The effects of chronic methylphenidate administration on operant test battery performance in juvenile rhesus monkeys
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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2021, Neurotoxicology and TeratologyCitation Excerpt :No apparent MPH-induced neurochemical changes in the vesicular monoamine transporter or the dopaminergic system were detected. These findings complement previous behavioral and imaging studies and suggest that the use of methylphenidate from adolescences and into adulthood is not associated with changes in the monoamine system (Morris et al., 2009; Rodriguez et al., 2010; Zhang et al., 2016). A series of human imaging studies have shown that MPH can alter the structure and function of the stratum in individuals with ADHD (Teicher et al., 2000; Hoekzema et al., 2014; Birn et al., 2019).
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