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