Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report. 887 16

The A1 (minor) allele of the D2 dopamine receptor (DRD2) gene has been shown to be associated with alcoholism, particularly the severe form of this disorder. This allele has also been found to be involved in a variety of other substance use disorders including, cocaine and nicotine dependence, polysubstance abuse and obesity. Moreover, reduced dopaminergic function has been found in subjects carrying the DRD2 A1 allele, suggesting that the DRD2 may be a reinforcement or reward gene. Analysis of the available data suggests that the DRD2 variants represent one of the most prominent single-gene determinants of susceptibility to severe alcoholism and other substance use disorders. However, environmental factors and other genes must, in combination, play the larger role.
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PMID:Polymorphisms of the D2 dopamine receptor gene and alcoholism and other substance use disorders. 897 14

The most common major comorbid disorders associated with eating disorders include substance use disorders, personality disorders, mood disorders, anxiety disorders, and obesity. To test conceptual models of the relationship between the eating disorders and these comorbid disorders, complex research paradigms are needed, including epidemiological studies, behavior-genetic studies, and longitudinal research designs. Comorbidity may be a significant factor to consider as approaches to the treatment of eating disorders continue to evolve.
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PMID:Eating disorders and comorbidity: empirical, conceptual, and clinical implications. 955 Aug 82

Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.
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PMID:Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications. 1076 57

Since 1990, association studies have amassed strong evidence implicating the D(2) dopamine receptor (DRD2) gene in alcoholism. Specifically, the TaqI A minor (A1) allele of the DRD2 gene has been associated with alcoholism. The DRD2 gene has also been found to be involved in other substance use disorders including cocaine, nicotine and opioid dependence, and obesity. Beyond association studies, pharmacologic studies have shown reduced brain D(2) dopamine receptor numbers in A1(+) allele carriers (A1A1 and A1A2 genotypes) compared to A1(-) allele carriers (A2A2 genotype). Through a number of other approaches, different phenotypes have also been identified in subjects with the A1(+) and A1(-) alleles. These include metabolic, neurophysiological, neuropsychological, personality, stress and treatment studies. It is hypothesized that in an effort to compensate for deficiencies in the dopaminergic system, substance abusers may seek to stimulate the mesocorticolimbic circuits of the brain, long thought to be important in behavioral reward and reinforcement. In effect, one form of the DRD2 gene, the A1 allele, renders the dopaminergic system inefficient and rewards substance abuse that increases brain dopamine levels.
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PMID:Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. 1088 Dec 3

The TaqIA D2 dopamine receptor (DRD2) minor (A1) allele was first associated with severe alcoholism a decade ago. Since then, studies both confirming and not confirmnning this finding were reported. However, a meta-analysis of a large number of Caucasian alcoholics (both more severe and less severe) and controls (both assessed and unassessed for substance use disorders) revealed a significantly higher frequency (p < 10(-6)) and prevalence (p < 10(-8)) of the DRD2 A1 allele in the alcoholics. Further analysis showed that the more severe alcoholics had a 3-fold higher prevalence of the DRD2 A1 allele than the assessed controls (p < 10(-10)), whereas no difference was found between the less severe alcoholics and the unassessed controls. DRD2 exonic or promoter mutations have not yet been associated with alcoholism, although two intronic variants at the TaqIB and intron 6 sites, which are in linkage disequilibrium with the TaqIA site, were associated with this disorder. Variants of the DRD2 gene have also been associated with cocaine, nicotine and opioid dependence, obesity and gambling. It is hypothesised that the DRD2 is a reinforcement or reward gene. Although less intensively studied than substance use disorders, the DRD2 gene has been implicated in Tourette's syndrome (TS), post-traumatic stress disorder (PTSD) and certain symptoms associated with affective disorders and schizophrenia. Further, DRD2 variants have been implicated in Parkinson's disease (PD) and in iatrogenically-induced movement disorders, as well as in certain migraineurs. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in the brain of subjects who carry the DRD2 A1 allele. In addition, phenotypic differences have been found in neurocognitive and personality characteristics, and in treatment outcome of DRD2 variants. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the prevention and treatment of these disorders.
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PMID:The DRD2 gene in psychiatric and neurological disorders and its phenotypes. 1125 81

The presentation and course of bipolar disorder differs between women and men. The onset of bipolar disorder tends to occur later in women than men, and women more often have a seasonal pattern of the mood disturbance. Women experience depressive episodes, mixed mania, and rapid cycling more often than men. Bipolar II disorder, which is predominated by depressive episodes, also appears to be more common in women than men. Comorbidity of medical and psychiatric disorders is more common in women than men and adversely affects recovery from bipolar disorder more often in women. Comorbidity, particularly thyroid disease, migraine, obesity, and anxiety disorders occur more frequently in women than men, whereas substance use disorders are more common in men. Although the course and clinical features of bipolar disorder differ between women and men, there is no evidence that gender affects treatment response to mood stabilizers. However, women may be more susceptible to delayed diagnosis and treatment. Treatment of women during pregnancy and lactation is challenging because available mood stabilizers pose potential risks to the developing fetus and infant. Pregnancy neither protects nor exacerbates bipolar disorder, and many women require continuation of medication during the pregnancy. The postpartum period is a time of high risk for onset and recurrence of bipolar disorder in women, and prophylaxis with mood stabilizers might be needed. Individualized risk/benefit assessments of pregnant and postpartum women with bipolar disorder are required to promote the health of the woman and avoid or limit exposure of the fetus or infant to potential adverse effects of medication.
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PMID:Gender differences in bipolar disorder. 1456

In order to survive, animals must acquire information about the reward value of stimuli in their environment. This process partly depends on the ability of the organism to make associations between the environmental context and the internal representation of value. While this type of learning probably evolved in order to promote behaviors that increase fitness (e.g., ingestive and sexual behavior), neuropsychological research utilizing addictive drugs, which are potent artificial reinforcers, has led to a deeper understanding of reinforcement mechanisms. Through these associations, sensory cues can acquire emotional salience and motivational properties. Exposure to drug-related cues in human addicts results in drug craving and localized activation of central circuits that are known to mediate cue-induced reinstatement of drug-seeking behavior in animal models of relapse. Similar regional activation patterns occur in humans in response to cues associated with foods. Furthermore, drug- and food-related cues not only activate common neuroanatomical regions but also result in similar activity-regulated gene expression programs within these shared areas. Here we discuss recent studies from our laboratory that investigate gene expression patterns elicited by exposure to palatable food- or drug-related cues. These studies suggest that the central nervous system stores and utilizes information about 'natural' and drug reinforcers in similar ways, both neuroanatomically and biochemically. These considerations may have important implications for the pharmacological and cognitive-behavioral treatments of substance use disorders, addiction, eating disorders, and obesity.
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PMID:Neural systems recruited by drug- and food-related cues: studies of gene activation in corticolimbic regions. 1613 15

We have advocated the idea of agonist therapy for treating cocaine addiction. This strategy involves administration of stimulant-like medications (eg, monoamine releasers) to alleviate withdrawal symptoms and prevent relapse. A major limitation of this approach is that many candidate medicines possess significant abuse potential because of activation of mesolimbic dopamine (DA) neurons in central nervous system reward circuits. Previous data suggest that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is important to consider when developing medications with reduced stimulant side effects. In this article, we discuss several issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, we discuss evidence supporting the existence of a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Then we summarize studies that have tested the hypothesis that 5-HT neurons can dampen the effects mediated by mesolimbic DA. For example, it has been shown that pharmacological manipulations that increase extracellular 5-HT attenuate stimulant effects produced by DA release, such as locomotor stimulation and self-administration behavior. Finally, we discuss our recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine DA-/5-HT-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers might be useful therapeutic adjuncts for the treatment of cocaine and alcohol addiction, obesity, and even attention deficit disorder and depression.
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PMID:Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions. 1740 32

The purpose of this study was to characterize the Night Eating Syndrome (NES) and its correlates among non-obese persons with NES, and to compare them to non-obese healthy controls. Nineteen non-obese persons with NES were compared to 22 non-obese controls on seven-day, 24-hour prospective food and sleep diaries, the Eating Disorder Examination and the Structured Clinical Interview for DSM-IV Diagnoses interviews, and measures of disordered eating attitudes and behavior, mood, sleep, stress, and quality of life. Compared to controls, persons with NES reported significantly different circadian distribution of food intake, greater depressed mood, sleep disturbance, disordered eating and body image concerns, perceived stress, decreased quality of life, and more frequent Axis I comorbidity, specifically anxiety, mood, and substance use disorders. These findings are the first to describe the clinical significance of night eating syndrome among non-obese individuals in comparison to a non-obese control group, and they suggest that NES has negative health implications beyond that associated with obesity.
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PMID:A descriptive study of non-obese persons with night eating syndrome and a weight-matched comparison group. 1854 94


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