title: Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex.
abstract: Prenatal exposure to the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone) mesylate (WIN) at a daily dose of 0.5 mg/kg, and Delta9-tetrahydrocannabinol (Delta9-THC) at a daily dose of 5 mg/kg, reduced dialysate glutamate levels in frontal cerebral cortex of adolescent offspring (40-day-old) with respect to those born from vehicle-treated mothers. WIN treatment induced a statistically significant enhancement of Vmaxl-[3H]glutamate uptake, whereas it did not modify glutamate Km, in frontal cerebral cortex synaptosomes of adolescent rats. Western blotting analysis, performed either in membrane proteins derived from homogenates and in proteins extracted from synaptosomes of frontal cerebral cortex, revealed that prenatal WIN exposure enhanced the expression of glutamate transporter 1 (GLT1) and excitatory amino acid carrier 1 (EAAC1). Moreover, immunocytochemical analyses of frontal cortex area revealed a more intense GLT1 and EAAC1 immunoreactivity (ir) distribution in the WIN-treated group. Collectively these results show that prenatal exposure to the cannabinoid CB1 receptor agonist WIN increases expression and functional activity of GLT1 and EAAC1 glutamate transporters (GluTs) associated to a decrease of cortical glutamate outflow, in adolescent rats. These findings may contribute to explain the mechanism underlying the cognitive impairment observed in the offspring of mothers who used marijuana during pregnancy.
authors.affiliation: Section of Pharmacology, Department of Neuroscience, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60020 Ancona, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Castaldo
authors.forename: Simona
authors.initials: S
authors.lastname: Magi
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaetani
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.forename: Tiziana
authors.initials: T
authors.lastname: Antonelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Amoroso
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cuomo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage; D027342:Excitatory Amino Acid Transporter 2 / Q000819:agonists* / Q000502:physiology; D050580:Excitatory Amino Acid Transporter 3 / Q000819:agonists* / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D048588:Benzoxazines; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D005904:Glial Fibrillary Acidic Protein; D009025:Morpholines; D009281:Naphthalenes; C493398:Slc1a1 protein, rat; D018698:Glutamic Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol