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

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

doi:10.1016/j.pnpbp.2018.12.004

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

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

4 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume	90
Issue number	2
Pages (from-to)	264-276
Number of pages	13
ISSN	0278-5846
DOIs	https://doi.org/10.1016/j.pnpbp.2018.12.004
Publication status	Published - 2 Mar 2019

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Fitzpatrick, C. M., Runegaard, A. H., Christiansen, S. H., Hansen, N. W., Jørgensen, S. H., McGirr, J. C., de Diego Ajenjo, A., Sørensen, A. T., Perrier, J-F., Petersen, A., Gether, U., Woldbye, D. P. D., & Andreasen, J. T. (2019). Differential effects of chemogenetic inhibition on dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 90(2), 264-276. https://doi.org/10.1016/j.pnpbp.2018.12.004

Differential effects of chemogenetic inhibition on dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task. / Fitzpatrick, Ciarán M; Runegaard, Annika H; Christiansen, Søren H et al.

In: Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol. 90, No. 2, 02.03.2019, p. 264-276.

Research output: Contribution to journal › Journal article › Research › peer-review

Fitzpatrick, CM, Runegaard, AH, Christiansen, SH, Hansen, NW , Jørgensen, SH, McGirr, JC, de Diego Ajenjo, A , Sørensen, AT , Perrier, J-F, Petersen, A, Gether, U , Woldbye, DPD & Andreasen, JT 2019, 'Differential effects of chemogenetic inhibition on dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task', Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 90, no. 2, pp. 264-276. https://doi.org/10.1016/j.pnpbp.2018.12.004

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title = "Differential effects of chemogenetic inhibition on dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task",

abstract = "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.",

author = "Fitzpatrick, {Ciar{\'a}n M} and Runegaard, {Annika H} and Christiansen, {S{\o}ren H} and Hansen, {Nikolaj W.} and J{\o}rgensen, {S{\o}ren H.} and McGirr, {Julia C} and {de Diego Ajenjo}, Amaia and S{\o}rensen, {Andreas T} and Jean-Fran{\c c}ois Perrier and Anders Petersen and Ulrik Gether and Woldbye, {David P D} and Andreasen, {Jesper T}",

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doi = "10.1016/j.pnpbp.2018.12.004",

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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

PY - 2019/3/2

Y1 - 2019/3/2

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

SN - 0278-5846

VL - 90

SP - 264

EP - 276

JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry

JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry

IS - 2

ER -

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

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