title: Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex.
abstract: Current concepts suggest that exposure to THC during adolescence may act as a risk factor for the development of psychiatric disorders later in life. However, the molecular underpinnings of this vulnerability are still poorly understood. To analyze this, we investigated whether and how THC exposure in female rats interferes with different maturational events occurring in the prefrontal cortex during adolescence through biochemical, pharmacological and electrophysiological means. We found that the endocannabinoid system undergoes maturational processes during adolescence and that THC exposure disrupts them, leading to impairment of both endocannabinoid signaling and endocannabinoid-mediated LTD in the adult prefrontal cortex. THC also altered the maturational fluctuations of NMDA subunits, leading to larger amounts of gluN2B at adulthood. Adult animals exposed to THC during adolescence also showed increased AMPA gluA1 with no changes in gluA2 subunits. Finally, adolescent THC exposure altered cognition at adulthood. All these effects seem to be triggered by the disruption of the physiological role played by the endocannabinoid system during adolescence. Indeed, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses. These results suggest that vulnerability of adolescent female rats to long-lasting THC adverse effects might partly reside in disruption of the pivotal role played by the endocannabinoid system in the prefrontal cortex maturation.
authors.affiliation: Department of Theoretical and Applied Science, Biomedical Research Division, and Neuroscience Center, University of Insubria, 21052 Busto Arsizio, VA, Italy. Electronic address: tiziana.rubino@uninsubria.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.affiliation: Department of Theoretical and Applied Science, Biomedical Research Division, and Neuroscience Center, University of Insubria, 21052 Busto Arsizio, VA, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Prini
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli, NA, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Department of Theoretical and Applied Science, Biomedical Research Division, and Neuroscience Center, University of Insubria, 21052 Busto Arsizio, VA, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Zamberletti
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), 16163 Genova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Trusel
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, CA, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.affiliation: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, CA, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sagheddu
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli, NA, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), 16163 Genova, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Tonini
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli, NA, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Department of Theoretical and Applied Science, Biomedical Research Division, and Neuroscience Center, University of Insubria, 21052 Busto Arsizio, VA, Italy; Zardi Gori Foundation, 21100 Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000367:Age Factors; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D003511:Cyclohexanols / Q000493:pharmacokinetics; D002658:Developmental Disabilities / Q000139:chemically induced*; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D013759:Dronabinol / Q000494:pharmacology*; D004958:Estradiol / Q000097:blood; D030762:Estrous Cycle / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D066298:In Vitro Techniques; D016501:Neurites / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D011720:Pyrazoles / Q000494:pharmacology; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011720:Pyrazoles; D017470:Receptors, Glutamate; D014316:Tritium; C103505:AM 251; D004958:Estradiol; D016291:Dizocilpine Maleate; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
keywords: AMPA receptors; Adolescence; Endocannabinoid system; NMDA receptors; Prefrontal cortex; Spine density; THC