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  Towards trans-diagnostic mechanisms in psychiatry: Neurobehavioral profile of rats with a loss of function point mutation in the dopamine transporter gene

Vengeliene, V., Bespalov, A., Rossmanith, M., Horschitz, S., Berger, S., Relo, A., et al. (2017). Towards trans-diagnostic mechanisms in psychiatry: Neurobehavioral profile of rats with a loss of function point mutation in the dopamine transporter gene. Disease Models Mechanisms, 10(4), 451-461. doi:10.1242/dmm.027623.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-C327-8 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-C7CF-7
Genre: Journal Article

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Vengeliene, V, Author
Bespalov, A, Author
Rossmanith, M, Author
Horschitz, S, Author
Berger, S, Author
Relo, AL, Author
Noori, HR1, Author              
Schneider, P, Author
Enkel, T, Author
Bartsch, P, Author
Schneider, M, Author
Behl, B, Author
Hansson, AC, Author
Schloss, P, Author
Spanagel, R, Author
Affiliations:
1Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, ou_persistent22              

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 Abstract: The Research Domain Criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here we used a new genetic rat model with a loss of function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix (www.nimh.nih.gov/research-priorities/rdoc/constructs/rdoc-matrix.shtml). First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains – negative and positive valence systems, cognitive, social, and in arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach, metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, well-established medications to reduce hyperactivity in humans. mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity.

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 Dates: 2017-04
 Publication Status: Published in print
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 Identifiers: DOI: 10.1242/dmm.027623
BibTex Citekey: VengelieneBRHBRNSEBSBHSS2017
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Title: Disease Models Mechanisms
Source Genre: Journal
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Pages: - Volume / Issue: 10 (4) Sequence Number: - Start / End Page: 451 - 461 Identifier: -