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

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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-HT6 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-HT6 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-HT6 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-HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers.

Original languageEnglish (US)
Article numbere10605
JournalEMBO Molecular Medicine
Volume12
Issue number5
DOIs
StatePublished - May 8 2020
Externally publishedYes

Keywords

  • 5HT receptor
  • adolescent cannabis abusers
  • cognitive deficits
  • mTOR
  • synaptic transmission

ASJC Scopus subject areas

  • Molecular Medicine

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