Fig. 6.

Neural mechanisms underlying cannabinoid reward vs. aversion. CB₁Rs are expressed in VTA GABAergic neurons and glutamatergic neurons as well as their afferents projected from other brain regions to VTA DA neurons (data shown). CB₂Rs are found in VTA DA neurons. Cannabinoids modulate the mesolimbic DA system via activation of brain CB₁Rs and CB₂Rs. Cannabinoids such as Δ⁹-THC or WIN55,212-2 produce rewarding effects by binding to CB₁Rs on VTA GABAergic interneurons and/or their afferents, thereby reducing GABA-mediated disinhibition of VTA DA neurons and cannabinoid reward. Conversely, Δ⁹-THC or WIN55,212-2 may also produce aversive effects by activating CB₁Rs on glutamatergic neurons in the VTA or glutamatergic afferents, and CB₂Rs on midbrain DA neurons, thereby inhibiting VTA DA release to the NAc. The subjective effects of cannabinoids may thus depend on the balance of opposing CB1R and CB₂R effects and individual differences in expression of cannabinoid receptors. DA, dopamine; GABA, γ-aminobutyric acid; NAc, nucleus accumbens; VTA, ventral tegmental area.