Format

Send to

Choose Destination
J Neurosci. 2018 Feb 21;38(8):1959-1972. doi: 10.1523/JNEUROSCI.1931-17.2018. Epub 2018 Jan 18.

Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats.

Author information

1
Fondazione Istituto Italiano di Tecnologia, Neuroscience and Brain Technologies Department Via Morego, 30 16163 Genoa, Italy.
2
Pavlov First Saint Petersburg State Medical University, Valdman Institute of Pharmacology, St. Petersburg, Russia.
3
Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Roma, Italy.
4
Università degli Studi di Milano, Department of Pharmacological and Biomolecular Sciences, Via Balzaretti 9, 20133 Milan, Italy.
5
University of Cagliari, Department of Biomedical Sciences, Cittadella Universitaria, 09042 Monserrato (CA), Italy.
6
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, North Carolina.
7
St. Petersburg State University, Institute of Translational Biomedicine, Universitetskaya Emb. 7-9, 199034 St. Petersburg, Russia.
8
Neuroscience Research, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland, and.
9
St. Petersburg State University, Institute of Translational Biomedicine, Universitetskaya Emb. 7-9, 199034 St. Petersburg, Russia, gainetdinov.raul@gmail.com.
10
Skolkovo Institute of Science and Technology, 143025 Moscow, Russia.

Abstract

Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms.SIGNIFICANCE STATEMENT Here, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.

KEYWORDS:

ADHD; BDNF; dopamine; dopamine transporter; rat knock-out

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center