Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine

Implications for animal models of the motivational symptoms of depression

Eric J. Nunes, Patrick A. Randall, Evan E. Hart, Charlotte Freeland, Samantha E. Yohn, Younis Baqi, Christa E. Müller, Laura López-Cruz, Mercè Correa, John D. Salamone

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.

Original languageEnglish
Pages (from-to)19120-19130
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number49
DOIs
Publication statusPublished - 2013

Fingerprint

Tetrabenazine
Animal Models
Depression
Choice Behavior
Dopamine
Bupropion
Food Preferences
Dopamine D1 Receptors
Dopamine D2 Receptors
Nucleus Accumbens
Adenosine
Antidepressive Agents
Cost-Benefit Analysis
Fatigue
Eating
Neurons

Keywords

  • Basal ganglia
  • DAT inhibitor
  • Decision making
  • Motivation
  • Negative symptoms
  • Vigor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine : Implications for animal models of the motivational symptoms of depression. / Nunes, Eric J.; Randall, Patrick A.; Hart, Evan E.; Freeland, Charlotte; Yohn, Samantha E.; Baqi, Younis; Müller, Christa E.; López-Cruz, Laura; Correa, Mercè; Salamone, John D.

In: Journal of Neuroscience, Vol. 33, No. 49, 2013, p. 19120-19130.

Research output: Contribution to journalArticle

Nunes, EJ, Randall, PA, Hart, EE, Freeland, C, Yohn, SE, Baqi, Y, Müller, CE, López-Cruz, L, Correa, M & Salamone, JD 2013, 'Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: Implications for animal models of the motivational symptoms of depression', Journal of Neuroscience, vol. 33, no. 49, pp. 19120-19130. https://doi.org/10.1523/JNEUROSCI.2730-13.2013
Nunes, Eric J. ; Randall, Patrick A. ; Hart, Evan E. ; Freeland, Charlotte ; Yohn, Samantha E. ; Baqi, Younis ; Müller, Christa E. ; López-Cruz, Laura ; Correa, Mercè ; Salamone, John D. / Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine : Implications for animal models of the motivational symptoms of depression. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 49. pp. 19120-19130.
@article{c8f7d67ac7a54601801063f887316d61,
title = "Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: Implications for animal models of the motivational symptoms of depression",
abstract = "Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.",
keywords = "Basal ganglia, DAT inhibitor, Decision making, Motivation, Negative symptoms, Vigor",
author = "Nunes, {Eric J.} and Randall, {Patrick A.} and Hart, {Evan E.} and Charlotte Freeland and Yohn, {Samantha E.} and Younis Baqi and M{\"u}ller, {Christa E.} and Laura L{\'o}pez-Cruz and Merc{\`e} Correa and Salamone, {John D.}",
year = "2013",
doi = "10.1523/JNEUROSCI.2730-13.2013",
language = "English",
volume = "33",
pages = "19120--19130",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "49",

}

TY - JOUR

T1 - Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine

T2 - Implications for animal models of the motivational symptoms of depression

AU - Nunes, Eric J.

AU - Randall, Patrick A.

AU - Hart, Evan E.

AU - Freeland, Charlotte

AU - Yohn, Samantha E.

AU - Baqi, Younis

AU - Müller, Christa E.

AU - López-Cruz, Laura

AU - Correa, Mercè

AU - Salamone, John D.

PY - 2013

Y1 - 2013

N2 - Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.

AB - Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.

KW - Basal ganglia

KW - DAT inhibitor

KW - Decision making

KW - Motivation

KW - Negative symptoms

KW - Vigor

UR - http://www.scopus.com/inward/record.url?scp=84888998855&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888998855&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2730-13.2013

DO - 10.1523/JNEUROSCI.2730-13.2013

M3 - Article

VL - 33

SP - 19120

EP - 19130

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 49

ER -