Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: on the path to an animal model of attention-deficit hyperactivity disorder.

Mergy MA, Gowrishankar R, Davis GL, Jessen TN, Wright J, Stanwood GD, Hahn MK, Blakely RD
Neurochem Int. 2014 73: 56-70

PMID: 24332984 · PMCID: PMC4177817 · DOI:10.1016/j.neuint.2013.11.009

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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Amphetamine Animals Attention Deficit Disorder with Hyperactivity Central Nervous System Stimulants Disease Models, Animal Dopamine Plasma Membrane Transport Proteins Gene Knock-In Techniques Humans Methylphenidate Mice Mice, Neurologic Mutants Mutation Sensation

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