Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum

Abstract

Methylphenidate is a psychostimulant which inhibits the dopamine transporter and produces dopamine overflow in the striatum, similar to the effects of cocaine. Excessive dopamine action is often associated with changes in gene expression in dopamine-receptive neurons. Little is known about methylphenidate's effects on gene regulation. We investigated whether a methylphenidate treatment regimen known to produce behavioural changes would alter gene expression in the striatum. Using in situ hybridization histochemistry, we assessed the effects of acute and repeated methylphenidate treatment on the expression of immediate-early genes (c-fos, zif 268) and neuropeptides (dynorphin, substance P, enkephalin) in adolescent rats. Acute methylphenidate treatment (0-10 mg/kg, i.p.) produced a dose-dependent increase in the expression of c-fos and zif 268. These effects were most pronounced in the dorsal striatum at middle to caudal striatal levels, and were found for doses as low as 2 mg/kg. Repeated treatment with methylphenidate (10 mg/kg/day, 7 days) increased the expression of dynorphin, which was highly correlated with the acute immediate-early gene response across different striatal regions. Moreover, after repeated methylphenidate treatment, cocaine-induced expression of c-fos and zif 268, as well as of substance P, was significantly attenuated throughout the striatum. These effects of repeated methylphenidate treatment mirror those produced by repeated treatment with cocaine or other psychostimulants and are considered to reflect drug-induced neuroadaptations. Thus, our findings demonstrate that acute and repeated methylphenidate treatment can produce molecular alterations similar to other psychostimulants.

Motor-Skill Learning-Associated Gene Regulation in the Striatum: Effects of Cocaine

“…Our results demonstrate that both acute molecular effects of cocaine, as well as neuroadaptive changes after repeated cocaine treatment are maximal in specific dorsal striatal sectors of Online publication: 28 October 2005 at http://www.acnp.org/citations/ Npp102805050423/default.pdf the middle to caudal striatum (Willuhn et al, 2003). A principally similar topography was found for gene regulation effects of acute and repeated treatment with the psychostimulants methylphenidate (Brandon and Steiner, 2003;Yano and Steiner, 2005a, b) and amphetamine (Meredith and Steiner, 2006). In all of these studies, the most affected striatal sectors are parts of the sensorimotor striatum that receive convergent cortical inputs predominantly from the medial agranular (premotor) and sensorimotor cortex (see Willuhn et al, 2003).…”

Topography of Methylphenidate (Ritalin)-Induced Gene Regulation in the Striatum: Differential Effects on c-Fos, Substance P and Opioid Peptides

“…Our results showed that repeated treatment with 10 mg/kg once daily for 7 days produced increased expression of the neuropeptide dynorphin and attenuated the inducibility of immediate-early genes (c-fos, zif 268) and substance P in the striatum (Brandon and Steiner, 2003). These effects were principally similar to those of repeated cocaine and amphetamine treatments (see Brandon and Steiner, 2003;Willuhn et al, 2003, for discussion).…”

“…Our results showed that repeated treatment with 10 mg/kg once daily for 7 days produced increased expression of the neuropeptide dynorphin and attenuated the inducibility of immediate-early genes (c-fos, zif 268) and substance P in the striatum (Brandon and Steiner, 2003). These effects were principally similar to those of repeated cocaine and amphetamine treatments (see Brandon and Steiner, 2003;Willuhn et al, 2003, for discussion). Substance P and dynorphin are contained in neurons of the direct striatal output pathway (striatonigral neurons) (Gerfen and Young, 1988;Graybiel, 1990;Gerfen and Wilson, 1996), and our results thus suggested that repeated methylphenidate treatment produces molecular alterations in the direct pathway.…”

“…We investigated effects of acute methylphenidate treatment in adult rats for comparison with the wealth of findings on acute molecular effects of psychostimulants such as cocaine and amphetamine (Harlan and Garcia, 1998;Torres and Horowitz, 1999). Acute effects are often predictive of longterm molecular changes in terms of location and magnitude (eg Brandon and Steiner, 2003;Willuhn et al, 2003). Of the few studies that have examined effects of acute methylphenidate on striatal gene expression, most focused on c-fos induction (Lin et al, 1996;Acheson et al, 2001;Penner et al, 2002;Brandon and Steiner, 2003;Chase et al, 2003).…”

“…Acute effects are often predictive of longterm molecular changes in terms of location and magnitude (eg Brandon and Steiner, 2003;Willuhn et al, 2003). Of the few studies that have examined effects of acute methylphenidate on striatal gene expression, most focused on c-fos induction (Lin et al, 1996;Acheson et al, 2001;Penner et al, 2002;Brandon and Steiner, 2003;Chase et al, 2003). Acute effects on the expression of neuropeptides in the striatum have so far not been investigated.…”