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

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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  • These lower doses in rats improve PFC attention and working memory function, enhance PFC neuronal response, and reduce locomotor hyperactivity in juveniles.

    “These lower doses in rats improve PFC attention and working memory function, enhance PFC neuronal response, and reduce locomotor hyperactivity in juveniles (Arnsten and Dudley, 2005; Berridge et al., 2006; Kuczenski and Segal, 2002).”

    From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Kuczenski and Segal, 2002

    The Behavioral responses section (page not available in our copy) reports a small reduction in locomotor activity in adolescent rats given lower oral methylphenidate doses; it was statistically significant only when activity was accumulated over nine hours after three administrations. The Neurotransmitter responses section discusses possible prefrontal-cortex effects but does not report improved attention or working memory, or enhanced PFC neuronal responses, in these rats. (LLM, conf=0.88)

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  • When administered in appropriate doses, stimulant medications improve PFC function both in healthy human subjects and in animals, including the reduction of locomotor hyperactivity in juvenile rats.

    “When administered in appropriate doses, these medications improve PFC function both in healthy human subjects (Elliott et al., 1997) and in animals (Arnsten and Dudley, 2005), including the reduction of locomotor hyperactivity in juvenile rats (Kuczenski and Segal, 2002).”

    From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Kuczenski and Segal, 2002

    The ‘Behavioral response to acute oral MP’ section reports that oral methylphenidate reduced cumulative locomotor activity in adolescent rats. The Methods describe a typical activity pattern in the control animals, not locomotor hyperactivity, so the source does not establish a reduction of hyperactivity specifically. The PFC and human findings are attached to other citations in the citing sentence. (LLM, conf=0.85)

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Research works printed but not linked: 3

  1. Sagvolden T (2001) The spontaneously hypertensive rat as a model for ADHD. In: Stimulant drugs and ADHD: basic and clinical neuro- science (Solanto MV, Arnsten AFT, Castellanos FX, eds), pp 221-237. New York: Oxford UP.
  2. Solanto MV, Arnsten AFT, Castellanos FX (2001) The neuroscience of stimulant drugs in ADHD. In: Stimulant drugs and ADHD: basic and clinical neuroscience (Solanto MV, Arnsten AFT, Castellanos FX, eds), pp 355-379. New York: Oxford UP.
  3. Taylor JR, Jentsch JD (2001) Stimulant effects on striatal and cortical dopamine systems involved in reward-related behavior and impulsivity: implications for ADHD. In: Stimulant drugs and ADHD: basic and clinical neuroscience (Solanto MV, Arnsten AFT, Castellanos FX, eds), pp 104 -133. New York: Oxford UP.

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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
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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