Methylphenidate regulates c-fos and fosB expression in multiple regions of the immature rat brain

Methylphenidate (Ritalin, MPH) is a common psychostimulant used to treat childhood attention-deficit hyperactivity disorder (ADHD). Little is known about the long-term developmental effects on gene expression and behavior, which may occur with extended MPH use. We reported previously that the striatum is a major target of MPH, consistent with human MRI studies. In the present study, we tested the hypothesis that MPH is likely to have widespread effects in extra-striatal regions of the brain. We used the expression of two immediate early genes, c-fos and fosB, as probes to map the response of the immature rat brain to single (1 day) versus repeated (14 days) MPH treatment (2 or 10 mg/kg; s.c.) from postnatal day 25 to 38. Consistent with previous reports, the striatum is a major target of acute MPH action, as indicated by elevated levels of cFOS-immunoreactivity (-ir). Increases in c-fos expression were also seen in the nucleus accumbens, cingulate/frontal cortex and piriform cortex, and Islands of Calleja. FosB expression was elevated only in the striatum following a single stimulation. Chronic MPH treatment (10 mg/kg/day for 14 days) resulted in an attenuation of c-fos expression in the striatum and Islands of Calleja. However, levels of cFOS-ir remained elevated in the nucleus accumbens and frontal cortex. In contrast to the inhibitory effect of repeated MPH exposure on c-fos expression, FOSB-ir was further elevated in the striatum, and an increase was observed in the cingulate/frontal and piriform cortices. Thus, chronic MPH differentially regulated expression of c-fos and fosB in several brain regions. Our data suggest that MPH may exert its stimulant effects at multiple sites in the immature brain, which has implications for long-term treatment in children.