TY - JOUR

T1 - Behavioral phenotyping of dopamine transporter knockout rats

T2 - Compulsive traits, motor stereotypies, and anhedonia

AU - Cinque, Stefano

AU - Zoratto, Francesca

AU - Poleggi, Anna

AU - Leo, Damiana

AU - Cerniglia, Luca

AU - Cimino, Silvia

AU - Tambelli, Renata

AU - Alleva, Enrico

AU - Gainetdinov, Raul R.

AU - Laviola, Giovanni

AU - Adriani, Walter

PY - 2018/2/22

Y1 - 2018/2/22

N2 - 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.

AB - 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.

KW - Appetitive food eating

KW - Behavioral rigidity

KW - Intolerance-to-Delay Task

KW - Reward sensitivity

KW - Sucrose consumption

KW - ADHD

KW - DEFICIT HYPERACTIVITY DISORDER

KW - AMINE-ASSOCIATED RECEPTOR

KW - SCHIZOPHRENIA

KW - appetitive food eating

KW - MONOAMINE TRANSPORTERS

KW - MICE LACKING

KW - behavioral rigidity

KW - sucrose consumption

KW - IMPULSIVE BEHAVIOR

KW - ANIMAL-MODELS

KW - reward sensitivity

KW - SEROTONIN

KW - AMPHETAMINE

UR - http://www.scopus.com/inward/record.url?scp=85042356588&partnerID=8YFLogxK

U2 - 10.3389/fpsyt.2018.00043

DO - 10.3389/fpsyt.2018.00043

M3 - Article

AN - SCOPUS:85042356588

VL - 9

JO - Frontiers in Psychiatry

JF - Frontiers in Psychiatry

SN - 1664-0640

IS - FEB

M1 - 43

ER -