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Sensitization of Midbrain Dopamine Neuron Reactivity Promotes the Pursuit of Amphetamine

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Vezina, Paul, Lorrain, Daniel S., Arnold, Gretchen M., Austin, Jennifer D., Suto, Nobuyoshi·2002·The Journal of Neuroscience

DOI 10.1523/jneurosci.22-11-04654.2002PMC PMC6758806

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Abstract

Stimulant drugs such as amphetamine are readily self-administered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons of the midbrain. Repeated exposure to this drug systemically or exclusively in the cell body region of these neurons in the ventral tegmental area (VTA) leads to long-lasting changes in dopaminergic function that can be assessed by increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug. Three experiments were conducted to evaluate the possibility that this enduring sensitized reactivity underlies compulsive drug self-administration. In all experiments, rats were pre-exposed to amphetamine and, starting 10 d later, their intravenous self-administration of the drug was assessed. In the first experiment, rats previously exposed to amphetamine systemically or exclusively in the VTA subsequently worked harder than untreated animals to obtain the drug when the work required to obtain successive infusions was increased progressively. In the second experiment, this progressively increasing workload was found to decrease the magnitude of amphetamine-induced DA overflow observed with successive infusions until responding ceased. Rats previously exposed to amphetamine were more resistant to this decline and more apt to maintain responding. Finally, in experiment three, a noncontingent priming injection of the drug produced a greater NAcc DA response and a greater parallel increase in lever pressing in drug compared with saline pre-exposed rats. Together, these results demonstrate a direct relation between drug-induced sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of an abused substance.

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“In particular, following repeated exposure to drugs of abuse, which progressively increases Bwanting^ and desire for more drug (Vezina, 2004; Vezina, Lorrain, Arnold, Austin, & Suto, 2002), individuals tend to escalate their consumption by increasing both the frequency with which drug is taken and the quantity consume…”
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Authors: Vezina, P., Lorrain, D. S., Arnold, G. M., Austin, J. D., & Suto, N.
Affiliations: University of Chicago (US)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
ORCID: Suto, Nobuyoshi
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2002-06-01
Volume: 22
Issue: 11
Pages: 4654-4662
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.22-11-04654.2002
PMC: PMC6758806
OpenAlex: W1556555813
Cited by: 206
References: 58
Citations by year: 2026: 1 · 2025: 2 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 4 · 2014: 4 · 2013: 10 · 2012: 6
FWCI: 5.47
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01da009860-04)
U.S. Public Health Service
National Institute on Drug Abuse (R01DA009397, T32DA007255)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords: amphetamine, self-administration, midbrain dopaminergic neurons, ventral tegmental area, compulsive drug seeking, locomotor activity, stimulant abuse
MeSH terms: Amphetamine, Animals, Behavior, Animal, Disease Models, Animal, Dopamine, Drug Administration Routes, Drug Administration Schedule, Extracellular Space, Injections, Intraperitoneal, Male, Mesencephalon, Motor Activity, Neurons, Nucleus Accumbens, Self Administration, Microdialysis, Ventral Tegmental Area, Amphetamine-Related Disorders, Rats, Long-Evans, Rats

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Sensitization of Midbrain Dopamine Neuron Reactivity Promotes the Pursuit of Amphetamine

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