title: Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: on the path to an animal model of attention-deficit hyperactivity disorder.
abstract: Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued the creation of a mouse model derived from a functional nonsynonymous variant in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD.
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Marc A
authors: MA
authors: Mergy
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Raajaram
authors: R
authors: Gowrishankar
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Gwynne L
authors: GL
authors: Davis
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Tammy N
authors: TN
authors: Jessen
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Jane
authors: J
authors: Wright
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Gregg D
authors: GD
authors: Stanwood
authors: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Maureen K
authors: MK
authors: Hahn
authors: Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: randy.blakely@vanderbilt.edu.
authors: Randy D
authors: RD
authors: Blakely
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics; D055879:Gene Knock-In Techniques; D006801:Humans; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics; D012677:Sensation / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008774:Methylphenidate; D000661:Amphetamine
keywords: ADHD; Animal model; Dopamine; Mouse; Transgenic; Transporter