--These results suggest the A1 allele of the DRD2 gene is associated with a number of behavior disorders in which it may act as a modifying gene rather than as the primary etiological agent.

Abnormalities in the dopaminergic reward pathways have frequently been implicated in substance abuse and addictive behaviors. Recent studies by Self and coworkers have suggested an important interaction between the dopamine D 1 and D 2 receptors in cocaine abuse. To test the hypothesis that the DRD1 gene might play a role in addictive behaviors we examined the alleles of the Dde I polymorphism in three independent groups of subjects with varying types of compulsive, addictive behaviors -Tourette syndrome probands, smokers and pathological gamblers. In all three groups there was a significant increase in the frequency of homozygosity for the DRD1 Dde I 1 or 2 alleles in subjects with addictive behaviors. The DRD1 11 or 22 genotype was present in 41.3% of 63 controls and 57.3% of 227 TS probands (P = 0.024). When 23 quantitative traits were examined by ANOVA those carrying the 11 genotype consistently had the highest scores. Based on these results, we examined the prevalence of the 11 genotype in controls, TS probands without a specific behavior, and TS probands with a specific behavior. There was a progressive, linear increase, significant at ␣ Յ 0.005 for scores for gambling, alcohol use and compulsive shopping. Problems with three additional behaviors, drug use, compulsive eating and smoking were significant at ␣ Յ 0.05. All six variables were related to addictive behaviors. In a totally separate group of controls and individuals attending a smoking cessation clinic, and smoking at least one pack per day, 39.3% of the controls versus 66.1% of the smokers carried the 11 or 22 genotype (P = 0.0002). In a third independent group of pathological gamblers, 55.8% carried the 11 or 22 genotype (P = 0.009 vs the combined controls). In the TS group and smokers there was a significant additive effect of the DRD1 and DRD2 genes. The results for both the DRD1 and DRD2 genes, which have opposing effects on cyclic AMP, were consistent with negative and positive heterosis, respectively. These results support a role for genetic variants of the DRD1 gene in some addictive behaviors, and an interaction of genetic variants at the DRD1 and DRD2 genes.

The factors responsible for producing some degree of order to the arrangement of chromatin in the nucleus are reviewed. They are following: 1. Chromosomes are attached to the nuclear membrane, nucleolus and intranuclear matrix. As a result they have a relatively fixed position in the nucleus. 2. In some species somatic pairing results in alignment of homologs. This is rare in mammals. 3. The association of ribosomal DNA and 5S DNA with the nucleolous results in the close approximation of the chromosomes carrying these DNA sequences. In man and other animals the most obvious consequence is satellite association. 4. Heterochromatin is condensed onto the inner nuclear membrane and periphery of the nucleolous while genetically active chromatin occupies the more central portion of the nucleus. The results is a peripheral location of late replicating DNA and a central location of early relicating DNA. 5. The DNA replication points tend to be associated with the nuclear matrix. Autoradiography of briefly labelled cells shows a high frequency of grains associated with nuclear matrix material. 6. Heterochromatin association results in chromocenters and ectopic pairing. 7. In addition to all these is the Rabl orientation or alignment of centromeres with centromeres and telomeres with telomeres. This polarization of the chromosomes results from the traction on the centromeres by the spindle fibers. There is no firm evidence for any higher degrees of order that might bring specific functioning genes into close proximity.

Cloninger (Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987: 236: 410-416) proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance, and reward dependence. He suggested that novelty seeking primarily utilized dopamine pathways, harm avoidance utilized serotonin pathways, and reward dependence utilized norepinephrine pathways. Subsequently, one additional temperament dimension (persistence) and three character dimensions (cooperativeness, self-directedness, and self-transcendence) were added to form the temperament and character inventory (TCI). We have utilized a previously described multivariate analysis technique (Comings DE, Gade-Andavolu R, Gonzalez N et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196; Comings DD, Gade-Andavolu R, Gonzalez N et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clin Genet 2000: in press) to examine the relative role of 59 candidate genes in the seven TCI traits and test the hypothesis that specific personality traits were associated with specific genes. While there was some tendency for this to be true, a more important trend was the involvement of different ratios of functionally related groups of genes, and of different genotypes of the same genes, for different traits.

As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling, known as pathological gambling. Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role. Polymorphisms at 31 different genes involved in dopamine, serotonin, norepinephrine, GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age, race, and sex-matched controls. Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable, and the 31 coded genes as the independent variables. Fifteen genes were included in the regression equation. The most significant were the DRD2, DRD4, DAT1, TPH, ADRA2C, NMDA1, and PS1 genes. The r(2) or fraction of the variance was less than 0.02 for most genes. Dopamine, serotonin, and norepinephrine genes contributed approximately equally to the risk for pathological gambling. These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling. Multi-gene profiles in specific individuals may be of assistance in choosing the appropriate treatment.

No abstract

No abstract

The above observations suggest that genetic variants of the CNR1 gene might be associated with a reduced amplitude of the P300 wave and with substance abuse.Keywords: drug abuse; marijuana; cannabinoid receptor;In the present manuscript we present data on 35 male ERP Caucasian subjects from an addiction treatment unit with drug dependence or drug and alcohol depenIn our prior study we observed a significant association between homozygosity for the Ն5 alleles of a microsatdence, suggesting the first is true. In a companion ellite polymorphism of cannabinoid receptor gene manuscript we present studies suggesting the second (CNR1) and drug dependence. Decreased amplitude of may also be true. Table 1 shows the result for the P300 amplitude for long been shown to be associated with alcohol and drug the three electrodes and two genotype groups. The dependence. The P300 wave reflects attentional amplitude was significantly lower for subjects carrying resource allocation and active working memory. Since the Ն5/Ն5 genotype for all three electrodes by marijuana intoxication has a potent blocking effect on MANOVA multivariate test (P = 0.028). The MANOVA short-term memory we examined the association univariate analysis showed that the effect was most sigbetween the CNR1 alleles and the P300 wave amplitude nificant for the P300 amplitude from the frontal lobes at three electrodes in 35 alcohol and drug addicts, by (P = 0.008). While the latency was also longer for the P300 wave of evoked related potentials (ERP) hasMANOVA. There was a significant decrease in amplitude of the P300 wave for all three electrodes (P = 0.028) that Ն5/Ն5 homozygotes for all three electrodes, this was was most marked for the frontal lobes (P = 0.008) in subnot significant for all three combined by MANOVA jects homozygous for the CNR1 Ն5 repeat alleles. Multi- (P = 0.192 The results of univariate regression analysis for the discriminate events.1 Depth electrode recordings in P300 amplitude and latency for all three electrodes are humans indicate that limbic and hippopcampal formashown in Table 2. With the Ն5/Ն5 homozygotes being tions are the subcortical structures involved in the generation of the P300 wave [2][3][4] and that the P300 wave is involved in the maintenance of working memory.5 Table 2 Multivariate regression analysis of the CNR1 genotypes Reduced amplitude of the P300 wave has been found in alcoholics, sons of alcoholics and drug addicts. scored as 2, and the other genotypes scored as 1, the Ն5/Ն5 genotype was a history of having been placed in a special education or learning disorder class. total r for amplitude was −0.446 and the r 2 was 0.20, indicating that the CNR1 gene accounted for 20% of the variance of the P300 amplitude (P = 0.008). The corMethods relation was only significant for the P300 from the frontal electrodes. The total r for latency was 0.36, and r 2 Subjects Thirty-five Caucasian male patients on the was 0.13, P = 0.035. The correlation was only signifiAddiction Treatment Unit of the Jerry L Pettis Veterans cant fo...