Details

Autor(en) / Beteiligte

• Fitzpatrick, Ciarán M.
• Runegaard, Annika H.
• Christiansen, Søren H.
• Hansen, Nikolaj W.
• Jørgensen, Søren H.
• McGirr, Julia C.
• de Diego Ajenjo, Amaia
• Sørensen, Andreas T.
• Perrier, Jean-François
• Petersen, Anders
• Gether, Ulrik
• Woldbye, David P.D.
• Andreasen, Jesper T.

Titel

Differential effects of chemogenetic inhibition of dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task

Ist Teil von

• Progress in neuro-psychopharmacology & biological psychiatry, 2019-03, Vol.90, p.264-276

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. •Selective chemogenetic control of catecholamine neurons was achieved.•Effects of chemogenetic inhibition were assessed in the 5-Choice Serial Reaction Time Task.•Ventral tegmental area dopamine inhibition reduced speed and overall probability of responding.•Locus coeruleus norepinephrine inhibition decreased attentional performance when task difficulty increased•Dopamine and norepinephrine signaling differentially affect attention, impulsive, and motivational control.