isoforms and their human and rodent variants should be carefully considered in the
development of CB2R based therapeutic agents (Liu et al. 2009 ; Zhang et al. 2004 ).
The ubiquitous CBRs and other elements of the eCB system are probably the
most abundant binding sites in the CNS and are known to be involved in most
biological processes with impact on psychological and neuropsychiatric disorders.
Therefore the eCB system has been implicated in the regulation of a variety of
physiological processes, including a crucial involvement in brain reward systems
and the regulation of motivational processes (Vlachou and Panagis 2014 ).
Gene-environment interactions likely play a significant role in the pathogenesis of
schizophrenia (Kannan et al. 2013 ) and underlie differences in pathological,
behavioral, and clinical presentations (Kannan et al. 2013 ). Such gene-environment
interactions can be extended to depression, bipolar disorders, Tourette syndrome,
drug reward and addiction, and appetite (dys) regulation in obesity. Now many
studies (summarized in Table10.1), have shown thatCNR1andFAAHSNPs may
contribute to these disorders. In our ongoing studies many features of CBR gene
structures, SNPs, CNVs, CPG island, microRNA regulation and the impact in
neuropsychiatry and where possible in rodents models are evaluated. Accumulating
evidence suggests the importance of CNVs in the etiology of neuropsychiatric
disorders (Horev et al. 2011 ). The clinical consequences of CNV in the coding and
non-codingCNRgene sequences associated with human phenotypes and disorders
are mostly unknown and under investigation. Advances in genomic technologies
and the analysis and identification ofCNRgene CNVs may uncover the relationship
(if any), betweenCNRgene CNVs to phenotype and disease. WhileCNR1and
CNR2SNPs have been associated with a number of neuropsychiatric disorders (see
Table10.1focused on CB2R polymorphisms), it is unclear to what extentCNR
gene CNVs are involved in psychological and psychiatric disorders. Therefore,
more studies are needed to determine the role and contribution ofCNRgene CNV
to conditions of eCB dysregulation in psychological and psychiatric disorders.
10.8 CB2Rs as Potential Therapeutic Target
in Neurological and Mental Diseases
For many years it was thought that marijuana use, phytocannabinoids and eCBs act
by activating brain-type cannabinoid receptors called CB1Rs. A second type of
cannabinoid receptor was found in peripheral tissues and mainly in immune cells
and was referred to as peripheral CB2Rs. This was because many investigators were
not able to detect the presence of neuronal CB2Rs in healthy brains (Galiegue et al.
1995 ; Griffin et al. 1999 ; Munro et al. 1993 ).
Functional neuronal CB2Rs have ignited debate and controversy on its possible
involvement in drug addiction and neuropsychiatric disorders. While the role of
CB2Rs in CNS disturbances involving neuroinflammation and neuropathic pain
have been extensively reported, our studies provided evidence for a role of CB2-Rs
240 E.S. Onaivi et al.