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.
Highlights
Attention Deficit Hyperactivity Disorder (ADHD), with typical symptoms of inattention, hyperactivity, and impulsivity beginning in childhood, is one of the most frequently diagnosed neuropsychiatric disorders
Male high dose (HD) MP rats showed decreased fluid intake in comparison to male water control rats throughout treatment, as well as decreased consumption compared to low dose (LD) MP rats in early treatment weeks
Male LD MP rats showed decreased fluid intake in comparison to male water control rats in later treatment weeks
Summary
Attention Deficit Hyperactivity Disorder (ADHD), with typical symptoms of inattention, hyperactivity, and impulsivity beginning in childhood, is one of the most frequently diagnosed neuropsychiatric disorders. Diagnosis rates of ADHD have jumped to ∼11% of school-aged children in the United States, an increase of over 40% during the last decade (Visser et al, 2014). Concern has arisen about the use of MP during critical periods of neurodevelopment, such as adolescence, when the brain is susceptible to external stimuli (Spear, 2000; Dahl, 2004) During this stage of development, the brain undergoes numerous changes in regions such as the prefrontal cortex, hippocampus, and limbic system, including the sprouting and pruning of synapses and changes in neurotransmitter concentrations and receptor levels (Rice and Barone, 2000; Spear, 2000; Dahl, 2004; Giedd, 2005). This presents concerns regarding subsequent effects of MP on neurobiology, development, and behavior
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