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

Inés Ibarra‐Lecue, Irene Mollinedo-Gajate, J. Javier Meana, Luis Felipe Callado, Rebeca Dı́ez-alarcia, Leyre Urigüen

Neuropsychopharmacology April 27, 2018 DOI: 10.1038/s41386-018-0076-y (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Animal experimental study Peer reviewed
Population Mice exposed to chronic THC early in life
Intervention rapamycin
Topics Cannabis Serotonin
Citations 78
Key findings Chronic early THC exposure in mice induced a pro-hallucinogenic 5-HT2AR conformation and supersensitive coupling to inhibitory G-proteins, accompanied by exacerbated schizophrenia-like responses such as prepulse inhibition disruption; rapamycin blocked these changes. The authors propose this as a mechanistic link between adolescent cannabis exposure and later psychosis-like behaviors.

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 Δ 9 -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 effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

Comparable studies

Other preclinical and animal studies on cannabis, most cited first.

Study Year Design Participants
Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors Mice 2015 Preclinical study
Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). hMDR1- and hBCRP-transfected HEK293 cells and hMDR1- and hBCRP-MDCKII cells 2010 In vitro study
Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure Mice prenatally exposed to THC, including conditional CB1R knockout mice 2020 Animal experimental study
Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain Spontaneously hypertensive rats (SHRs) and Wistar rats 2014 Animal experimental study
Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors Rats 2018 Experimental study

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Cannabis Serotonin