The consequences of lighting up


Chronic cannabis use has been associated with defects in the regions of the brain, such as the cerebellum, that regulate motor control, but how the active component of the drug, THC, mediates these defects is incompletely understood. Laura Cutando and colleagues exposed mice to sub-chronic doses of THC and observed deficiencies in learning and coordination associated with brain inflammation and downregulation of the THC receptor CB1R. Furthermore, Cutando and colleagues found that the defects in these animals could be prevented by treatment with an anti-inflammatory agent. This work suggests that brain inflammation resulting from decreased CB1R is directly related to the learning and motor coordination side effects associated with cannabis consumption. The accompanying image shows the expression of CB1R red) in mouse cerebellum after 5 days of treatment with vehicle (left), THC-5 (middle), or THC-20 (left).  

Published June 24, 2013, by Jillian Hurst

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Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure
Laura Cutando, Arnau Busquets-Garcia, Emma Puighermanal, Maria Gomis-González, José María Delgado-García, Agnès Gruart, Rafael Maldonado, Andrés Ozaita
Laura Cutando, Arnau Busquets-Garcia, Emma Puighermanal, Maria Gomis-González, José María Delgado-García, Agnès Gruart, Rafael Maldonado, Andrés Ozaita
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Research Article

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

Abstract

Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1β. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1–/– mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1–/– and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure.

Authors

Laura Cutando, Arnau Busquets-Garcia, Emma Puighermanal, Maria Gomis-González, José María Delgado-García, Agnès Gruart, Rafael Maldonado, Andrés Ozaita

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