CB1R and CB2R were previously called central and peripheral cannabinoid receptors because Northern blot and conventional ISH methods only detected CB1R in brain regions and CB2R in peripheral tissues. Mouse CB1R expression in the brain is several thousand-fold higher than that of the liver, and mouse CB2R expression in the spleen is several hundred-fold higher than that of the brain. The classical tetrad effects of marihuana are hypomobility, hypothermia, analgesia, and catalepsy in rodents, and cannabinoid receptor 1 (CB1R) and 2 (CB2R) expressed in various tissues and cell types are the main receptors involved. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders. Alcohol conditioned place preference was abolished in DAT-Cnr2 Δ mice and remained intact in Cx3cr1-Cnr2 Δ mice in comparison to WT mice. Dat-Cnr2 Δ and Cx3cr1-Cnr2 Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Our data reveals that neuron and microglia CB2Rs are involved in the “tetrad” effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2′-chloroethylamide (ACEA), and CB2R selective agonist JWH133.
For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1 Δ, Dat-Cnr2 Δ, and Cx3cr1-Cnr2 Δ) of CB1R and CB2R by crossing Cnr1 f/f and Cnr2 f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver.
While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues.
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