Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB1 receptors expressed in medium spiny neurons

Activation of cannabinoid 1 receptors (CB1R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB1R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB1R activation, yet the involvement of CB1R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB1R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB1R in MSN on a CB1R knockout (KO) background (CB1R(MSN) mice). The absence of cannabimimetic responses measured in CB1R KO mice was not rescued in CB1R(MSN) mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine-triggered hyperlocomotion measured in CB1R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB1R KO mice were fully rescued in CB1R(MSN) mice. Impaired motor coordination in CB1R KO mice measured on the Rotarod was partially rescued in CB1R(MSN) mice. Thus, CB1R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB1R expression and their causal link in the control of specific behaviors.

Automated summary

The study shows that CB1R expressed by MSNs play a crucial role in controlling exploration, motor coordination, and amphetamine sensitization. However, the effects on certain behaviors may only be partially or fully rescued.