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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
Open accessAbstract
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 (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
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“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
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- 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.
- 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.
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Berridge, C. W., & Waterhouse, B. D. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(03)00143-7 · Cited by 2,529
Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions
Arnsten, A. F. T., & Li, B.-M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.08.019 · Cited by 948
Berridge, C. W., Devilbiss, D. M., Andrzejewski, M. E., Arnsten, A. F. T., Kelley, A. E., Schmeichel, B., Hamilton, C., & Spencer, R. C. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.04.022 · Cited by 617
Stimulants: Therapeutic Actions in ADHD
Arnsten, A. F. T. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301164 · Cited by 473
Arnsten, A. F. T., & Pliszka, S. R. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.01.020 · Cited by 383
Metadata
- 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
- 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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