title: Chronic exposure to cannabinoids during adolescence causes long-lasting behavioral deficits in adult mice.
abstract: Regular use of marijuana during adolescence enhances the risk of long-lasting neurobiological changes in adulthood. The present study was aimed at assessing the effect of long-term administration of the synthetic cannabinoid WIN55212.2 during adolescence in young adult mice. Adolescent mice aged 5 weeks were subjected daily to the pharmacological action of WIN55212.2 for 3 weeks and were then left undisturbed in their home cage for a 5-week period and finally evaluated by behavioral testing. Mice that received the drug during adolescence showed memory impairment in the Morris water maze, as well as a dose-dependent memory impairment in fear conditioning. In addition, the administration of 3 mg/kg WIN55212.2 in adolescence increased adult hippocampal AEA levels and promoted DNA hypermethylation at the intragenic region of the intracellular signaling modulator Rgs7, which was accompanied by a lower rate of mRNA transcription of this gene, suggesting a potential causal relation. Although the concrete mechanisms underlying the behavioral observations remain to be elucidated, we demonstrate that long-term administration of 3 mg/kg of WIN during adolescence leads to increased endocannabinoid levels and altered Rgs7 expression in adulthood and establish a potential link to epigenetic changes.
authors: Department of Psychiatry and Psychotherapy, University of Göttingen, Germany.|Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Germany.
authors: J
authors: J
authors: Tomas-Roig
authors: Research Group for Epigenetic Mechanisms in Dementia, German Center for Neurodegenerative Diseases (DZNE), Germany.
authors: E
authors: E
authors: Benito
authors: Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany.|Instituto de Investigación Sanitaria Galicia Sur, Spain.
authors: R C
authors: http://orcid.org/0000-0001-9899-9569
authors: RC
authors: Agis-Balboa
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Italy.
authors: F
authors: F
authors: Piscitelli
authors: Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, Developmental Biology, Germany.
authors: S
authors: S
authors: Hoyer-Fender
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Italy.
authors: V
authors: V
authors: Di Marzo
authors: Department of Psychiatry and Psychotherapy, University of Göttingen, Germany.|Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Germany.
authors: U
authors: U
authors: Havemann-Reinecke
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002186:Cannabinoids / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Adolescence; CA regions; DNA methylation and Rgs7; WIN55212.2; learning and memory