Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
Inés Ibarra-LecueLeyre Urigüen

Abstract

Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like eff...Continue Reading

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Jul 5, 2019·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Sophie Laguesse, Dorit Ron
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Aug 5, 2021·Psychopharmacology·Hiba Z VohraJavier González-Maeso
Aug 10, 2021·Frontiers in Psychiatry·Alex J MurrayRachel Upthegrove

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Methods Mentioned

BETA
saturation binding
scintillation spectrometry
scintillation proximity assay
Infrared Imaging

Software Mentioned

InVivoStat
GraphPad

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