Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse

Abstract

A number of lines of evidence make the gene that encodes the G-protein-coupled CB1/Cnr1 receptor a strong candidate to harbor variants that might contribute to individual differences in human addiction vulnerability. The CB1/Cnr1 receptor is the major brain site at which cannabinoid marijuana constituents are psychoactive as well as the principal brain receptor for endogenous anandamide ligands. It is densely expressed in brain circuits likely to be important for both the reward and mnemonic processes important for addiction. Altered drug effects in CB1/Cnr1 knockout mice and initial association studies also make variants at the CB1/Cnr1 locus candidates for roles in human vulnerabilities to addictions. However, many features of this gene's structure, regulation and variation remain poorly defined. This poor definition has limited the ability of previous association studies to adequately sample variation at this locus. We now report improved definition of the human CB1/Cnr1 locus and its variants. Novel exons 1-3, splice variant and candidate promoter region sequences add to the richness of the CB1/Cnr1 locus. Candidate promoter region sequences confer reporter gene expression in cells that express CB1/Cnr1. Common polymorphisms reveal patterns of linkage disequilibrium in European-and in African-American individuals. A 5 0 CB1/Cnr1 'TAG' haplotype displays significant allelic frequency differences between substance abusers and controls in European-American, African-American and Japanese samples. Post-mortem brain samples of heterozygous individuals contain less mRNA transcribed from the TAG alleles than from other CB1/Cnr1 haplotypes. CB1/ Cnr1 genomic variation thus appears to play roles in human addiction vulnerability. Molecular Psychiatry (2004) 9, 916-931.

(AAT)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African-Caribbean population

“…Variability of these results could be explained by several confounding factors. Stratification bias could be the first of these factors because of the differences in allelic distribution among various ethnicities as it was recently demonstrated in a study by Zhang et al 16 In previous studies reviewed in Table 2, the most common allele types were the (AAT)15 and (AAT)16 in Chinese 17 and Japanese 19 controls, and the (AAT)13, (AAT)15 and (AAT)17 in French-Caucasian controls; 6 between African-American controls 16 and the AfricanCaribbean controls in the present study inconsistent results were found.…”

“…One other study found a positive association in African-American polysubstance abusers, but the authors did not discuss this result. 16 Three other studies did not confirm the association. The first one 17 was performed with heroin dependents in a male and female Chinese population.…”

Association study of the CNR1 gene exon 3 alternative promoter region polymorphisms and substance dependence

“…Using a case-control design, Comings et al (1997) reported an excess frequency of long (AAT) n repeats in a group of drug-dependent non-Hispanic Caucasians from Southern California (Comings et al 1997). Other groups have been unable to replicate this finding (Covault et al 2001;Heller et al 2001;Li et al 2000;Zhang et al 2004).…”

“…Single nucleotide polymorphisms (SNPs) adjacent to this site were reported to be associated with polysubstance abuse (Zhang et al 2004). We examined the association of 4 SNPs (rs6928499, rs806379, rs1535255, rs2023239) in the distal region of intron 2 of CNR1 both with individual substance dependence diagnoses (i.e., alcohol, cocaine, and opioids), as well as with polysubstance dependence.…”

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans

“…18 CNR1 polymorphisms were found to be associated with polysubstance abuse, including alcoholism. 19 Thus, cannabinoids, which are the main component of marijuana, act with exocannabinoids on the endocannabinoid system, which plays a significant role in vulnerability to development of addiction and other mental disturbances. 20 CNR2 may also be associated with addiction vulnerability as a modulator of the reward system.…”