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

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.

Fig. 1

MPH effects on overall performance in the OTB as measured by cumulative training score for weeks 1–66. Analysis of group means (±sem) revealed that the vehicle group attained a significantly higher overall score in the OTB as compared to the high dose group for weeks 43–66 (*, p<0.05). Similarly, the low dose group attained a higher overall score than the high dose group for weeks 45–66 (+, p<0.05). Closed and open diamonds represent MPH plasma concentrations (right y-axis) for the low and high dose MPH groups, respectively. Number of subjects is given in parentheses. Arrows indicate changes in MPH doses (all doses given twice daily) as follows: weeks 1–2: 0.15 mg/kg for low and high dosed groups; 1st arrow, weeks 3–4: low=0.15 mg/kg, high=0.30 mg/kg; 2nd arrow, weeks 5–6: low=0.15 mg/kg, high=0.45 mg/kg; 3rd arrow, weeks 7–8: low=0.15 mg/kg, high=0.75 mg/kg; 4th arrow, weeks 9–22: low=0.15 mg/kg, high=1.50 mg/kg; 5th arrow, weeks 23–24: low=0.30 mg/kg, high=3.0 mg/kg; 6th arrow, weeks 25–26: low=0.60 mg/kg, high=6.0 mg/kg; 7th arrow, week 27–30: low=1.25 mg/kg, high=12.5 mg/kg; 8th arrow, week 31 and beyond: low=2.5 mg/kg, high=12.5 mg/kg.

Fig. 2

Arrows indicate the dose changes denoted as arrows 5–8 in Fig. 1 legend. A) Analysis of the means (±sem) of IRA Percent Task Completed (PTC) for weeks 21 through 66 revealed that the vehicle group performed better than both the low dose group (#, p<0.05) and the high dose group (*, p<0.05) when indicated by symbols. The low dose group performed better than the high dose group when indicated (+, p<0.05). Note: For the IRA task the number of animals per group is 8 and not 10 due to the fact that data for only those subjects that had completed the subsequent CPR training prior to dose escalation at week 23 were analyzed. B) Analysis of the means (±sem) of response rate (RR) revealed the vehicle group responded faster than both the low dose group (#, p<0.05) and high dose group (*, p<0.05) when indicated by symbols. The low dose group responded faster than the high dose group when indicated (+, p<0.05). C) Analysis of the means (±sem) of IRA Accuracy (ACC) revealed the vehicle group performed better than both the low dose group (#, p<0.05) and high dose group (*, p<0.05) when indicated by symbols. The low dose group performed better than the high dose group when indicated (+, p<0.05).

Fig. 3

Arrows indicate the dose changes denoted as arrows 5–8 in Fig. 1 legend. A) Analysis of the means (±sem) of CPR PTC for weeks 23–66 revealed that the vehicle group completed more of the task than the high dose group on weeks indicated (*, p<0.05). There no differences between the vehicle and low dose groups. The low dose group completed more of the task than the high dose group when indicated (+, p<0.05). Note: For the CPR task the number of animals per group is 8 and not 10 due to the fact that data for only those subjects that had completed CPR training prior to dose escalation at week 23 were analyzed. B) Analysis of the means (±sem) of CPR RR for week's 23–66 revealed that the vehicle group responded faster than the high dose group during weeks indicated (*, p<0.05). There no differences between the vehicle and low dose groups. The low dose group responded faster than the high dose group when indicated (+, p<0.05). C) Analysis of the means (±sem) of CPR ACC for week's 23–66 revealed that the vehicle group performed better than the high dose group during weeks indicated (*, p<0.05). There was a significant difference between the vehicle and low dose group ACC during week 41 only (#, p<0.05). The low dose group performed better than the high dose group on weeks indicated (+, p<0.05).

Fig. 4

Arrows indicate the dose changes denoted as arrows 5–8 in Fig. 1 legend. A) Analysis of the means (±sem) of Progressive Ratio PTC for weeks 22–66 revealed that the vehicle group completed more of the task than the high dose group on weeks indicated (*, p<0.05). There were no significant differences between the vehicle and low dose groups. The low dose group completed more of the task than the high dose group on weeks indicated (+, p<0.05). Note: The number of animals per group is only 3 due to the fact that data for only those subjects that had completed PR training prior to dose escalation at week 23 were analyzed. B) Analysis of the means (±sem) of Progressive Ratio RR for week's 22–66. Analysis revealed that the vehicle group responded faster than the high dose group on weeks indicated (*, p<0.05). There was a significant difference between the vehicle and low dose group during week 49 only (#, p<0.05). The low dose group responded faster than the high dose group on weeks indicated (+, p<0.05).

Fig. 5

These results are of the 24 weeks of DMTS training which represent weeks 43–66 of OTB testing. DMTS recall delay set acquisition analysis revealed differences between the vehicle versus the low dose group on weeks 17–22 (#, p<0.05) and versus the high dose group on weeks 13–24 (*, p<0.05). The number of animals per group (in parentheses) reflects only those subjects that had reached the full DMTS task prior to dose escalation at week 23.