10.5 Central Nervous System (CNS) Effects
and Distribution of CB2Rs
Our discovery of functional neuronal CB2Rs has successfully challenged the dogma
that CB2Rs are peripheral CBRs and that they are not expressed in neurons. We
have used multidisciplinary approaches including RT-PCR, in situ hybridization
RNAscope assay, immunoelectron and confocal microscopy, stereotaxic surgery
and behavioral assays to determine the CNS effects of CB2Rs. We have reported
that CB2Rs and their gene transcripts are expressed in different mouse brain regions
and are modulated following exposure to stressors and administration of drugs of
abuse and CB2R ligands alters mouse behavior in activity and plus-maze tests (Liu
et al. 2009 ; Onaivi et al.2008a,b, Onaivi 2009 ; Ishiguro et al. 2007 ,2010a,b;
Zhang et al. 2015 ). In addition to ourfindings other independent groups have
demonstrated a functional role for brain CB2Rs in terms of genetic association with
neuropsychiatric disorders, cellular distributions and neuronal localizations (lan-
ciego et al. 2011 ; Suarez et al. 2009 ), and pharmacological and behavioral effects
using CB2R transgenic mice (Callen et al. 2012 ; García-Gutiérrez et al. 2011, 2013 ;
Navarrete et al. 2013 ). While we and others have now resolved some of the con-
troversial issues associated with the detection and location of CB2Rs in the CNS,
by using CB2 isoform specific TaqMan probes that could differentiate the
isoform-specific expression patterns and are more sensitive and specific than the
CB2 probes and primers previously used (Onaivi et al.2008a,b; Liu et al. 2009 ),
the controversial CB2R brain expression could also be due to the low expression
levels of CB2A isoform in brain regions and the less specific CB2R commercial
antibodies in immunohistochemical studies, especially those studies using anti-
bodies against human hCB2 epitopes for rodent brain immunostaining. There are
also problems with the use of the CB2R KO mice (Buckley et al. 2000 ) in Western
blots and in behavioral analysis. When we analyzed the CB2 knockout mice using
the three TaqMan probes against two promoters of mouse CB2 gene and the deleted
Fig. 10.2 The development of Cnr2-floxed mouse model. Cnr2 gene (TSS: transcription start site)
has been selectively deleted in specific cell types by breeding them withaDAT-Cre and
bCx3cr1-Cre; dopamine and microglia promoter linked Cre recombinase mice. We have
generated DAT-Cnr2-Lox and Cx3cr1-Cnr2-Lox transgenic and their control littermates
234 E.S. Onaivi et al.