Cannabinoid conditioned reward and aversion: behavioral and neural processes

The discovery that delta-9-tetrahydrocannabinol (Δ(9)-THC) is the primary psychoactive ingredient in marijuana prompted research that helped elucidate the endogenous cannabinoid system of the brain. Δ(9)-THC and other cannabinoid ligands with agonist action (CP 55,940, HU210, and WIN 55,212-2) increase firing of dopamine neurons and increase synaptic dopamine in brain regions associated with reward and drug addiction. Such changes in cellular processes have prompted investigators to examine the conditioned rewarding effects of the cannabinoid ligands using the place conditioning task with rats and mice. As reviewed here, these cannabinoid ligands can condition place preferences (evidence for rewarding effects) and place aversions (evidence for aversive qualities). Notably, the procedural details used in these place conditioning studies have varied across laboratories. Such variation includes differences in apparatus type, existence of procedural biases, dose, number of conditioning trials, injection-to-placement intervals, and pre-training drug exposure. Some differences in outcome across studies can be explained by these procedural variables. For example, low doses of Δ(9)-THC appear to have conditioned rewarding effects, whereas higher doses have aversive effects that either mask these rewarding effects or condition a place aversion. Throughout this review we highlight key areas that need further research.