Sex Differences in the Physiological and Behavioral Effects of Chronic Oral Methylphenidate Treatment in Rats

Abstract

Methylphenidate (MP) is a psychostimulant prescribed for Attention Deficit Hyperactivity Disorder. Previously, we developed a dual bottle 8-h-limited-access-drinking-paradigm for oral MP treatment of rats that mimics the pharmacokinetic profile of treated patients. This study assessed sex differences in response to this treatment. Male and female Sprague Dawley rats were assigned to one of three treatment groups at 4 weeks of age (n = 12/group): Control (water), low dose (LD) MP, and high dose (HD) MP. Rats drank 4 mg/kg MP (LD) or 30 mg/kg MP (HD) during the first hour, and 10 mg/kg (LD) or 60 mg/kg MP (HD) for the remaining 7 h each day. Throughout 3 months of treatment, rats were monitored for body weight, food intake, and fluid intake; as well as tested for open field behavior, circadian activity, novel object recognition, and social interaction. Chronic MP treated rats exhibited reduced fluid intake during distinct treatment weeks to a greater extent in males, and reduced total fluid intake in males only. HD MP treatment decreased body weight in both sexes, while HD MP increased total food intake in females only, likely to offset energy deficits resulting from MP-induced hyperactivity. LD and HD MP increased locomotor activity in the open field, particularly in females and during later treatment weeks. MP dose-dependently increased activity during the dark cycle of circadian testing in females, while in males hyperactivity was only exhibited by HD rats. HD MP increased center activity to a greater extent in males, while MP increased rearing behavior in females only. MP had no effect on social behavior or novel object recognition in either sex. This study concludes that chronic oral MP treatment at clinically-relevant dosages has significant effects on food intake, body weight, open field behavior, and wake cycle activity. Particularly marked sex differences were apparent for locomotor activity, with females being significantly more sensitive to the hyperactivating effects of the drug. These findings suggest that chronic MP exposure beginning in adolescence can have significant behavioral effects that are both dose- and sex-dependent, and raise concerns regarding the reversibility of these effects post-discontinuation of treatment.

Weekday-only chronic oral methylphenidate self-administration in male rats: Reversibility of the behavioral and physiological effects

“…MP also reduces impulsivity and inattention, suppresses anxiety- and depressive-like behaviors, and improves social interaction skills and sleep parameters [3, 7–10]. These wide ranging behavioral effects suggest that non-prescription MP use may cause similar effects in healthy subjects, as were recently reported with rats in terms of behavior [11] and development [12]. Moreover, the known side effects of MP administration such as insomnia, stomachache, headache, anorexia, and the potential for abuse due to MP-induced euphoria may pose additional risks for healthy individuals using MP [13].…”

“…Using this experimental paradigm, the present study investigated the behavioral and developmental effects of 13-week-long MP treatment in rats that excluded weekends, and their reversal following a 5-week abstinence period. We hypothesized that during the treatment phase, chronic MP exposure, regardless of weekend abstinence, would produce the same effects as we previously reported [11]. Furthermore, we expected the effects of chronic MP treatment to be generally reversed following prolonged abstinence, as our recent data indicated [23].…”

“…The 24-hour circadian locomotor activity was assessed as previously described [11] during weeks 1, 2, 4, and 8 of the treatment phase and week 4 of the abstinence phase. Circadian locomotor activity, designated by beam breaks, was measured using a photo beam activity monitor attached to the cage top of each animal’s original home cage (50 cm × 25 cm × 30 cm high) (Starr Life Sciences Corp, VitalView software 1.1; Oakmont, Pennsylvania).…”

“…Anxiety-like behavior was assessed using an elevated plus maze during treatment week 10 and abstinence weeks 2 and 5 as previously described [11]. Briefly, each rat was placed on the center of the elevated plus maze and then allowed to explore the four arms of the maze for 5 minutes.…”

Adolescent food restriction in rats alters prefrontal cortex microglia in an experience-dependent manner

“…The paradigm was developed based on earlier experiments in our laboratory wherein we observed that free-fed males and females between P35-P55 consume between 15-25g or 12-23g, respectively, increasing daily intake by approximately one gram every two days [unpublished observations, but similarly reported in (Amancio-Belmont, Romano-Lopez, Ruiz-Contreras, Mendez-Diaz, & Prospero-Garcia, 2017) and (Robison et al, 2017)]. We have observed that limiting food to 85-90% of free-fed intake reduced subject weight to ~80% of free-fed weight.…”