title: Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model.
abstract: Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Takano
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Katashiba
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Atsuki
authors.initials: A
authors.lastname: Taruta
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Higashino
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Electronic address: matsuda@phs.osaka-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000139:chemically induced / Q000378:metabolism*; D015306:Biogenic Monoamines / Q000032:analysis; D003342:Corpus Striatum / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D005260:Female; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D014635:Valproic Acid / Q000633:toxicity
chemical_list: D015306:Biogenic Monoamines; D016760:Proto-Oncogene Proteins c-fos; D011954:Receptors, Dopamine; D008694:Methamphetamine; D014635:Valproic Acid; D004298:Dopamine
keywords: Autism model; Dopamine; Methamphetamine; Prefrontal cortex; Valproic acid