TY - JOUR
T1 - Differential effects of chemogenetic inhibition on dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task
AU - Fitzpatrick, Ciarán M
AU - Runegaard, Annika H
AU - Christiansen, Søren H
AU - Hansen, Nikolaj W.
AU - Jørgensen, Søren H.
AU - McGirr, Julia C
AU - de Diego Ajenjo, Amaia
AU - Sørensen, Andreas T
AU - Perrier, Jean-François
AU - Petersen, Anders
AU - Gether, Ulrik
AU - Woldbye, David P D
AU - Andreasen, Jesper T
N1 - Copyright © 2018. Published by Elsevier Inc.
PY - 2019
Y1 - 2019
N2 - Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, aberrant impulsivity, and hyperactivity. Although the underlying pathophysiology of ADHD remains unclear, dopamine and norepinephrine signaling originating from the ventral tegmental area (VTA) and locus coeruleus (LC) is thought to be critically involved. In this study, we employ Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) together with the mouse 5-Choice Serial Reaction Time Task (5-CSRTT) to investigate the necessary roles of these catecholamines in ADHD-related behaviors, including attention, impulsivity, and motivation. By selective inhibition of tyrosine hydroxylase (TH)-positive VTA dopamine neurons expressing the Gi-coupled DREADD (hM4Di), we observed a marked impairment of effort-based motivation and subsequently speed and overall vigor of responding. At the highest clozapine N-oxide (CNO) dose tested (i.e. 2 mg/kg) to activate hM4Di, we detected a reduction in locomotor activity. DREADD-mediated inhibition of LC norepinephrine neurons reduced attentional performance in a variable stimulus duration test designed to increase task difficulty, specifically by increasing trials omissions, reducing mean score, and visual processing speed. These findings show that VTA dopamine and LC norepinephrine neurons differentially affect attention, impulsive and motivational control. In addition, this study highlights how molecular genetic probing of selective catecholamine circuits can provide valuable insights into the mechanisms underlying ADHD-relevant behaviors.
AB - Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, aberrant impulsivity, and hyperactivity. Although the underlying pathophysiology of ADHD remains unclear, dopamine and norepinephrine signaling originating from the ventral tegmental area (VTA) and locus coeruleus (LC) is thought to be critically involved. In this study, we employ Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) together with the mouse 5-Choice Serial Reaction Time Task (5-CSRTT) to investigate the necessary roles of these catecholamines in ADHD-related behaviors, including attention, impulsivity, and motivation. By selective inhibition of tyrosine hydroxylase (TH)-positive VTA dopamine neurons expressing the Gi-coupled DREADD (hM4Di), we observed a marked impairment of effort-based motivation and subsequently speed and overall vigor of responding. At the highest clozapine N-oxide (CNO) dose tested (i.e. 2 mg/kg) to activate hM4Di, we detected a reduction in locomotor activity. DREADD-mediated inhibition of LC norepinephrine neurons reduced attentional performance in a variable stimulus duration test designed to increase task difficulty, specifically by increasing trials omissions, reducing mean score, and visual processing speed. These findings show that VTA dopamine and LC norepinephrine neurons differentially affect attention, impulsive and motivational control. In addition, this study highlights how molecular genetic probing of selective catecholamine circuits can provide valuable insights into the mechanisms underlying ADHD-relevant behaviors.
U2 - 10.1016/j.pnpbp.2018.12.004
DO - 10.1016/j.pnpbp.2018.12.004
M3 - Journal article
C2 - 30529002
VL - 90
SP - 264
EP - 276
JO - Progress in Neuro-Psychopharmacology & Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology & Biological Psychiatry
SN - 0278-5846
IS - 2
ER -