Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB 1 receptors expressed in medium spiny neurons

Activation of cannabinoid 1 receptors (CB 1 R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB 1 R expressed by either excitatory or inhibitory neurons mediates different behavioural 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 behaviour 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. Our study demonstrates a new functional roles for cell specific CB 1 R expression and their causal link in the control of specific behaviors.