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

Francesca Zoratto,Enrico Alleva,Anna Poleggi,Luca Cerniglia,Silvia Cimino,Damiana Leo,Raul R. Gainetdinov,Walter Adriani,Giovanni Laviola,Stefano Cinque,Renata Tambelli

doi:10.3389/fpsyt.2018.00043

Abstract

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.

Highlights

Brain dopamine (DA) is closely involved in the modulation of several neurobiological and behavioral processes, including decision making, reward processing, motivational states, habits, and movement control
They show a reduced sensitivity for rewarding properties of food and sweet fluids, generalization to other natural stimuli like sex or novelty would deserve further work (33)
These behavioral abnormalities are not associated with alterations in the expression levels of some genes correlated with Dopamine transporter (DAT) (TH, dopamine receptor 2 (D2), serotonin transporter (SERT), and trace amine-associated receptor 1 (TAAR1)) in the ventral striatum, it is possible that the final protein levels could differ between WT and KO

Summary

Introduction

Brain dopamine (DA) is closely involved in the modulation of several neurobiological and behavioral processes, including decision making, reward processing, motivational states, habits, and movement control. The importance of DAT activity in DA circuitry is supported by the effects of many drugs of abuse and neurotoxins; current pharmacological therapeutic strategies for diseases like ADHD or a major depression involve drugs such as psychostimulants or triple reuptake inhibitors (6–8). Psychostimulants such as amphetamine (AMPH) or meth ylphenidate can, have an effect on trace amineassociated receptor 1 (TAAR1), another protein that has a significant role in DA neurotransmission. Research in this field needs to move across preclinical studies in animal models, and this allows direct insights into the neurobiological, genetic, and biopsychological functioning, in the aforementioned mental diseases

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