title: Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia.
abstract: Clinical studies report associations between cannabis use during adolescence and later onset of schizophrenia. We examined the causal relationship between developmental cannabinoid administration and long-term behavioral and molecular alterations in mice. Mice were administered either WIN 55,212-2 (WIN), a cannabinoid receptor 1 (CB1) agonist or vehicle (Veh) during adolescence (postnatal day 30-35) or early adulthood (postnatal day 63-70). Behavioral testing was conducted after postnatal day 120 followed by biochemical assays. Adolescent cannabinoid treatment (ACU) leads to deficits in prepulse inhibition and fear conditioning in adulthood. Metabotropic glutamate receptors type 5 (mGluR5), a receptor critically involved in fear conditioning and endocannabinoid (eCB) signaling, is significantly reduced in the ACU mouse hippocampus. Next, we examined expression profiles of genes involved in eCB synthesis (diacylglycerol lipase (DGL)) and uptake (monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH)) in the experimental mice. We find evidence of increased MGL and FAAH in ACU mice, reflecting increases in eCB uptake and degradation. These data suggest that administration of cannabinoids during adolescence leads to a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations in sensorimotor gating and hippocampal-dependent learning and memory deficits. Further, these deficits are associated with a reduction in hippocampal mGluR5 and a sustained change in eCB turnover, suggesting reduced eCB signaling in the ACU hippocampus. These data suggest that significant cannabis use during adolescence may be a contributory causal factor in the development of certain features of schizophrenia and may offer mGluR5 as a potential therapeutic target.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Gleason
authors.forename: S G
authors.initials: SG
authors.lastname: Birnbaum
authors.forename: A
authors.initials: A
authors.lastname: Shukla
authors.forename: S
authors.initials: S
authors.lastname: Ghose
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000139:chemically induced; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007266:Inhibition, Psychological; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; C578936:Grm5 protein, mouse; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone