Cannabinoid Receptor Gene Variations in Neuropsychiatric Disorders

The ubiquitous cannabinoid receptors (CBRs) – probably the most abundant binding sites in the CNS - are known to be involved in a number of neuropsychiatric disturbances. CBRs are coded in human chromosomes 1 and 6 and activated by endocannabinoids, phytocannabinoids and marijuana use (medical/recreational use). The components of the endocannabinoid system (ECS) include CNR1 and CNR2 genes encoding these CBRs (CB1Rs and CB2Rs), endocannabinoids (eCBs), and their synthesizing and degradation enzymes are major targets of investigation for their impact in neuropsychiatry. Hence we have continued to study the influence of CBR variants in neuropsychiatric disorders. Many studies have shown that CNR1 and FAAH single nucleotide polymorphisms (SNPs) may contribute to drug addiction, depression, eating disorders, schizophrenia, and multiple sclerosis. But little attention has been paid to the neuronal and functional expression of CB2Rs in the brain and their role in neuropsychiatric disorders has been much less well characterized. Indeed our studies provided the first evidence for neuronal CNS effects of CB2Rs and their possible role in drug addiction, eating disorders, psychosis, depression and autism spectrum disorders (ASDs). In the current ongoing studies many features of CBR gene structures, SNPs, copy number variations (CNVs), CpG islands, microRNA regulation and the impact of CBR gene variants in neuropsychiatry and where possible in rodent models have been assessed. Although CNR1 gene has more CpG islands than CNR2 gene, both have CPG islands less than 300 bases, but they may be regulated by DNA methylation. MicroRNA binding to the 3′ untranslated region of the CNR1 gene with two polyadenylation sites may also potentially regulate CB1R expression. CNR1 gene has 4 exons and there are 135 SNPs reported in more than 1% of the population with no common SNP that changes amino acids of CB1R currently known or reported. A copy number variant (CNV) which is 19.5kb found in 4 out of 2026 people covers exons 3 and 4 and codes amino acid that could alter the expression of CB1Rs. CNR2 has 4 exons with CB2A with 3 exons and CB2B with 2 exons; and there are about 100 SNPs found in more than 1% of the population, which include common cSNPs that change amino acids of the CB2R, including R63Q, Q66R and H316Y. CNVs in Asian and Yoruba population have been reported. We also report on the identification of novel human and rodent CB2R isoforms, their differential tissue expression patterns and regulation by CBR ligands. Our findings also indicate increased risk of schizophrenia, depression, drug abuse, and eating and autism spectrum disorders in low CB2R function. Therefore, studying the CBR genomic structure, its polymorphic nature, subtype specificity, its variants and associated regulatory elements that confer vulnerabilities to a number of neuropsychiatric disturbances may provide deeper insight in unraveling the underlining mechanisms. Thus, understanding CBR variants and other components of the ECS may provide novel targets for the effects of cannabinoids in neuropsychiatry. Support R15DA032890 and WPUNJ.

Keywords: Cannabinoid, cannabinoid receptors, cannabinoid receptor genes, CNR1, CNR2, endocannabinoids, polymorphism, variants, CNVs, SNPs, cannabis, drug addiction, neuropsychiatric disorders.