Cited by 317Neurotransmitter Receptor Influence on BehaviorAttention Deficit Hyperactivity DisorderNeuroscience and Neuropharmacology Research

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Exposure of Adolescent Rats to Oral Methylphenidate: Preferential Effects on Extracellular Norepinephrine and Absence of Sensitization and Cross-Sensitization to Methamphetamine

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Kuczenski, Ronald, Segal, David S.·2002·The Journal of Neuroscience

DOI 10.1523/jneurosci.22-16-07264.2002PMC PMC6757883

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Abstract

Methylphenidate (MP) (ritalin) is widely used in the treatment of children and adolescents with attention deficit hyperactivity disorder, but little is known about therapeutic mechanisms or about possible consequences of long-term exposure. To more closely simulate the clinical use of the drug, we orally administered MP to adolescent rats during the dark-active phase of the circadian cycle at doses (0.75-3.0 mg/kg) below threshold for locomotor activation. We found that doses in this range increased extracellular norepinephrine in hippocampus without affecting dopamine in nucleus accumbens. These results suggest that norepinephrine systems may play an important role in the therapeutic action of this drug. To examine one potential consequence of long-term exposure to MP, i.e., the development of locomotor sensitization, an adaptational change that has been implicated in drug abuse liability, animals received three daily oral administrations of these doses of MP for up to 4 weeks through adolescence. The animals were then challenged with methamphetamine (0.5 mg/kg). We found that the behavioral response to MP did not change during the course of chronic treatment and that MP-pretreated animals did not exhibit a sensitized locomotor response to the methamphetamine challenge. We propose that, to the extent that this treatment protocol more closely reflects clinical exposure patterns, the relative insensitivity of accumbens dopamine to the acute administration of these MP doses, and the corresponding absence of evidence for the development of locomotor sensitization, supports one clinical view that there is little abuse liability associated with low dose, long-term MP treatment.

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Authors: Kuczenski, R., & Segal, D. S.
Affiliations: University of California San Diego (US)
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2002-08-15
Volume: 22
Issue: 16
Pages: 7264-7271
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.22-16-07264.2002
PMC: PMC6757883
OpenAlex: W2159875740
Cited by: 316
References: 75
Citations by year: 2026: 5 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 12 · 2017: 12 · 2016: 10 · 2015: 28 · 2014: 16 · 2013: 21 · 2012: 21
FWCI: 4.66
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Veterans Affairs
University of California, San Diego
National Institute on Drug Abuse (R01DA001568)
NIH Clinical Center
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: methylphenidate, adolescent rats, hippocampus, nucleus accumbens dopamine, locomotor sensitization, cross-sensitization, abuse liability, attention deficit hyperactivity disorder, long-term drug exposure
MeSH terms: Administration, Oral, Age Factors, Animals, Behavior, Animal, Dopamine, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Interactions, Extracellular Space, Hippocampus, Male, Methamphetamine, Methylphenidate, Motor Activity, Norepinephrine, Nucleus Accumbens, Time, Rats, Sprague-Dawley, Microdialysis, Rats

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Exposure of Adolescent Rats to Oral Methylphenidate: Preferential Effects on Extracellular Norepinephrine and Absence of Sensitization and Cross-Sensitization to Methamphetamine

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