Dissociation of the Pharmacological Effects of THC by mTOR Blockade

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 38; no. 7; pp. 1334 - 1343
• Main Authors: PUIGHERMANAL, Emma, BUSQUETS-GARCIA, Arnau, GOMIS-GONZALEZ, Maria, MARSICANO, Giovanni, MALDONADO, Rafael, OZAITA, Andres
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.06.2013
• Subjects: Amnesia - chemically induced; Amnesia - prevention & control; Animals; Anti-Anxiety Agents - pharmacology; Anxiety; Anxiety - chemically induced; Anxiety - prevention & control; Behavior, Animal - drug effects; Behavior, Animal - physiology; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - physiology; Down-Regulation - drug effects; Drogues; Dronabinol - pharmacology; Drug dosages; Drug Interactions; Drug Tolerance; Efectes secundaris; Hypothermia; Hypothermia - chemically induced; Hypothermia - physiopathology; Hàbits i conducta; Kinases; Locomotion - drug effects; Locomotion - physiology; Male; Medical sciences; Memory; Mice; Mice, Knockout; Nociception - drug effects; Nociception - physiology; Original; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Tetrahydrocannabinol; THC; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - physiology; France; Spain; CBI cannabinoid receptor; delta9-tetrahydrocannabinol; Memory; Cannabinoid receptor; Mammalian target of rapamycin; Tolerance; mTOR pathway; Anxiety; Drug of abuse; Behavior; Dissociation; anxiety-like behavior
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2013.31

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.