Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients

SIR – The mesolimbic dopaminergic system seems to be the main system responsible for the rewarding properties of the brain in response to abuse substances.1 The endocannabinoid system is in turn known to regulate the dopaminergic system through the CB1 presynaptic receptors. This property might well account for the role of these systems in learning, memory, behavior, as well as the reinforcing properties of abuse substances.2

The CB1 receptor is encoded by the CNR1 gene (6q14–q15), which is known to carry a nine-allele microsatellite polymorphism containing repeats of a single trinucleotide, ATT, which localizes to the 3′UTR of the gene and has been related to drug dependency states in Caucasian populations.3 Moreover, a link has been found between this polymorphism and the properties of the event-related wave p300,4 some studies having suggested that p300 variations might function as a marker for an underlying, hereditary, predisposition to alcoholism.5

Moreover, a direct relationship has been found between p300 wave fluctuations and attention deficit/hyperactivity disorder (ADHD).6 In recent years, the relationship between ADHD and addictions has been stressed.7 ADHD has been linked to the malfunctioning of catecholaminergic systems, which also play a fundamental role in the brain's rewarding system.8 These data suggest that the link between the cannabinoid system and the p300 wave could be related to some aspects of ADHD. In this study, we found a quantitative relationship between the largest-sized alleles of the CNR1 gene and the presence of ADHD during childhood in Spanish male alcoholic patients.

This study was conducted with 107 male alcoholic patients below the age of 50 years both with and without ADHD antecedents during childhood. Other 92 male individuals were taken as controls, and were also subject to a genetic study. Such study was preceded by a clinical interview to ensure the absence of disorders because of substance abuse. Alcohol dependency was assessed with a structured clinical interview for DSM-IV (SCID 4.0). ADHD was diagnosed by doing semistructured clinical interviews to patients and their relatives. Such interviews contained DSM-IV criteria for ADHD, and the validated Spanish version of the Wender-Utah Rating Scale (WURS) was used.9 The Cloninger three-dimensional questionnaire was used to assess personalities. PCR amplification was performed with the primers 5′-IndexTermGCTGCTTCTGTTAACCCTGC-3′ and 5′-IndexTermTCCCACCTATGAGTGAGAACAT-3′. The PCR was performed in a 10 μl reaction volume containing 2.5 mM MgCl2, DMSO (4%) and α-dCTP,32 with 58°C being the annealing temperature. Nine allelic types were identified in autoradiographs of polyacrylamide gels and distributed according to Comings et al,3 so that the shorter alleles (<5) were separated from the longer ones (≥5). This led to three different genotypes (<5/<5, <5/≥5, and ≥5/≥5), which were analyzed as a qualitative variable. Statistical calculations were performed with the SPSS statistical package.

In comparison with non-ADHD patients and control individuals, those alcoholic patients who suffered from ADHD during childhood were found to carry the longer forms of alleles (≥5) (χ2=9.665, df=2, P=0.008 and χ2=8.525, df=2, P=0.014, respectively). Moreover, the average in WURS score is greater in individuals homozygous for the ≥5 forms than in the <5 homozygous individuals, with the heterozygous lying in between. Such difference is statistically significant for the overall score (ANOVA, F=3.210; P=0.044) and for factor 4, which contains items specifically related to inattention (ANOVA, F=4.209; P=0.017). A grading of the results was observed, which probably indicates a quantitative influence of the different alleles. It has been suggested that the microsatellites might form Z-DNA structures and thereby may play a role in gene regulation, and that the magnitude of the effect could be dependent upon the length of the repeats.10 The number of ATT repeats of the allele with the greatest score for each genotype was taken as a quantitative variable. A statistically significant correlation was also observed between allele sizes and WURS scores, and also with the novelty seeking score (see Table 1), in agreement with previous studies that relate novelty seeking with ADHD.

Table 1 Correlation between the number of repeats of the genotype's longest allele with the WURS and TCI scales

The case–control design used in this study may give rise to spurious associations influenced by population stratification. This study is preliminary, and a family-based study will be useful to verify these associations.

To the best of our knowledge, this is the first study relating the CNR1-gene polymorphisms with ADHD in alcoholic patients. These data are consistent with the fact that the cannabinoid system is known to affect dopaminergic transmission, with the malfunctioning of the dopaminergic system being regarded as a potential physiopathological cause of ADHD. Further studies are needed to determine the functional basis of the observed association.

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Correspondence to J Hoenicka.

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Ponce, G., Hoenicka, J., Rubio, G. et al. Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients. Mol Psychiatry 8, 466–467 (2003). https://doi.org/10.1038/sj.mp.4001278

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