Methylphenidate differentially regulates c-fos and fosB expression in the developing rat striatum

Abstract

Methylphenidate (MPH, Ritalin) is a psychostimulant drug used in very young children with attention deficit hyperactivity disorder (ADHD). To explore the central effects of MPH, we compared repeated MPH treatments on c-fos and fosB expression in the striatum of immature and adult rats. Prepubertal (PD25-38) or adult (PD53-66) male rats were treated once daily for: (a) 14 days with either saline or MPH (2 or 10 mg/kg) or (b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg) on day 14. To determine long-term effects of MPH, another group of prepubertal rats was allowed a drug-free period of 4 weeks following the initial 14 days of treatment, and received a challenge dose of MPH at adulthood. All rats were sacrificed 2 h post-injection on the final day. Expression of c-fos and fosB was quantified by densitometric analysis of cFOS and FOSB-immunoreactivity (-ir). We demonstrated that FOSB-ir was increased by a single dose of MPH in the prepubertal and adult striatum, and this effect was further elevated by chronic MPH in prepubertal rats, in contrast to the inhibitory effect of MPH (2 and 10 mg/kg) on cFOS-ir. In adult rats, repeated MPH down-regulated cFOS-ir only at the higher dose (10 mg/kg), while fosB expression remained at levels comparable to acute MPH. The reduction in cFOS-ir observed in prepubertal rats given repeated MPH (10 mg/kg) persisted in the adult striatum following MPH challenge at adulthood. Our results suggest that (1) repeated MPH treatment differentially regulates c-fos and fosB expression in the immature and adult brain; (2) MPH-induced changes in gene expression may be enduring, and (3) the immature brain is more sensitive to the stimulant effects of MPH than the adult. Thus, our findings have implications for the long-term use of MPH in ADHD.