UC San Diego

Activation of cannabinoid 1 receptors (CB₁ R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB₁ R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB₁ R activation, yet the involvement of CB₁ R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB₁ R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB₁ R in MSN on a CB₁ R knockout (KO) background (CB₁ R_(MSN) mice). The absence of cannabimimetic responses measured in CB₁ R KO mice was not rescued in CB₁ R_(MSN) mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine-triggered hyperlocomotion measured in CB₁ R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB₁ R KO mice were fully rescued in CB₁ R_(MSN) mice. Impaired motor coordination in CB₁ R KO mice measured on the Rotarod was partially rescued in CB₁ R_(MSN) mice. Thus, CB₁ R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB₁ R expression and their causal link in the control of specific behaviors.