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Cited by 340Neurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology StudiesGambling Behavior and Treatments

An Animal Model of Genetic Vulnerability to Behavioral Disinhibition and Responsiveness to Reward-Related Cues: Implications for Addiction

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Flagel, Shelly B, Robinson, Terry E, Clark, Jeremy J, Clinton, Sarah M, Watson, Stanley J, Seeman, Phillip, Phillips, Paul E M, Akil, Huda·2010·Neuropsychopharmacology
DOI 10.1038/npp.2009.142PMC PMC2794950
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Abstract

Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of 'impulsive choice', bHRs were more impulsive on a measure of 'impulsive action'- ie, they had difficulty withholding an action to receive a reward, indicative of 'behavioral disinhibition'. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2(high) receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine 'release events' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to 'externalizing disorders' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic 'tone.'

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  • These two approach strategies are thought to differ in the amount of incentive salience assigned to the CS.

    “These two approach strategies are thought to differ in the amount of incentive salience assigned to the CS.40, 56”

    From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [56]

  • Another feature of an incentive stimulus is to be 'wanted' and as such animals should work to obtain it.

    “Another feature of an incentive stimulus is to be “wanted” and as such animals should work to obtain it10,16.”

    From A selective role for dopamine in stimulus-reward learning (2011) · cites this paper as [16]

  • The attribution of incentive salience is the product of previous experience (i.e., learned associations) interacting with an individual's genetic propensity and neurobiological state.

    “The attribution of incentive salience is the product of previous experience (i.e., learned associations) interacting with an individual’s genetic propensity and neurobiological state 16,24–27.”

    From A selective role for dopamine in stimulus-reward learning (2011) · cites this paper as [16]

  • The USA mice and the rat model were bred for varying phenotypes: increased reactivity toward stimulation, novelty exploration, impulsivity, and vulnerability to psychostimulant abuse.

    “The USA mice and the rat model were bred for varying phenotypes: increased reactivity toward stimulation [42], novelty exploration, impulsivity, and vulnerability to psychostimulant abuse [29, 44].”

    From An integrated analysis of genes and functional pathways for aggression in human and rodent models (2019) · cites this paper as [44]

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  1. Weeks J Meyer R Long-term intravenous infusion Methods in psychobiology 1972 London Academic Press 155 168

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Authors
Flagel, S. B., Robinson, T. E., Clark, J. J., Clinton, S. M., Watson, S. J., Seeman, P., Phillips, P. E. M., & Akil, H.
Affiliations
  • University of Michigan (US)
  • University of Washington (US)
  • University of Toronto (CA)
Corresponding author
Flagel, Shelly B
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2009-09-30
Volume
35
Issue
2
Pages
388-400
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2009.142
PMC
PMC2794950
OpenAlex
W2159689947
Cited by
339
References
77
Citations by year
2026: 12 · 2025: 12 · 2024: 10 · 2023: 8 · 2022: 21 · 2021: 15 · 2020: 20 · 2019: 26 · 2018: 18 · 2017: 20 · 2016: 19 · 2015: 29 · 2014: 37 · 2013: 32 · 2012: 26
FWCI
8.29
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Office of Naval Research (N00014-02-1-0879, N00014)
  • National Institute of Mental Health (K99MH085859)
  • National Institute on Drug Abuse (P01DA021633, F32DA024540, R37DA004294, R37 DA04294, R01 DA012286)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Social Sciences › Psychology › Clinical Psychology › Gambling Behavior and Treatments
Keywords
addiction vulnerability, behavioral disinhibition, incentive salience, reward cues, impulsive action, impulsive choice, dopamine supersensitivity, dopamine D2 receptor, dopamine release, nucleus accumbens, quinpirole, externalizing disorders, self-administration
MeSH terms
Animals, Conditioning, Classical, Cues, Disease Models, Animal, Dose-Response Relationship, Drug, Exploratory Behavior, Genetics, Behavioral, Impulsive Behavior, Male, Phenotype, Psychomotor Performance, Reward, RNA, Messenger, Behavior, Addictive, Rats, Sprague-Dawley, Receptors, Dopamine D2, Dopamine Agonists, Quinpirole, Rats

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