title: Cadherin 13: humancis-regulation and selectively-altered addiction phenotypes and cerebral cortical dopamine in knockout mice.
abstract: The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5 choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factornpas4in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.
authors: Molecular Neurobiology, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Jana
authors: J
authors: Drgonova
authors: Molecular Neurobiology, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Donna
authors: D
authors: Walther
authors: Molecular Neurobiology, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: G Luke
authors: GL
authors: Hartstein
authors: Medicinal Chemistry, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Mohammad O
authors: MO
authors: Bukhari
authors: Medicinal Chemistry, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Michael H
authors: MH
authors: Baumann
authors: Medicinal Chemistry, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Jonathan
authors: J
authors: Katz
authors: Molecular Neurobiology, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Frank Scott
authors: FS
authors: Hall
authors: Molecular Neurobiology, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: Elizabeth R
authors: ER
authors: Arnold
authors: Dept of Psychology, American Univ, Washington, DC.
authors: Shaun
authors: S
authors: Flax
authors: Dept of Psychology, American Univ, Washington, DC.
authors: Anthony
authors: A
authors: Riley
authors: Translational Neurobiology, Dept Psychiatry, Univ Würzburg, Würzburg Germany.
authors: Olga
authors: O
authors: Rivero-Martin
authors: Translational Neurobiology, Dept Psychiatry, Univ Würzburg, Würzburg Germany.
authors: Klaus-Peter
authors: KP
authors: Lesch
authors: Div Neuropathology, Johns Hopkins Sch Med, Baltimore MD 21202.
authors: Juan
authors: J
authors: Troncoso
authors: Sanford-Burnham Med Res Inst, La Jolla CA 92037.
authors: Barbara
authors: B
authors: Ranscht
authors: Molecular Neurobiology, NIH-IRP, NIDA, Baltimore, Maryland 21224.
authors: George R
authors: GR
authors: Uhl
keywords: addiction; attention deficit hyperactivity disorder; cell adhesion molecule; cocaine; conditioned place preference