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

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. 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.

Novelty‐related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns

“…This difference can be ascribed to different maturation of central nervous system since, during the transition from preadolescence to adulthood, the limbic system and PFC mature differentially. While adolescent behavior typically shows less habituation, due to innate curiosity and age‐related hyperactivity, DAT‐KO adolescents paradoxically exhibited less restless arousal, consistently with calming effects of psychostimulants …”

“…However, generally rats remain a most preferable model in behavioral neuroscience due to their more developed cognitive skills, allowing operant testing as it was performed on other ADHD rat models like SHR and NHE rats. 40 Just recently DAT-KO rats were developed (see 12 ), however, to be validated as a promising model for ADHD, they should be tested for hyperactivity, altered attentional skills and potential deficits in executive functions.…”

“…The biomedical research continuously exploits modern strategies to create new animal models of ADHD, first by replicating the biochemical mechanism within brain areas involved in this disorder and thereafter by performing a deeper endophenotype characterization. We presently use an innovative animal model of ADHD, the DAT‐knockout (DAT‐KO) rats . The goal of our study is a characterization of curiosity‐related phenotype.…”

“…We presently use an innovative animal model of ADHD, the DAT-knockout (DAT-KO) rats. 11,12 The goal of our study is a characterization of curiosity-related phenotype. We tested rats with all 3 genotypes for DAT: while the +/+ genotype (wild type [WT]) is a control, we wish to ascertain between the +/− (DAT-heterozygous [DAT-HET]) and −/− (DAT-KO) which are the animals that best model ADHD, at least respecting the criterion of face validity.…”

Trace Amines and Their Receptors

“…With respect to potential TAAR1-mediated regulation of DAT, it should be noted that in other studies, no difference in dopamine uptake rate was observed in either the nucleus accumbens or striatum of TAAR1-KO mice or after TAAR1 agonist/ antagonist treatment of wild-type animals . Furthermore, the partial TAAR1 agonist RO5203648 prevents cocaine-induced dopamine overflow in the nucleus accumbens without altering dopamine uptake (Pei et al, 2014), and TAAR1 agonists are effective in inhibiting dopamine-dependent hyperactivity in DAT-KO mice (Revel et al, 2011(Revel et al, , 2012bLeo et al, 2018) and when DAT has been inhibited by administration of cocaine (Revel et al, 2013). As such, it now appears unlikely that TAAR1-mediated effects occur after a regulation of DAT function.…”