title: A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior.
abstract: Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (quicker and higher peak concentrations). We evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic clinical drug delivery. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60mg/kg/day; as well as dual-dosages of 4 and 10mg/kg/day, 20 and 30mg/kg/day, or 30 and 60mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30ng/mL), while the 4/10mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8ng/mL). Treatment with the higher dual-dosage (HD: 30/60mg/kg) resulted in hyperactivity, while the lower (LD: 4/10mg/kg) had no effect. Chronic effects of these dual-dosages were assessed throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle, decreased exploratory behavior, and increased anxiolytic behavior. Findings suggest that these dual-dosage-drinking-paradigms can be used to examine the effects of clinically relevant pharmacokinetic doses of MP and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes.
authors: Department of Psychology, Stony Brook University, Stony Brook, NY, United States. Electronic address: peter.thanos@stonybrook.edu.
authors: Panayotis K
authors: PK
authors: Thanos
authors: Department of Psychology, Stony Brook University, Stony Brook, NY, United States.
authors: Lisa S
authors: LS
authors: Robison
authors: Department of Psychology, Stony Brook University, Stony Brook, NY, United States.
authors: Jessica
authors: J
authors: Steier
authors: Department of Psychology, Stony Brook University, Stony Brook, NY, United States.
authors: Yu Fen
authors: YF
authors: Hwang
authors: Nathan Kline Institute, Orangeburg, NY, United States.
authors: Thomas
authors: T
authors: Cooper
authors: Department of Pediatrics, University of California, Irvine, United States.
authors: James M
authors: JM
authors: Swanson
authors: Department of Orthopaedics, Stony Brook University, Stony Brook, NY 11794-8181, United States.
authors: David E
authors: DE
authors: Komatsu
authors: Department of Life Sciences, New York Institute of Technology, Old Westbury, NY 11568-8000, United States.
authors: Michael
authors: M
authors: Hadjiargyrou
authors: Laboratory of Neuroimaging, NIAAA, NIH, Bethesda, MD, United States.
authors: Nora D
authors: ND
authors: Volkow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D008297:Male; D008774:Methylphenidate / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate
keywords: Attention deficit hyperactivity disorder; Dopamine transporter; Methylphenidate; Psychostimulant; Ritalin
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