Dissecting the role of CB1 and CB2 receptors in cannabinoid reward versus aversion using transgenic CB1- and CB2-knockout mice

Cannabinoids produce both rewarding and aversive effects in humans and experimental animals. However, the mechanisms underlying these conflicting findings are unclear. Here we examined the potential involvement of CB₁ and CB₂ receptors in cannabinoid action using transgenic CB₁-knockout (CB₁-KO) and CB₂-knockout (CB₂-KO) mice. We found that Δ⁹-tetrahydrocannabinol (Δ⁹-THC) induced conditioned place preference at a low dose (1 mg/kg) in WT mice that was attenuated by deletion of the CB₁ receptor. At 5 mg/kg, no subjective effects of Δ⁹-THC were detected in WT mice, but CB₁-KO mice exhibited a trend towards place aversion and CB₂-KO mice developed significant place preferences. This data suggests that activation of the CB₁ receptor is rewarding, while CB₂R activation is aversive. We then examined the nucleus accumbens (NAc) dopamine (DA) response to Δ⁹-THC using in vivo microdialysis. Unexpectedly, Δ⁹-THC produced a dose-dependent decrease in extracellular DA in WT mice, that was potentiated in CB₁-KO mice. However, in CB₂-KO mice Δ⁹-THC produced a dose-dependent increase in extracellular DA, suggesting that activation of the CB₂R inhibits DA release in the NAc. In contrast, Δ⁹-THC, when administered systemically or locally into the NAc, failed to alter extracellular DA in rats. Lastly, we examined the locomotor response to Δ⁹-THC. Both CB₁ and CB₂ receptor mechanisms were shown to underlie Δ⁹-THC-induced hypolocomotion. These findings indicate that Δ⁹-THC’s variable subjective effects reflect differential activation of cannabinoid receptors. Specifically, the opposing actions of CB₁ and CB₂ receptors regulate cannabis reward and aversion, with CB₂-mediated effects predominant in mice.