Dissociation of the pharmacological effects of THC by mTOR blockade.
Neuropsychopharmacol. 2013-01-28; 38(7): 1334-1343
DOI: 10.1038/npp.2013.31
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1. Neuropsychopharmacology. 2013 Jun;38(7):1334-43. doi: 10.1038/npp.2013.31. Epub
2013 Jan 28.
Dissociation of the pharmacological effects of THC by mTOR blockade.
Puighermanal E(1), Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R,
Ozaita A.
Author information:
(1)Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la
Salut, Universitat Pompeu Fabra, Barcelona, Spain.
The potential therapeutic benefits of cannabinoid compounds have raised interest
in understanding the molecular mechanisms that underlie cannabinoid-mediated
effects. We previously showed that the acute amnesic-like effects of
delta9-tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of
the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess
the relevance of the mTOR pathway in other acute and chronic pharmacological
effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR
pathway approved by the Food and Drug Administration, prevents both the
anxiogenic- and the amnesic-like effects produced by acute THC. In contrast,
THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not
sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced
anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after
chronic treatment, but not to its anxiogenic- and amnesic-like effects.
Temsirolimus pre-treatment prevented the amnesic-like effects of chronic THC
without affecting the downregulation of CB1 receptors (CB1R) induced by this
chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did
not prevent the residual cognitive deficit produced by chronic THC. Using
conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we
found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment
conditions, and CB1-GABA-KO mice did not develop cognitive deficits after chronic
THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation
of the potentially beneficial effects of cannabinoid agonists, such as the
anxiolytic and antinociceptive effects, from the negative effects, such as
anxiogenic- and amnesic-like responses. Altogether, these results provide new
insights for targeting the endocannabinoid system in order to prevent possible
side effects.
DOI: 10.1038/npp.2013.31
PMCID: PMC3656376
PMID: 23358238 [Indexed for MEDLINE]