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

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.