Abdalla Bowirrat

Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome.

In this review, we described the neural substrates underlying Reward Deficiency syndrome which, in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder that results from the interplay between genetic and environmental factors. The D2 dopamine receptor (DRD2) has been associated with pleasure, and the DRD2 A1 allele has been referred to as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine receptor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups having a greater tendency toward alcoholism than others. The DRD2 has been one of the most widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor, also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking, and related traits. The mesocorticolimbic dopaminergic pathway system plays an especially important role in mediating reinforcement by abused drugs, and it may be a common denominator for addictions such as alcoholism. When the mesocorticolimbic dopamine reward system dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency syndrome and subsequent drug‐seeking behaviors. Reward Deficiency syndrome refers to the breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings. A deficiency or absence of DRD2 receptors then predisposes individuals to a high risk for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g., glutamate, gamma‐aminobutyric acid (GABA), and serotonin) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html.

Prevalence of Alzheimer's type dementia in an elderly Arab population.

The aim of this study was to estimate the prevalence of dementia of the Alzheimer type (DAT) in an Arab Israeli community. Epidemiological studies of dementia have rarely been reported in Arab populations. The target population, aged 60 years or older, comprised 821 persons (362 males) who, on 1 October 1995, were residents of the rural area of Wadi Ara. These persons were examined for symptoms of dementia (DSM‐IV criteria), using a semistructured questionnaire for collection of demographic and medical data. Age, gender, and education‐specific prevalence rates were calculated for this population and compared to those obtained in other studies. DAT was diagnosed in 20.5% of this population. Its prevalence increased steeply with age, from 8% among those younger than 70 years to 33% among those aged 70–79 and 51% among those 80 years or older. Illiteracy was very common in this population, and strongly associated with higher prevalence of DAT (27% vs. 4%, P < 0.001). DAT was more prevalent among females than males (25% vs. 15%, P < 0.001). However, illiteracy was also significantly more frequent among women (96% vs. 42%, P < 0.001). After correction for illiteracy, the gender difference lost statistical significance. Few women smoked, but among men, the prevalence of DAT in those who smoked was lower as compared to non‐smokers (14% vs. 23%, a non‐significant difference). These results were confirmed by logistic regression wherein DAT was included as the dependent variable and age, illiteracy, gender and smoking as independent variables (OR=2.8, 2.8, 1.2 and 0.7, respectively; P < 0.005 for each, except for smoking). Our findings suggest that this population is unique because of extremely high rates of dementia. While the results support a protective effect of schooling against the development of dementia, other factors (e.g. genetic) must be sought to explain this high frequency.

Neurogenetics of Dopaminergic Receptor Supersensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART)

Abstract 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.

Sex, Drugs, and Rock ‘N’ Roll: Hypothesizing Common Mesolimbic Activation as a Function of Reward Gene Polymorphisms

Abstract The nucleus accumbens, a site within the ventral striatum, plays a prominent role in mediating the reinforcing effects of drugs of abuse, food, sex, and other addictions. Indeed, it is generally believed that this structure mandates motivated behaviors such as eating, drinking, and sexual activity, which are elicited by natural rewards and other strong incentive stimuli. This article focuses on sex addiction, but we hypothesize that there is a common underlying mechanism of action for the powerful effects that all addictions have on human motivation. That is, biological drives may have common molecular genetic antecedents, which if impaired, lead to aberrant behaviors. Based on abundant scientific support, we further hypothesize that dopaminergic genes, and possibly other candidate neurotransmitter-related gene polymorphisms, affect both hedonic and anhedonic behavioral outcomes. Genotyping studies already have linked gene polymorphic associations with alcohol and drug addictions and obesity, and we anticipate that future genotyping studies of sex addicts will provide evidence for polymorphic associations with specific clustering of sexual typologies based on clinical instrument assessments. We recommend that scientists and clinicians embark on research coupling the use of neuroimaging tools with dopaminergic agonistic agents to target specific gene polymorphisms systematically for normalizing hyper- or hypo-sexual behaviors.

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

Genetic and environmental risk factors for alzheimer’s disease in israeli arabs

Objective: We studied the genetic and environmental risk factors and prevalence, and incidence of dementia of the Alzheimer type (DAT) among the elderly in an Arab community in Israel. Background: Epidemiological and genetic studies of dementia have rarely been reported in an Arab population. Methods: All persons aged 60 years or older who were residents of the rural area of Wadi Ara were examined for identification of DAT, vascular dementia (VaD) and conversion from age related cognitive decline (ARCD) to DAT using DSM-IV criteria and a semi-structured questionnaire for collection of demographic and medical data. ApoE genotype was also determined. Total plasma homocysteine (tHcy) was determined using HPLC with fluorescence detection. Vitamins B12 and plasma folate were determined using a commercial radioisotope dilution kit assay (ICN). Results: DAT was diagnosed in 20.5% of this population. Its prevalence increased steeply with age. Illiteracy was very common, and strongly associated with higher prevalence of DAT. The annual incidence of DAT among ARCD cases was 4.4%. Subjects with ARCD who developed DAT were older than ARCD subjects who did not develop dementia. Hypertension was significantly more common among converted patients than among nonconverted. Illiteracy was insignificantly more common among those who developed DAT than among those who remained ARCD. Vascular dementia (VaD) constitutes about 22% of the total dementia population. We also confirm the association between VaD, illiteracy and hypertension. Smoking did not represent a risk factor for VaD. The survival rates among the three groups (healthy subjects, ARCD and DAT) was 80.5%, 58.8% and 55.5% respectively. Homocysteine levels were significantly higher than found in studies in Cleveland. Plasma B12 and plasma folate levels did not differ significantly between DAT patients and controls after adjusting for year of birth. Conclusions: Our findings suggest that the Wadi Ara population is unique because of high prevalence rates of dementia. We found old age, female gender and lack of education to be risk factors for the development of DAT. The ApoE □4; allele is relatively uncommon in this population and it cannot explain the high DAT prevalence. We also confirm the association between VaD, illiteracy and hypertension and older age and hypertension are risk factors for the transformation of ARCD to DAT.

Neuro-psychopharmacogenetics and Neurological Antecedents of Posttraumatic Stress Disorder: Unlocking the Mysteries of Resilience and Vulnerability.

Background and Hypothesis: Although the biological underpinnings of immediate and protracted trauma-related responses are extremely complex, 40 years of research on humans and other mammals have demonstrated that trauma (particularly trauma early in the life cycle) has long-term effects on neurochemical responses to stressful events. These effects include the magnitude of the catecholamine response and the duration and extent of the cortisol response. In addition, a number of other biological systems are involved, including mesolimbic brain structures and various neurotransmitters. An understanding of the many genetic and environmental interactions contributing to stress-related responses will provide a diagnostic and treatment map, which will illuminate the vulnerability and resilience of individuals to Posttraumatic Stress Disorder (PTSD). Proposal and Conclusions: We propose that successful treatment of PTSD will involve preliminary genetic testing for specific polymorphisms. Early detection is especially important, because early treatment can improve outcome. When genetic testing reveals deficiencies, vulnerable individuals can be recommended for treatment with “body friendly” pharmacologic substances and/or nutrients. Results of our research suggest the following genes should be tested: serotoninergic, dopaminergic (DRD2, DAT, DBH), glucocorticoid, GABAergic (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor, Monamine B, CNR1, Myo6, CRF-1 and CRF-2 receptors, and neuropeptide Y (NPY). Treatment in part should be developed that would up-regulate the expression of these genes to bring about a feeling of well being as well as a reduction in the frequency and intensity of the symptoms of PTSD.

Plasma homocysteine, vitamin B12 and folate in Alzheimer's patients and healthy Arabs in Israel

High plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and stroke and Alzheimers disease (AD). An inverse relationship has been reported between tHcy and plasma B12 and folate levels. Seventy-nine AD patients and 156 controls from three Arab villages in northern Israel participated. Plasma tHcy, B12 and folate levels were determined. Data were analyzed using univariate statistical tests and logistical regression with confounders. tHcy was significantly higher in AD patients (20.6+/-8.7 micromol/l) than in controls (16.4+/-6.5 micromol/l) (p=0.03) after correction for year of birth, gender and smoking status. Plasma B12 (322.9+/-136.0/350.5+/-175.3 pmol/l) and plasma folate (4.5+/-3.8/4.9+/-2.6 nmol/l) levels did not differ significantly between AD patients and controls. Subjects in the highest tHcy tertile or in the lowest B12 and folate tertiles did not have greater risk to develop AD. In this population residing in Arab villages in northern Israel, tHcy levels were significantly higher among AD patients than in controls. Plasma B12 and folate levels were lower among cases but were not significant. There was not a significant association between plasma tHcy, B12 and folate levels in controls or AD patients. High levels of tHcy may suggest the need for folate and vitamin B12 supplementation in this population.

Acute intravenous synaptamine complex variant KB220™ "normalizes" neurological dysregulation in patients during protracted abstinence from alcohol and opiates as observed using quantitative electroencephalographic and genetic analysis for reward polymorphisms: part 1, pilot study with 2 case reports.

Abstract It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or “normalizes” aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced “dopamine sensitivity” and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.

Vascular dementia among elderly Arabs in Wadi Ara.

Dementia of the Alzheimer type (DAT) and vascular dementia (VaD) are the two major subtypes of dementia. In our epidemiological study of DAT in an Arab community in Wadi Ara, Israel, we found a high prevalence of late onset DAT. Illiteracy, smoking, diabetes mellitus (DM) and hypertension are very frequent in Wadi Ara. These factors led us to study the prevalence of VaD and various risk factors in this population. All people aged 60 years or older (n=823) in a defined region were examined for identification of DAT and VaD (DSM-IV criteria), using clinical examinations and a semi-structured questionnaire for detecting cognitive dysfunction. We identified 49 demented patients (29 males) fulfilling criteria of VaD with a prevalence rate of 49/823 (5.9%), compared to 168/823 (20.5%) for DAT. All had suffered from strokes. Male gender and hypertension were more common among VaD cases. Illiteracy was significantly more common among VaD patients than among healthy subjects (79.6% vs. 40.2%, P=0.001) but less common than among DAT patients (94.6%, P=0.001). Thus, our results show that VaD constitutes about 22% of the total dementia population in Wadi Ara. We confirm the association between VaD, illiteracy and hypertension. Smoking and gender do not represent risk factors for VaD in this population. While suggestive, DM is not a statistically significant risk factor for VaD.