Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine β‐hydroxylase (DβH), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive‐compulsive, mania, alcohol abuse, and general anxiety‐behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique. © 1996 Wiley‐Liss, Inc.

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The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microsatellite polymorphism (AAT) n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls vs IV drug use showed a decrease in the frequency of the 4 allele, and the Ͻ4 alleles were rare, the alleles were divided into two groups, Ͻ5 and Ն5, and three genotypes Ͻ5/Ͻ5, heterozygotes, and Ն5/Ն5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the Ն5 repeat alleles showed the greatest effect. The number of IV drugs used was significantly greater for those carrying the Ն5/Ն5 genotype than for other genotypes (P = 0.005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways. Independent studies should be designed to further confirm the hypothesis that cannabinoid receptors may contribute to the susceptibility to drug abuse.

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.

Prior studies have reported an association between the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), pathological gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine whether we could replicate these associations we genotyped 737 individuals from four different groups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pathological gambling, TS, and ADHD. Chi-square analysis of those carrying the 7 allele versus non-7 allele carriers was not significant for any of the groups using a Bonferroni corrected alpha of.0125. However, chi-square analysis of those carrying any 5 to 8 allele versus noncarriers was significant for pathological gambling (p <.0001), ADHD (p

Abnormalities in monoamine oxidase (MAO) levels have been implicated in a wide range of psychiatric disorders. We have examined a VNTR polymorphism at the X-linked MAOA gene to test two hypotheses: (1) Do variants of the MAOA gene play a role in any of the behavioral disorders associated with Tourette syndrome or drug abuse? (2) If so, is there any correlation between the length of the alleles and the phenotypic effect? We examined two independent groups: 375 TS patients, relatives and controls, and 280 substance abusers and controls. The alleles were divided into four groups of increasing size. There was a significant association between the MAOA gene and behavioral phenotypes in both groups, and in both the longest alleles were associated with the greatest phenotypic effect. The strongest effect was for the diagnosis of drug dependence (P = 0.00003). The VNTR allele groups were in significant linkage disequilibrium with the Fnu4H1 polymorphism previously shown to be associated with MAO-A activity. While these results are consistent with the possibility that different-sized alleles of the short-repeat polymorphisms themselves may play a role in gene regulation, further studies directly linking these alleles with enzyme levels need to be done.

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...

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