Elsevier

Neurotoxicology and Teratology

Volume 32, Issue 2, March–April 2010, Pages 142-151
Neurotoxicology and Teratology

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

https://doi.org/10.1016/j.ntt.2009.08.011Get rights and content

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.

Introduction

The chronic administration of methylphenidate (MPH) in the pediatric population for attention deficit–hyperactivity disorder (ADHD) is prevalent in today's society. MPH acts mainly by blocking the dopamine transporter [40] to facilitate an increase in extracellular dopamine [40]. This neurochemical effect is believed to compensate for a deficiency in extracellular dopamine concentration [41] which acts on either pre- [13] or post-synaptic dopamine receptors [5]. However, the long-term effects of this psychostimulant remain unknown [38]. Behavioral outcomes for subjects receiving MPH over extended periods of time are equivocal [14] and its long-term administration may have effects on systems other than the CNS including the cardiovascular system [42] or may exacerbate undiagnosed conditions such as Tourette's syndrome [37]. High doses produce effects opposite to those intended and include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia [16]. Bedford et al. [4] have shown that high doses of MPH produce stereotypic behaviors in monkeys, such as increased vocalization and self-grooming and intense idiosyncratic behavior, while others have reported adverse side effects in children [3], [12] but positive behavioral and cognitive effects at lower doses (for review see [1], [39]).

In addition to its noted behavioral effects, MPH was recently reported to increase metrics of mutagenesis in a population of pediatric patients with ADHD treated with MPH over a period of 3 months [11]. Therefore, studies were initiated to rigorously explore the genotoxic effects of chronic MPH treatment in a primate model (findings to be reported elsewhere [22]) and, in conjunction we sought to determine the concomitant behavioral effects. For this effort the National Center for Toxicological Research's (NCTR) Operant Test Battery (OTB) was employed to assess cognitive function in adolescent monkeys. The doses of MPH administered were adjusted to attain clinically relevant plasma levels (low dose group) and plasma levels well beyond (high dose group).

The OTB has been used extensively to assess aspects of cognitive function in both primates and children [8], [30], [31] and to monitor both acute and chronic drug effects in monkeys [19], [25], [26]. The tasks and the particular brain functions they are thought to model include the: Incremental Repeated Acquisition task (IRA), learning; Progressive Ratio task (PR), motivation; Conditioned Position Responding task (CPR), color and position discrimination; Delayed Matching-To-Sample task (DMTS), short-term memory. Children and well-trained rhesus monkeys perform similarly on OTB tasks [27], [25], [26]. This is particularly important when extrapolating the neurobehavioral effects of drugs and toxicants from monkeys to humans. Additionally, the demonstration that several measures of OTB performance correlate significantly with measures of intelligence in children serves to highlight the human relevance of such measures in animals [29], [7]. Here, OTB training required that subjects perform to a certain criteria at each level of training before moving on to the next training level (Table 1). The age of the animals used in the present study was chosen to model those comparable to pediatric patients.

Section snippets

Subjects

The experimental subjects were 30 male rhesus monkeys, approximately two years old at the beginning of the experiment, an age approximately equivalent to six-to-eight-year old children. The animals were randomly assigned (10/group) to either the vehicle control, low dose or high dose groups and housed individually. Subjects were removed from their home cages and placed into restraint/transport chairs (Primate Products, Miami, FL) for subsequent daily weighing, dosing, behavioral testing and

Methylphenidate and ritalinic acid plasma levels

As indicated in Table 2, MPH and RA plasma levels increased with administered dose and were relatively stable at a given dose, although there is considerable variability as would be expected with oral drug administration. A marked increase in MPH plasma levels occurred in both groups at week 23 when MPH doses increased from 0.15 to 0.3 mg/kg for the low dose group and 1.5 to 3.0 mg/kg for the high dose group. At 3.0 mg/kg (high dose group), MPH plasma levels were equivalent to or higher than

Discussion

The findings presented here indicate that in young rhesus monkeys substantial doses of MPH are necessary to attain clinically relevant plasma levels when given orally. Also, the concomitantly high RA plasma concentrations speak of the difference in MPH dose, when comparing between monkeys and children, required to reach the clinical range. Doses of 2.5 mg/kg (low dose group) were required to attain plasma levels in the human therapeutic range of 4–12 ng/ml [33]. On a mg/kg basis, this dose is

Conflict of interest

This declaration is for the purpose of disclosing any conflict of interest between authors and other parties. There are no conflict of interest for any authors involved.

Acknowledgements

Funding: These studies were supported through an interagency agreement between the National Institute on Child Health and Human Development and the National Center for Toxicological Research, 224-05-0003 and a postdoctoral fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA (to J. Rodriguez).

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