Cannabinoid CB2 receptors modulate alcohol induced behavior, and neuro-immune dysregulation in mice.

The identification of additional lipid mediators, enzymes, and receptors revealed an expanded endocannabinoid system (ECS) called the endocannabinoidome (eCBome). Furthermore, eCBome research using wild type and genetically modified mice indicate the involvement of this system in modulating alcohol induced neuroinflammatory alterations associated with behavioral impairments and the release of proinflammatory cytokines. We investigated the role of cannabinoid type 2 receptors (CB2Rs) in modulating behavioral and neuro-immune changes induced by alcohol using conditional knockout (cKO) mice with selective deletion of CB2Rs in dopamine neurons (DAT-Cnr2) and in microglia (Cx3Cr1-Cnr2) cKO mice. We used a battery of behavioral tests including locomotor and wheel running activity, rotarod performance test, and alcohol preference tests to evaluate behavioral changes induced by alcohol. ELISA assay was used, to detect alterations in IL-6, IL-1α, and IL-1ß in the prefrontal cortex, striatum, and hippocampal regions of mice to investigate the role of CB2Rs in neuroinflammation induced by alcohol in the brain. The involvement of cannabinoid receptors in alcohol-induced behavior was also evaluated using the non-selective cannabinoid receptor mixed agonist WIN 55,212-2. The results showed that cell-type specific deletion of CB2Rs in dopamine neurons and microglia significantly and differentially altered locomotor activity and rotarod performance activities. The result also revealed that cell-type specific deletion of CB2Rs enhanced alcohol-induced inflammation, and WIN significantly reduced alcohol preference in all genotypes compared to the vehicle controls. These findings suggest that the involvement of CB2Rs in modulating behavioral and neuroinflammatory alterations induced by alcohol may be potential therapeutic targets in the treatment of alcohol use disorder.

Alcohol induced behavioral and immune perturbations are attenuated by activation of CB2 cannabinoid receptors.

The endocannabinoidome (eCBome) is the expanded endocannabinoid system (ECS) and studies show that there is a link between this system and how it modulates alcohol induced neuroinflammation. Using conditional knockout (cKO) mice with selective deletion of cannabinoid type 2 receptors (CB2Rs) in dopamine neurons (DAT-Cnr2) and in microglia (Cx3Cr1-Cnr2), we investigated how CB2Rs modulate behavioral and neuroinflammation induced by alcohol. Behavioral tests including locomotor and wheel running activity, rotarod performance test, and alcohol preference tests were used to evaluate behavioral changes induced by alcohol. Using ELISA assay, we investigated the level of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1α (IL-1α), and interleukin-1ß (IL-1ß) in the hippocampus of mice. The findings demonstrated that locomotor activity, wheel running, and rotarod performance activities were significantly affected by cell-type specific deletion of CB2Rs in dopamine neurons and microglia. The non-selective CB2R agonist, WIN 55,212-2, reduced alcohol preference in the wild type and cell-type specific CB2R cKO mice. In addition, the result showed that cell-type specific deletion of CB2Rs per se and administration of alcohol to CB2R cKO mice increased the expression of proinflammatory cytokines in the hippocampus. These findings suggest the involvement of CB2Rs in modulating behavioral and immune alterations induced by alcohol.