Progress in brain cannabinoid CB2 receptor research: From genes to behavior

Abstract

The type 2 cannabinoid receptor (CB2R) was initially regarded as a peripheral cannabinoid receptor. However, recent technological advances in gene detection, alongside the availability of transgenic mouse lines, indicate that CB2Rs are expressed in both neurons and glial cells in the brain under physiological and pathological conditions, and are involved in multiple functions at cellular and behavioral levels. Brain CB2Rs are inducible and neuroprotective via up-regulation in response to various insults, but display species differences in gene and receptor structures, CB2R expression, and receptor responses to various CB2R ligands. CB2R transcripts also differ between the brain and spleen. In the brain, CB 2A is the major transcript isoform, while CB 2A and CB 2B transcripts are present at higher levels in the spleen. These new findings regarding brain versus spleen CB2R isoforms may in part explain why early studies failed to detect brain CB2R gene expression. Here, we review evidence supporting the expression and function of brain CB2R from gene and receptor levels to cellular functioning, neural circuitry, and animal behavior.

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB1/CB2 versus GPR55 receptors

“…CB 2 receptors were previously considered peripheral receptors modulating the immune system (Atwood & Mackie, ; Buckley, ). However, this view has been challenged by recent findings indicating that functional CB 2 receptors are expressed in the brain (Jordan & Xi, ). Although brain CB 2 receptor levels are very low in healthy subjects, the expression of CB 2 receptors in the brain is dynamic and inducible and can be up‐regulated in response to various insults (Jordan & Xi, ; Zhang et al, , ).…”

“…However, this view has been challenged by recent findings indicating that functional CB 2 receptors are expressed in the brain (Jordan & Xi, ). Although brain CB 2 receptor levels are very low in healthy subjects, the expression of CB 2 receptors in the brain is dynamic and inducible and can be up‐regulated in response to various insults (Jordan & Xi, ; Zhang et al, , ). Strikingly, systemic or intracranial microinjections of Δ 9 ‐THC produced full tetrad effects in WT, while genetic deletion of CB 2 receptors blocked Δ 9 ‐THC‐induced analgesia and catalepsy but had no effect on Δ 9 ‐THC‐induced hypothermia and immobility, suggesting an involvement of brain CB 2 receptors .…”

“…(e-h) The effects of pretreatment with AM251, AM630, or CID16020046 on XLR11-induced tetrad in WT mice (n = 6 per group). # P < .05, as compared to the baseline before the XLR11 injection in each group; *P < .05, as compared to "Veh + XLR" group been challenged by recent findings indicating that functional CB 2 receptors are expressed in the brain (Jordan & Xi, 2019). Although brain CB 2 receptor levels are very low in healthy subjects, the expression of CB 2 receptors in the brain is dynamic and inducible and can be up-regulated in response to various insults (Jordan & Xi, 2019;Zhang et al, 2014Zhang et al, , 2017.…”

“…However, little is known about other non-CB 1 receptor mechanisms in cannabinoid action. We and others have recently reported that functional CB 2 receptors are also expressed in the brain (see a comprehensive review by Jordan & Xi, 2019) and are involved in multiple behavioural effects of Δ 9 -THC or other cannabinoids in experimental animals (DeLong, Wolf, Poklis, & Lichtman, 2010;Lesniak et al, 2019;Liu et al, 2017). Although, little is known if brain CB 2 receptors are also involved in cannabinoidinduced tetrad effects.…”

β‐Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents

“…However, clinical trials with rimonabant, a CB 1 receptor antagonist/inverse agonist, were terminated worldwide due to serious adverse effects such as depression and suicidality (Le Foll, Gorelick, & Goldberg, ). Since then, cannabinoid‐based medication development has shifted to other targets in the eCB system such as the CB 2 receptor (Jordan & Xi, ), fatty acid amide hydrolase (FAAH), or phytocannabinoids without psychotomimetic effects (Galaj, Bi, Yang, & Xi, ).…”