The effects of chronic methylphenidate administration on operant test battery performance in juvenile rhesus monkeys

• Published in: Neurotoxicology and teratology Vol. 32; no. 2; pp. 142 - 151
• Main Authors: Rodriguez, J.S, Morris, S.M, Hotchkiss, C.E, Doerge, D.R, Allen, R.R, Mattison, D.R, Paule, M.G
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2010
• Subjects: Age Factors; Aging - physiology; Animals; Appetite - drug effects; Appetite Depressants - pharmacology; Attention; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain - drug effects; Brain - growth & development; Brain - physiopathology; Central Nervous System Stimulants - toxicity; Cognition Disorders - chemically induced; Cognition Disorders - physiopathology; Conditioning, Operant - drug effects; Conditioning, Operant - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Emergency; Juvenile; Learning; Macaca mulatta; Male; Medical Education; Memory; Methylphenidate; Methylphenidate - toxicity; Motivation - drug effects; Motivation - physiology; Neuropsychological Tests; Operant; Time; Juvenile; Learning; Operant; Memory; Methylphenidate; Attention
• ISSN: 0892-0362; 1872-9738
• DOI: 10.1016/j.ntt.2009.08.011

Abstract Methylphenidate (MPH) is an amphetamine derivative widely prescribed for the treatment of attention deficit–hyperactivity disorder. Recent concern over its genotoxic potential in children [11] spurred a study on the effects of chronic MPH treatment in a nonhuman primate population and the studies reported here were conducted in conjunction with that study in the same animals. Here, the focus was on the ability of juvenile rhesus monkeys to learn how to perform a battery of operant behavioral tasks while being treated chronically with MPH. Performance of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB) was used to quantify the learning of tasks thought to model specific aspects of cognitive function including learning, motivation, color and position discrimination, and short-term memory. The OTB tasks designed to assess these specific behaviors included Incremental Repeated Acquisition (IRA), Progressive Ratio (PR), Conditioned Position Responding (CPR), and Delayed Matching-to-Sample (DMTS), respectively. Juvenile males ( n = 10/group) pressed levers and press-plates for banana-flavored food pellets. Subjects were treated orally, twice a day, five days per week (M–F) for 66 weeks with escalating doses (0.15 mg/kg initially, increased to 2.5 mg/kg for the low dose group and to 12.5 mg/kg for the high dose group) and tested in OTB tasks 30 to 60 min after the morning dose. The findings indicate that MPH at doses up to 2.5 mg/kg twice per day were well tolerated (performance was no different than controls) but at doses of 12.5 mg/kg twice per day there was a significant decrement in OTB performance, characterized by decreases in both percent task completed and response rates for all tasks. These effects of MPH seem primarily due to decreases in motivation to perform for food, which is not surprising given the well known appetite suppressing effects of amphetamine-like stimulants. Thus, the current data do not strongly suggest cognitive impairments following chronic MPH administration.