neuropsychiatric disorders. However research on the involvement of CB2Rs in
neuroinflammatory conditions and in neuropathic pain has advanced in neuropsy-
chiatry and drug addiction more than other areas. Therefore, improved information
aboutCNR2gene and its human variants might add to our understanding, not only
the role of brain CB2Rs during neuroinflammatory conditions but also beyond
neuro-immuno-cannabinoid activity.
Several other functional studies have reveal roles for CB1Rs and CB2Rs.
However, our studies provided thefirst evidence for the CNS effects of CB2Rs and
its possible involvement in drug addiction and neuropsychiatric disorders (Ishiguro
et al. 2007 ; Onaivi et al. 2006 ,2008a,b; Uhl et al. 2006 ). We utilized behavioral
and molecular methods to study and determine whether there was a link between
depression that may be a risk factor in drug/alcohol addiction and brain CB2Rs.
First we established the use of mouse model of depression, i.e. the chronic mild
stress (CMS) model, which has been validated and a widely used model for
screening anti-depressants. Briefly the CMS model measures one of the core
symptoms of depression which is anhedonia, the inability to experience pleasure.
Then, mice were subjected daily for four weeks to CMS, and anhedonia was
measured by the consumption of sucrose solution. Behavioral and rewarding effects
of abused substances were determined in the CMS and control animals. The
expression of CB2Rs and their gene transcripts was compared in the brains of CMS
and control animals by Western blotting and real time (RT-PCR). CMS induced
gender-specific aversions in the test of anxiety which were blocked by the mixed
CB1R and CB2R agonist. In other studies we demonstrated that direct CB2R
antisense oligonucleotide microinjection into the mouse brain induced anxiolysis,
indicating that CB2Rs are functionally present in the brain and may influence
behavior (Ishiguro et al. 2007 ; Onaivi et al. 2006 ,2008a,b; Uhl et al. 2006 ).
10.9 Conclusion
The clinical and functional implication of neuronal CB2Rs in the brain will grad-
ually become clearer as more research will unravel their contribution in health and
disease. Knowledge from our data and recent studies that neuronal CB2Rs are
present in the brain raises many questions about their possible roles in the nervous
system. These results therefore extend the previous evidence that CB2Rs are
playing an important role in immune function to other putative neuronal function by
their apparent presence in neuronal processes. Our studies implicate neuronal and
glial CB2Rs in the CMS model of depression, and substance abuse. The
immunohistochemical localization of brain CB2Rs, when compared to that of
CB1Rs may be an indication of other putative functional roles of CB2Rs in the
CNS. Therefore both CB1Rs and CB2RS seem likely to work both independently
and/or cooperatively in differing neuronal populations to regulate important phys-
iological activities in the central nervous system. Events in the clinic have linked
the use of a CB1R antagonist, Accamplia, as an anti-obesity drug and an appetite
242 E.S. Onaivi et al.