Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research

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

peer reviewe

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

peer reviewe

Altered Sexual Behavior in Dopamine Transporter (DAT) Knockout Male Rats: A Behavioral, Neurochemical and Intracerebral Microdialysis Study

peer reviewe

Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397.

peer reviewe

Trace Amine-Associated Receptor 5 Provides Olfactory Input Into Limbic Brain Areas and Modulates Emotional Behaviors and Serotonin Transmission

peer reviewe

Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397.

peer reviewe

Dopamine transporter knockout rats as the new preclinical model of hyper- and hypo-dopaminergic disorders.

peer reviewe

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

Monoamine dysfunctions in the prefrontal cortex (PFC) can contribute to diverse neuropsychiatric disorders, including ADHD, bipolar disorder, PTSD and depression. Disrupted dopamine (DA) homeostasis, and more specifically dopamine transporter (DAT) alterations, have been reported in a variety of psychiatric and neurodegenerative disorders. Recent studies using female adult rats heterozygous (DAT+/−) and homozygous (DAT−/−) for DAT gene, showed the utility of those rats in the study of PTSD and ADHD. Currently, a gap in the knowledge of these disorders affecting adolescent females still represents a major limit for the development of appropriate treatments. The present work focuses on the characterization of the PFC function under conditions of heterozygous and homozygous ablation of DAT during early adolescence based on the known implication of DAT and PFC DA in psychopathology during adolescence. We report herein that genetic ablation of DAT in the early adolescent PFC of female rats leads to changes in neuronal and glial cell homeostasis. In brief, we observed a concurrent hyperactive phenotype, accompanied by PFC alterations in glutamatergic neurotransmission, signs of neurodegeneration and glial activation in DAT-ablated rats. The present study provides further understanding of underlying neuroinflammatory pathological processes that occur in DAT-ablated female rats, what can provide novel investigational approaches in human diseases

Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function

<p>Abstract</p> <p>Background</p> <p>Neurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc).</p> <p>Results</p> <p>DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D₂autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D₂autoreceptors, quinpirole (1 μM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D₂receptor antagonist, sulpiride (5 μM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8–13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D₂autoreceptors. In addition, initial blockade of D₂autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8–13).</p> <p>Conclusion</p> <p>Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D₂autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.</p