10.1 Introduction
The historical perspectives ofCannabis sativaL. (Cannabaceae) and the products
thereof (such as marijuana—a complex mixture of cannabinoids and hashish have
been well documented in this book and elsewhere (ElSholy and Slade 2005 ).
Unfortunately research on the biological basis of the effects of marijuana and
therefore its usefulness as medicine, may have been hampered by several decades of
irrational prejudice. However the discovery of specific genes coding for cannabi-
noid receptors (CBRs) that are activated by marijuana use, and that the human body
makes its own marijuana-like substances called endocannabinoids that also activate
CBRs, has transformed marijuana-cannabinoid research into mainstream science
(Onaivi 2006 ). There are two types of CBRs (CB1Rs and CB2Rs) that are ubiq-
uitous and with the elements of the endocannabinoid system are now major targets
of investigation for their impact in health and disease including neurological and
mental disorders. Yet little attention had been paid to the neuronal and functional
expression CB2Rs in the brain and therefore their role in neuropsychiatric disorders
has been much less well characterized. Our studies provided thefirst evidence for
neuronal brain effects of CB2Rs and its possible role in neuropsychiatric disorders
(Onaivi et al. 2012 ). We have identified novel human and rodent CB1R and CB2R
isoforms with differential tissue expression patterns (Liu et al. 2009 ). So just like
CB1R gene variants, ourfindings also indicate increased risk of schizophrenia,
depression, drug abuse, and eating and autism spectrum disorders in low CB2R
function (Onaivi et al. 2015 ; Ishiguro et al.2010a,b). The nature of the interaction
between CB1Rs and CB2Rs has not been well studied and characterized,
nonetheless emerging evidence suggests that CB1 and CB2 receptors may work
independently and/or cooperatively in different neuronal populations to regulate
diverse physiological and biological functions in mental and neurological disorders.
Therefore, studying the CBR genomic structure, it’s polymorphic nature, subtype
specificity, their variants and associated regulatory elements that confer vulnera-
bilities to a number of mental disturbances may provide deeper insight in unrav-
eling the underlining mechanisms. Thus, understanding gene variants of
components of the endocannabinoid system may provide novel targets for the
effects of cannabinoids in health and disease. The role of CB2Rs in the immune
system, its therapeutic potential in pain, inflammation and consequently in
autoimmune and neurodegenerative disorders is receiving a great deal of attention
and the subject of a number of studies and reviews (Tanasescu and Constantinescu
2010 ; Jean-Gilles et al. 2015 ; Nagarkatti et al. 2010 ). Thus, as CB2Rs are asso-
ciated with immune regulation and function, it is of interest to probe the role of
CB2Rs not only in neurological disorders associated with neuro-inflammation but
also in neuropsychiatric disturbances. Of significant interest is that signaling via the
CB2 sub-type cannabinoid receptor is emerging as a key player in
immuno-endocannabinoid crosstalk (Borrman et al. 2016 ), that has been implicated
in pathogenic mechanisms of depression. This chapter is focused on the neurobi-
ology of the sub-type CB2 cannabinoid receptors and describes its gene structure,
228 E.S. Onaivi et al.