores.
Experientia. 1976 Jan 15;32(1):79-82.

Morphine suppression of ethanol withdrawal in mice.

The acute administration of morphine, alcohol or dopamine results in a pronounced suppression of the convulsions produced by alcohol in mice. The suppressive action of morphine on alcohol withdrawal in the mouse apparently is not a product of morphine intoxication, but rather to some other specific interaction between alcohol and morphine in the central nervous system. The conclusion suggest that dopamine may play a significant role as a modulator in convulsions produced during alcohol withdrawal.
Am J Drug Alcohol Abuse. 1976;3(2):363-8.

Morphine withdrawal reactions in male and female mice.

In the present study we have used the morphine implantation method to investigate the intensity of the abstinence syndrome in both male and female Swiss Webster morphine-dependent mice. It is evident from our data that naloxone induced no significant difference in the jumping behavior of both morphine-dependent male and female mice when weight variables were controlled.
PMID: 1036445 [PubMed - indexed for MEDLINE]
Clin Toxicol. 1976;9(3):427-34.

Enhancement of alcohol withdrawal convulsions in mice by haloperidol.

Based on the data presented here and the clinical observations cited it would appear that although haloperidol has been used with a certain degree of success for the treatment of acute alcohol abstinence the authors would like to caution the clinician against widespread use of heloperidol for treatment of alcohol withdrawal. In experimentally induced ethanol withdrawal, chlordiazepoxide appears to be a more effective and safer agent for ameliorating symptoms associated with excitation such as tremor, insomnia, anxiety, and hyperexcitability. A double blind comparative clinical investigation between chlordiazepoxide and haloperidol for treatment of alcohol withdrawal is warranted.
Br J Pharmacol. 1974 May;51(1):109-11.

Effects of catecholamine synthesis inhibition on ethanol-induced withdrawal symptoms in mice.

alpha-Methyl-p-tyrosine, a catecholamine synthesis inhibitor, was studied to determine its effects against ethanol-induced withdrawal symptoms in mice. Signifilcant (P < 0.001) potentiation of the withdrawal convulsion score induced by ethanol vapour exposure for three days was observed in mice. The synergistic effect was not due to alteration of ethanol metabolism. These results indicate that reductions in catecholamines (dopamine and noradrenaline) augment seizure activity induced by subchronic exposure to ethanol.
Science. 1972 Apr 21;176(32):292-4.

Synergy of ethanol and putative neurotransmitters: glycine and serine.

The putative neurotransmitters, glycine and serine, significantly enhanced the sleeping time (loss of the righting reflex) that was induced by ethanol in mice. The observed synergistic effect between ethanol and the amino acids is probably not related to an alteration of ethanol metabolism, but rather to an interaction of these compounds in the central nervous system.

Pineal gland: evidence for an influence on ethanol preference in male Syrian hamsters.

Q J Stud Alcohol. 1973 Sep;34(3):937-9.

Effect of the pineal gland on alcohol consumption by congenitally blind male rats.

Nature. 1973 Apr 6;242(5397):407-9.

L-DOPA: effect on ethanol narcosis and brain biogenic amines in mice.

Pharmacology. 1973;9(5):294-9.

Synergy of ethanol and alcohol-like metabolites: tryptophol and 3,4-dihydroxyphenylethanol.

Curr Ther Res Clin Exp. 1973 Jan;15(1):25-30.

A possible relationship between the pineal gland and ethanol preference in the rat.

Eur J Pharmacol. 1972 Aug;19(2):218-22.

Diethanolamine: a possible weak agonist-antagonist to ethanol.

Curr Ther Res Clin Exp. 1972 Jun;14(6):324-9.

Effects of catecholamine synthesis inhibition on ethanol narcosis in mice.

Curr Ther Res Clin Exp. 1972 Apr;14(4):220-4.

The effects of low-dose combinations of D-amphetamine and cocaine on experimentally induced conflict in the rat.

Curr Ther Res Clin Exp. 1972 Feb;14(2):95-8.

Effects of vodka and bourbon on lever-pressing behavior of mice.

Br J Pharmacol. 1971 Sep;43(1):67-73.

Interaction effects of ethanol and pyrazole in laboratory rodents.

1. Interactions of pyrazole and ethanol were studied in three laboratory test procedures. They included sleeping time in mice, rotor rod balance in rats and lever pressing behaviour of rats.2. Equimolar concentrations of pyrazole and 3-methylpyrazole were compared for effects on enhancement of ethanol's activity on rotor rod holding time of rats.3. Minimally effective doses of pyrazole, the LADH inhibitor, and 3-methylpyrazole, a non-inhibitor of LADH, when administered before ethanol, resulted in an increased behavioural depression. These interaction effects are probably not caused by inhibition of LADH but rather by an increase in the direct depressant action of either one or both of the compounds.
PMID: 5136465 [PubMed - indexed for MEDLINE]
J Pharmacol Exp Ther. 1971 Aug;178(2):331-8.

The pharmacology of d- and l-carnitine and d- and l-acetylcarnitine. Comparison with choline and acetylcholine.

Psychopharmacologia. 1971;20(4):355-65.

Effects of nicotine, nicotine monomethiodide, lobeline, chlordiazepoxide, meprobamate and caffeine on a discrimination task in laboratory rats.

Res Commun Chem Pathol Pharmacol. 1970 May;1(3):383-94.

Protection against acute alcoholic intoication with diethanolamine-rutin.

Q J Stud Alcohol. 1970 May;5:Suppl 5:62-6.

Effects of vodka and bourbon on sleeping time in mice.

Arch Int Pharmacodyn Ther. 1969 Oct;181(2):297-306.
Psychopharmacologia. 1970;17(5):391-8.

Effects of chlordiazepoxide and pentobarbital on conflict behavior in rats.

Eur J Pharmacol. 1970 Mar;9(3):319-24.

The effects of 5-HTP on para-Chlorophenylalanine (p-CPA) attenuation of "conflict" behavior.

The effect of dopamine and other catecholamines on neuromuscular transmission.


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