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Daily methylphenidate administration attenuates c-fos expression in the striatum of prepubertal rats
Teena D Chase1, Richard E Brown, Normand Carrey
1Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3 H 4H7, Canada B3J 3G9.
Insights
Long-term methylphenidate (Ritalin) treatment significantly reduces immediate-early gene expression (c-fos) in the developing rat brain. This contrasts with a single dose, which dramatically increases c-fos levels, suggesting altered brain responses with chronic use.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Methylphenidate (Ritalin) is a widely prescribed psychostimulant for ADHD.
- Long-term effects of methylphenidate on gene expression in developing brains are not well understood.
Purpose of the Study:
- To investigate the impact of acute versus chronic methylphenidate administration on immediate-early gene c-fos expression in the developing rat striatum.
Main Methods:
- Prepubertal male rats received daily injections of saline or methylphenidate (1, 2, or 10 mg/kg) for 14 days.
- One group received saline for 13 days followed by a single methylphenidate dose on day 14.
- FOS immunoreactivity (marker of c-fos expression) was measured 2 hours post-injection.
Main Results:
- Methylphenidate dose-dependently increased FOS immunoreactivity.
- A single dose on day 14 (after saline pretreatment) caused a significant c-fos elevation.
- Chronic methylphenidate treatment (14 days) markedly attenuated this c-fos response.
Conclusions:
- Repeated methylphenidate administration, even at clinically relevant doses, significantly inhibits c-fos gene expression in the developing rat striatum.
- This study is the first to demonstrate methylphenidate-induced modifications in gene expression in the developing brain.
- Findings suggest potential implications for chronic methylphenidate use in children.
Abstract:
Methylphenidate (Ritalin) is a psychostimulant drug used to treat children with attention deficit hyperactivity disorder. Despite its widespread and increasing clinical use, little is known about the long-term consequences of drug treatment. We compared the effects of a single injection of methylphenidate with that of long-term methylphenidate injections (one/day; 14 days) on immediate-early gene expression (c-fos) in the striatum of prepubertal male rats. Rats (25 days old) were injected once daily for 14 days with either saline or methylphenidate (1, 2 or 10 mg/kg), or for 13 days with saline followed by one injection of methylphenidate (1, 2 or 10 mg/kg) on day 14, and were sacrificed 2 h post-injection. Methylphenidate dose-dependently increased FOS immunoreactivity in the striatum. A single injection of methylphenidate (2 or 10 mg/kg) on day 14, following saline treatment for 13 days, caused a dramatic elevation in c-fos expression. This effect was significantly attenuated in animals treated chronically with methylphenidate (2 or 10 mg/kg) for the entire 14 days. Our data suggest that repeated methylphenidate treatment, at a clinically relevant dose (2 mg/kg), markedly inhibits immediate-early gene expression in the brain. This is the first demonstration of methylphenidate-induced modification of gene expression in developing rat striatum and may have implications for chronic methylphenidate use in children.