Abstract
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.