Dissociation of the pharmacological effects of THC by mTOR blockade.
Emma Puighermanal, Arnau Busquets-García, Maria Gomis-Gonzalez, Giovanni Marsicano, Rafaël Maldonado, Andrés Ozaita
Neuropsychopharmacology June 2013 DOI: 10.1038/npp.2013.31 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice, including conditional knockout mice lacking CB1 receptors in GABAergic or glutamatergic neurons |
| Interventions | Temsirolimus delta9-tetrahydrocannabinol (THC) |
| Topics | Cannabis |
| Key points | Temsirolimus, an mTOR inhibitor, prevented the anxiogenic- and amnesic-like effects of acute and chronic THC while leaving THC's anxiolytic, hypothermic, hypolocomotor, and antinociceptive effects intact. Chronic THC produced tolerance to the latter effects but not to the anxiogenic and amnesic effects. GABAergic CB1 receptors were mainly downregulated under chronic THC, and mice lacking these receptors did not develop cognitive deficits, suggesting mTOR inhibition can segregate THC's beneficial and negative effects. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 8
- Long-term consequences of adolescent cannabinoid exposure in adult psychopathology Frontiers in Neuroscience November 10, 2014
- Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway Neuropsychopharmacology April 27, 2018
- Cannabis sativa – A matter of physical, mental, and social health Eastern Journal of Medical Sciences December 20, 2022
- Effects of Cannabis on Glutamatergic Neurotransmission: The Interplay between Cannabinoids and Glutamate. Cells June 29, 2024
- Impairment of Synaptic Plasticity by Cannabis, Δ9-THC, and Synthetic Cannabinoids. Cold Spring Harbor perspectives in medicine May 3, 2021
and 3 more in the library
Cites 8
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