Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB

Activation of cannabinoid 1 receptors (CB(1)R) modulates multiple behaviors, including exploration, motor coordination and response to psychostimulants. It is known that CB(1)R expressed by either excitatory or inhibitory neurons mediates different behavioral responses to CB(1)R activation, yet the involvement of CB(1)R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB(1)R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB(1)R in MSN on a CB(1)R knockout (KO) background (CB(1)R((MSN)) mice). The absence of cannabimimetic responses measured in CB(1)R KO mice was not rescued in CB(1)R((MSN)) mice, nor was decreased spontaneous locomotion, impaired instrumental behavior, or reduced amphetamine-triggered hyperlocomotion measured in CB(1)R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB(1)R KO mice were fully rescued in CB(1)R((MSN)) mice. Impaired motor coordination in CB(1)R-KO mice measured on the Rotarod was partially rescued in CB(1)R((MSN)) mice. Thus, CB(1)R expressed by MSN control exploration, motor coordination, and AS, demonstrating new functional roles for cell specific CB(1)R expression at the systems level and their causal link in the control of specific behaviors.