Methylphenidate Administration to Juvenile Rats Alters Brain Areas Involved in Cognition, Motivated Behaviors, Appetite, and Stress

Abstract

Thousands of children receive methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), yet the long-term neurochemical consequences of MPH treatment are unknown. To mimic clinical Ritalin treatment in children, male rats were injected with MPH (5 mg/kg) or vehicle twice daily from postnatal day 7 (PND7)-PND35. At the end of administration (PND35) or in adulthood (PND135), brain sections from littermate pairs were immunocytochemically labeled for neurotransmitters and cytological markers in 16 regions implicated in MPH effects and/or ADHD etiology. At PND35, the medial prefrontal cortex (mPFC) of rats given MPH showed 55% greater immunoreactivity (-ir) for the catecholamine marker tyrosine hydroxylase (TH), 60% more Nissl-stained cells, and 40% less norepinephrine transporter (NET)-ir density. In hippocampal dentate gyrus, MPH-receiving rats showed a 51% decrease in NET-ir density and a 61% expanded distribution of the new-cell marker PSA-NCAM (polysialylated form of neural cell adhesion molecule). In medial striatum, TH-ir decreased by 21%, and in hypothalamus neuropeptide Y-ir increased by 10% in MPH-exposed rats. At PND135, MPH-exposed rats exhibited decreased anxiety in the elevated plus-maze and a trend for decreased TH-ir in the mPFC. Neither PND35 nor PND135 rats showed major structural differences with MPH exposure. These findings suggest that developmental exposure to high therapeutic doses of MPH has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress. Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with MPH may exert effects on brain neurochemistry that modify some behaviors even in adulthood.

Juvenile toxicity assessment of d,l‐methylphenidate in rats

“…These results are in general agreement with previous studies (reviewed above) demonstrating enduring (Gray et al, 2007). The motor activity and passive avoidance results may reflect changes in these areas of the brain, which endured for the post-dosing period until the respective tests were conducted.…”

“…In the male rat, it has been shown that twice daily subcutaneous injections of 5 mg/kg MPH on postnatal days 7-35 can affect brain regions involved in appetite and that the changes were resolved by postnatal day 135 (Gray et al, 2007). However, there was no apparent effect on food consumption during the dosing phase of this study and there was an increase in food consumption in males and females at doses Z 50 mg/kg/day associated with the cessation of dosing.…”

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

“…We observed reduced development of body weight during methylphenidate treatment, which corresponds to earlier reports of reduced weight gain in rats (Gray et al, 2007). Similarly, the Multimodal Treatment of ADHD study has provided evidence for methylphenidate's potential growth suppression of weight and height (Faraone et al, 2008;Jensen et al, 2007).…”

Neonatal CX26 removal impairs neocortical development and leads to elevated anxiety

“…S7). We evaluated the anxiety-like behavior in the open field test (OF) and the elevated plus maze test (EPM) (30). In the OF test, mice were exposed to a flat arena during 15 min of spontaneous movement, and the movement path was simultaneously tracked (Fig.…”