Early 5-HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse.

Coralie Berthoux,Philippe Marin,Joël Bockaert,Emilie L Doucet,Rafael Maldonado,Fabrice Ango,Al Mahdy Hamieh,Carine Bécamel,Camille Coudert,Katarzyna Grychowska,Séverine Chaumont‐Dubel,Angelina Rogliardo,Pawel Zajdel

doi:10.15252/emmm.201910605

Abstract

Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5‐HT 6 receptor‐operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9‐tetrahydrocannabinol (THC) to mice during adolescence induces a long‐lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long‐term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5‐HT 6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5‐HT 6 receptor‐operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5‐HT 6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers.

Highlights

Cannabis is the most commonly used recreational drug worldwide, and the last 30 years have been marked by a dramatic increase in cannabis consumption at an increasingly early age by young people in most developed countries (Hall & Babor, 2000)
We show that this treatment induces a sustained activation of mechanistic Target Of Rapamycin (mTOR) signaling in prefrontal cortex (PFC), an alteration of both GABAergic and glutamatergic synaptic transmissions and impairment of long-term depression (LTD) in the PFC at layer I/V synapses and deficits in novel object recognition, sociability, and social discrimination in adulthood, which are all prevented by early administration of the 5-HT6 receptor antagonist SB258585 or the mTOR inhibitor rapamycin
In the present study, we showed that chronic exposure to THC during adolescence induces a sustained activation of mTOR signaling in the PFC but not in the hippocampus, reminiscent of previous observations in two neurodevelopmental models of schizophrenia, rats treated with phencyclidine at the neonatal stage or reared in social isolation after the weaning (Meffre et al, 2012)

Summary

Introduction

Cannabis is the most commonly used recreational drug worldwide, and the last 30 years have been marked by a dramatic increase in cannabis consumption at an increasingly early age by young people in most developed countries (Hall & Babor, 2000). It is conceivable that any interference with these maturational events such as chronic cannabis consumption during adolescence would lead to irreversible alterations of PFC connectivity and functionality that represent a risk factor for neuropsychiatric disorders in adulthood (Arseneault et al, 2004; Stefanis et al, 2004; Renard et al, 2014) Consistent with this hypothesis and underscoring the vulnerability of the adolescent brain to cannabis exposure, chronic administration of THC to adult rats (at similar doses to those injected in adolescent animals) does not reproduce the longlasting cognitive deficits observed in THC-injected adolescent animals (Spear, 2000; Rubino & Parolaro, 2013)

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Results

Conclusion