Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects

Abstract

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.

Keywords: Attention Deficit Hyperactivity Disorder; anxiety; methylphenidate; psychostimulant; ritalin.

Figure 1.

Physiological measures (n=24 per group). (A) Weekly food consumption presented as Mean + SEM (α - HD < W, p<.01; $ - HD < LD, p<.01; ^ - HD > W, p<.05; @ - HD > LD, p<.05). Insert: Weekly food consumption during week 11 (treatment) compared to week 18 (abstinence) presented as Mean + SEM. (B) Weekly body weight presented as Mean + SEM (α - HD < W, p<.01; $ - HD < LD, p<.01; * - W > HD & LD (main effect only), p<.05). Insert: Body weight during week 11 (treatment) compared to week 18 (abstinence) presented as Mean + SEM (*p<.05, ***p<.001).

Figure 2:

Open Field (n=24 per group). (A) Move time in the open field presented as Mean + SEM (^ - HD > W, p<.01; @ - HD > LD, p<.01). Insert: Move time during treatment (week 11) and abstinence (week 18) presented as Mean + SEM (*p<.05). (B) Distance traveled in the open field presented as Mean + SEM (^ - HD > W, p<.01; @ - HD > LD, p<.01). Insert: Distance traveled during treatment (week 11) and abstinence (week 18) presented as Mean + SEM (*p<.05). (C) Center distance traveled in the open field presented as Mean + SEM (^ - HD > W, p<.01; @ - HD > LD, p<.05). Insert: Center distance traveled during treatment (week 11) and abstinence (week 18) presented as Mean + SEM (*p<.05).

Figure 3:

Circadian Activity (n=24 per group). (A) Hourly circadian locomotor activity during week 11 of treatment presented as Mean + SEM (# - LD < W, p<.05; ^ - HD > W, p<.001; @ - HD > LD, p<.05; & - LD > W, p<.05). Insert: Total activity during week 11 of treatment presented as Mean + SEM (*p<.05). (B) Hourly circadian locomotor activity during the second week of prolonged abstinence (week 15) presented as Mean + SEM. Insert: Total activity during week 15 presented as Mean + SEM. (C) Beam breaks during the dark phase of the light cycle presented as Mean + SEM (***p<.001).

Figure 4:

Elevated Plus Maze (n=24 per group). Percent of time spent in open arms relative to total test time (+SEM) shown for testing conducted during week 10 of the treatment phase and weeks 2 and 5 of the abstinence phase. The HD group spent a greater proportion of time in the open arms compared to the LD and water groups during MP treatment and abstinence (***p<0.001).

Figure 5:

Forced Swim Test (n=24 per group). (A) Latency to Immobility is shown for testing conducted during week 10 of treatment phase and week 2 of the abstinence phase. During treatment, the HD group had a higher latency to immobility compared to both the LD (p<0.01) and water groups (p<0.001). (B) Immobility time is shown for testing conducted during week 10 of treatment phase and week 2 of the abstinence phase. The HD MP group had a significantly lower time spent immobile than the LD and water groups (p<0.001) during MP treatment. (C) High Activity time is shown for testing conducted during week 10 of treatment phase and week 2 of the abstinence phase. During the MP treatment phase, the HD group spent significantly more time in high activity than both the LD and water groups (p<0.001).