TY - JOUR

T1 - Behavioral characterization of DAT-KO rats and evidence of asocial-like phenotypes in DAT-HET rats

T2 - The potential involvement of norepinephrine system

AU - Adinolfi, Annalisa

AU - Zelli, Silvia

AU - Leo, Damiana

AU - Carbone, Cristiana

AU - Mus, Liudmila

AU - Illiano, Placido

AU - Alleva, Enrico

AU - Gainetdinov, Raul R.

AU - Adriani, Walter

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Dopamine (DA) is a key neurotransmitter of the central nervous system, whose availability is regulated by the dopamine transporter (DAT). Deletion of DAT gene leading to hyperdopaminergia was previously performed on mouse models. This enabled recapitulation of the core symptoms of Attention-Deficit / Hyper-activity Disorder (ADHD), which include hyperactivity, inattention and cognitive impairment. We used recently developed DAT knockout (DAT-KO) rats to carry out further behavioral profiling on this novel model of hyperdopaminergia. DAT-KO rats display elevated locomotor activity and restless environmental exploration, associated with a transient anxiety profile. Furthermore, these rats show pronounced stereotypy and compulsive-like behavior at the Marble-Burying test. Homozygous DAT-KO rats mantain intact social interaction when tested in a social-preference task, while heterozygous (HET) rats show high inactivity associated with close proximity to the social stimulus. Ex-vivo evaluation of brain catecholamines highlighted increased levels of norepinephrine in the hippocampus and hypothalamus exclusively of heterozygous rats. Taken together, our data present evidence of unexpected asocial tendencies in heterozygous (DAT-HET) rats associated with neurochemical alterations in norepinephrine neurotransmission. We shed light on the behavioral and neurochemical consequences of altered DAT function in a higher, more complex model of hyperdopaminergia. Unraveling the role of DA neurotransmission in DAT-KO rats has very important implications in the understanding of many psychiatric illnesses, including ADHD, where alterations in DA system have been demonstrated.

AB - Dopamine (DA) is a key neurotransmitter of the central nervous system, whose availability is regulated by the dopamine transporter (DAT). Deletion of DAT gene leading to hyperdopaminergia was previously performed on mouse models. This enabled recapitulation of the core symptoms of Attention-Deficit / Hyper-activity Disorder (ADHD), which include hyperactivity, inattention and cognitive impairment. We used recently developed DAT knockout (DAT-KO) rats to carry out further behavioral profiling on this novel model of hyperdopaminergia. DAT-KO rats display elevated locomotor activity and restless environmental exploration, associated with a transient anxiety profile. Furthermore, these rats show pronounced stereotypy and compulsive-like behavior at the Marble-Burying test. Homozygous DAT-KO rats mantain intact social interaction when tested in a social-preference task, while heterozygous (HET) rats show high inactivity associated with close proximity to the social stimulus. Ex-vivo evaluation of brain catecholamines highlighted increased levels of norepinephrine in the hippocampus and hypothalamus exclusively of heterozygous rats. Taken together, our data present evidence of unexpected asocial tendencies in heterozygous (DAT-HET) rats associated with neurochemical alterations in norepinephrine neurotransmission. We shed light on the behavioral and neurochemical consequences of altered DAT function in a higher, more complex model of hyperdopaminergia. Unraveling the role of DA neurotransmission in DAT-KO rats has very important implications in the understanding of many psychiatric illnesses, including ADHD, where alterations in DA system have been demonstrated.

KW - Anxiety

KW - Dopamine

KW - Fear conditioning

KW - Marble burying

KW - Norepinephrine

KW - Social preference

KW - Conditioning, Psychological/physiology

KW - Rats, Transgenic

KW - Rats, Wistar

KW - Attention Deficit Disorder with Hyperactivity/metabolism

KW - Compulsive Behavior/metabolism

KW - Motor Activity/physiology

KW - Fear/physiology

KW - Norepinephrine/metabolism

KW - Homozygote

KW - Phenotype

KW - Animals

KW - Social Behavior

KW - Grooming/physiology

KW - Heterozygote

KW - Exploratory Behavior/physiology

KW - Dopamine Plasma Membrane Transport Proteins/deficiency

KW - Brain/metabolism

KW - Disease Models, Animal

UR - http://www.scopus.com/inward/record.url?scp=85058009403&partnerID=8YFLogxK

U2 - 10.1016/j.bbr.2018.11.028

DO - 10.1016/j.bbr.2018.11.028

M3 - Article

C2 - 30472113

AN - SCOPUS:85058009403

VL - 359

SP - 516

EP - 527

JO - Behavioural Brain Research

JF - Behavioural Brain Research

SN - 0166-4328

ER -