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.

Keywords: Attention deficit hyperactivity disorder; Dopamine transporter; Methylphenidate; Psychostimulant; Ritalin.

Fig. 1

Mean (+SEM) volume consumption (mL) across treatment groups. Overall, no MP treatment group drank significantly different volumes compared to water-treated rats.

Fig. 2

A. Mean (+SEM) racemic (D + L) MP plasma levels (ng/mL) across treatment groups. The 30/60 mg/kg dual dosage produced the highest racemic MP plasma concentration (~30 ng/mL) within the clinically-relevant spectrum, while the 4/10 mg/kg dual dosage produced a peak concentration of ~8 ng/mL, which corresponds to the optimal plasma concentration produced in the clinical scenario. B. Mean (+SEM) D-isomer MP plasma levels (ng/mL) across treatment groups. C. Mean (+SEM) L-isomer MP plasma levels (ng/mL) across treatment groups.

Fig. 3

Mean (+SEM) percent change in locomotor activity (beam breaks) from baseline across all treatment groups. There were significant treatment effects at various time points after the initiation of drinking. *, 30/60 mg/kg

Fig. 4

Mean (+SEM) body weight by treatment group during MP treatment and abstinence periods. Rats expectedly gained weight as they grew from adolescents to adults. MP treatment dose-dependently attenuated body weight through most of the treatment period. Control rats weighed significantly more than both LD ($p <0.05) and HD (*p <0.05) MP rats in treatment weeks 5–13 and 2–13, respectively, and throughout all weeks of abstinence. HD MP rats also weighed less than LD MP rats during treatment weeks 2–13 (#p <0.05).

Fig. 5

Mean (+SEM) daily food intake by treatment group during MP treatment and abstinence periods. Generally, food intake increased over time as rats grew from adolescents to adults. MP treatment decreased food intake during some of the treatment period, particularly the first few weeks. Control rats ate significantly more than both LD ($p <0.05) and HD (*p <0.05) MP rats in treatment weeks 1–5, and 4–5 and 9–10, respectively. HD MP rats also ate less than LD MP rats during treatment weeks 1–2 (#p <0.05).

Fig. 6

A: Mean (+SEM) floor plane moves performed in the open field by treatment group during MP treatment and abstinence periods. HD MP treated rats performed a greater number of moves than both LD MP and water treated rats overall (p <0.001 for both), and in treatment weeks 1–9 and 11 (p <0.05 for all). *HD

Fig. 6

A: Mean (+SEM) floor plane moves performed in the open field by treatment group during MP treatment and abstinence periods. HD MP treated rats performed a greater number of moves than both LD MP and water treated rats overall (p <0.001 for both), and in treatment weeks 1–9 and 11 (p <0.05 for all). *HD

Fig. 7

A: Mean (+SEM) activity over the circadian cycle by treatment group during MP treatment. A normal circadian cycle was exhibited by all groups, with no apparent shift in cycle. HD MP treatment resulted in hyperactivity compared to both LD MP and water treatment overall (p <0.05), and at specific times during the dark cycle: 09:00–17:30 (#p <0.05) and 09:30–19:00 (*p <0.05), respectively. LD MP treatment decreased activity compared to controls at a few time points during the dark cycle, 10:00–10:30 and 13:00–13:30 ($p <0.05). B: Mean (+SEM) activity over the circadian cycle by treatment group during abstinence. A normal circadian cycle was exhibited by all groups, with no apparent shift in cycle. HD MP treatment resulted in hyperactivity compared to both LD MP and water treatment overall (p <0.05). C: Mean (+SEM) total activity during the dark and light cycles by treatment group during treatment (TX) and abstinence (AB). During treatment, HD MP resulted in increased activity (vs. water *p <0.001; vs. LD MP #p <0.001) and LD MP resulted in decreased activity during the dark compared to water ($p <0.05). During abstinence, previously-treated HD rats were more active during the dark cycle than water (*p <0.01) and previously-treated LD MP rats (#p <0.01). Dark cycle activity of HD MP rats was greater during treatment than during abstinence (^p <0.001).