Early 5‐ HT 6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse

Autor: Berthoux, Coralie, Hamieh, Al Mahdy, Rogliardo, Angelina, Doucet, Emilie L, Coudert, Camille, Ango, Fabrice, Grychowska, Katarzyna, Chaumont‐Dubel, Séverine, Zajdel, Pawel, Maldonado, Rafael, Bockaert, Joël, Marin, Philippe, Bécamel, Carine
Přispěvatelé: Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Department of Medicinal Chemistry, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Neuropharmacology Laboratory [Barcelone, Espagne], Universitat Pompeu Fabra [Barcelona] (UPF), Guerineau, Nathalie C., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: EMBO Molecular Medicine
EMBO Molecular Medicine, Wiley Open Access, 2020, 12 (5), pp.e10605. ⟨10.15252/emmm.201910605⟩
EMBO Molecular Medicine, 2020, 12 (5), pp.e10605. ⟨10.15252/emmm.201910605⟩
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201910605⟩
Popis: 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.
Early blockade of 5‐HT 6 receptor‐operated mTOR signaling could be a novel therapeutic strategy to prevent adult stage‐onset of cognitive deficits in cannabis abusers during adolescence.
Databáze: OpenAIRE
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