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.
