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November 10, 2014
Vanderbilt University Medical Center
A darting mouse may hold an important clue in the development
ofAttention Deficit Hyperactivity Disorder (ADHD), autism and
bipolardisorder, according to a study. The transgenic mouse, into
which wasinserted a rare human genetic variation in the dopamine
transporter(DAT), could lead to improvements in the diagnosis and
treatment ofthese all-too-common brain disorders, said the report's
senior author.
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Credit: Image courtesy of Vanderbilt UniversityMedical
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ARelated Articles
Mice inserted with a rare human genetic variation in the
dopamine transportercould lead to improvements in the diagnosis and
treatment of brain disorders.
darting mouse may hold an important clue in the development
ofAttention Deficit Hyperactivity Disorder (ADHD), autism and
bipolardisorder, according to a study by a Vanderbilt
University-led research
team recently published in the Proceedings of the National
Academy ofSciences.
The transgenic mouse, into which was inserted a rarehuman
genetic variation in the dopamine transporter(DAT), could lead to
improvements in the diagnosis andtreatment of these all-too-common
brain disorders, saidRandy Blakely, Ph.D., the report's senior
author.
The mutation, which has been found in people withADHD, autism
and bipolar disorder, affects the functionof DAT, a protein that
regulates the brain's supply ofthe neurotransmitter by removing
excess dopaminefrom the synapse, or the space between nerve
cells.
The DAT mutation causes the transporter to become"leaky" and
spew out dopamine like "a vacuum cleaner
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in reverse," said Blakely, Allan D. Bass Professor
ofPharmacology.
While mice with leaky DAT proteins have too much dopamine
hanging around theirsynapses, surprisingly they aren't particularly
hyperactive, possibly because DAT canstill remove some of the
dopamine.
But the mice exhibit an unusual "darting behavior." While their
wild-type littermates aredocile and quite unresponsive when
researchers pick them up, those with the mutation"take off."
"Early on," Blakely said, "we could tell which ones carried the
mutation by observingthis response." Heightened anxiety does not
appear to be the cause.
Blakely and his colleagues wonder whether this behavior is a
form of "impulsivity."Rather than acting on their memories of being
picked up a lot, the mice are opting foran inappropriate escape
strategy.
Normal mice also stand up a lot to explore their cage. This
"rearing" behavior isexacerbated by stimulant drugs. But not in
these mice.
"We wonder whether this may be a sign that their behavior is
driven less by searchingfor clues to appropriate behavior versus
acting on innate impulses," Blakely said.
Other, better tests of impulsivity that evaluate premature
decision-making can beapplied in rodents and humans. "These tests
are next on our docket," he said.
The actions of amphetamine and methylphenidate (Ritalin) are
also affected by themutation. In normal animals and people without
ADHD, the stimulants flood thesynapse with dopamine, eliciting
hyperactivity.
But when given to the mutant animals, the drug demonstrates a
"blunted" effect onboth dopamine release and on locomotor
activation compared to normal animals.
Blakely wonders whether stimulants like Adderall and Ritalin
quell hyperactive andimpulsive behaviors in some children with ADHD
by reducing inappropriate dopamineleak. "These mice may give us
much better clues as to how these drugs are acting,"he said.
To that end, Blakely recently received a five-year, $2-million
grant from the NationalInstitutes of Health (NIH grant number
MH109054) to pursue explorations of thesemice.
"Dopamine has classically been implicated in reward and the
ability to detect noveltyand to respond to pleasure and to engage
in effective social interactions," hecontinued. The darting mice
thus might shed light on a much broader spectrum ofbehaviors.
"We've got a lot to do," he said, "a lot of needy people (to
help)."
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MLA APA Chicago
Vanderbilt University Medical Center. "'Darting' mice may hold
clues to ADHD,autism, bipolar disorder." ScienceDaily.
ScienceDaily, 10 November 2014..
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Story Source:
The above story is based on materials provided by Vanderbilt
University MedicalCenter. The original article was written by Bill
Snyder. Note: Materials may be editedfor content and length.
Journal Reference:
1. M. A. Mergy, R. Gowrishankar, P. J. Gresch, S. C. Gantz, J.
Williams, G. L. Davis,C. A. Wheeler, G. D. Stanwood, M. K. Hahn, R.
D. Blakely. The rare DAT codingvariant Val559 perturbs DA neuron
function, changes behavior, and alters invivo responses to
psychostimulants. Proceedings of the National Academy ofSciences,
2014; 111 (44): E4779 DOI: 10.1073/pnas.1417294111
Cite This Page:
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