Enhanced Reactivity and Vulnerability to Cocaine Following Methylphenidate Treatment in Adolescent Rats

Abstract

Treatment of attention deficit hyperactivity disorder with the psychostimulant drug methylphenidate (MP) has increased dramatically among schoolchildren. We tested whether repeated exposure to moderate doses of MP (5 and 10 mg/kg IP for 5 or 7 days) in adolescent rats increased reactivity to cocaine measured by motor responses (ambulations and rearing) to a cocaine challenge in adulthood. We later tested whether repeated exposure to a low dose of MP (2 mg/kg IP for 7 days) enhanced the psychomotor effects of cocaine, measured by different challenge doses (0-30 mg/kg) as well as to the reinforcing effects of cocaine, measured by self-administration of lowdose infusion (75 g/kg, IV). We found that exposure to moderate doses of MP enhanced psychomotor responses to cocaine but exposure to a low dose only increased cocaine self-administration. These results suggest that adolescent exposure to low doses of MP in rats mayMethylphenidate (Ritalin ® ) is used widely in the treatment of attention deficit hyperactivity disorder (ADHD), the most commonly diagnosed disorder of childhood (Swanson et al. 1998). During the 1990s, diagnosis and treatment of this disorder grew dramatically in the United States. Estimates show that up to 15% of school age children may be affected in certain geographical locations (Scahill and Schwab-Stone 2000) and that prevalence is estimated to be 5-10% in the general population (Swanson et al. 1998). In addition, preschoolers (Zito et al. 2000) and children who do not meet the diagnostic criteria for ADHD (Marshall 2000) have recently been identified as two new groups increasingly exposed to this drug. The duration of treatment is several years in childhood, more often extending into adolescence and adulthood (Garland 1998;Robin 1999;Silver 2000;Spencer et al. 2000).Animal studies have shown that MP is a psychostimulant, which, as with cocaine, blocks the dopamine transporter (DAT) (Kuczenski and Segal 1997); thereby increasing extracellular dopamine (DA) levels in the striatum and nucleus accumbens (Kuczenski 1983), brain regions involved in the locomotor and reinforcing effects of psychostimulants and other drugs of abuse (Koob and Bloom 1988 NO . 5 et al. 1999). Oral therapeutic doses of MP effectively block more than 50% of DATs (Volkow et al. 1998); thereby increasing extracellular DA levels (Volkow et al. 2001). These actions are highly associated with the reinforcing properties of drugs (Ritz et al. 1987). Taken together, the well-documented abuse potential of psychostimulants (for reviews see White and Wolf 1991;Robinson and Berridge 1993;Self and Nestler 1995), studies linking ADHD with subsequent substance abuse (Wilens et al. 1997;Clure et al. 1999;Schubiner et al. 2000), and the dearth of controlled studies on the effects of long-term stimulant exposure on the brain, all make MP exposure an important public health issue.Animal models of drug addiction clearly indicate that repeated exposure to psychostimulants results in augmented behaviors (sensitization) that can be detected lo...

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

“…Administration of methylphenidate to periadolescent rats produces changes in subsequent cocaine self-administration (Brandon et al, 2001), cocaine-conditioned place preference (Andersen et al, 2002;Carlezon et al, 2003), and cocaineinduced hyperactivity (Torres-Reveron and Dow-Edwards, 2005) in adulthood. While the present findings demonstrate that methylphenidate can increase nicotine self-administration in adult rats, there is evidence that the behavioral effects of methylphenidate can differ between adolescent and adult rats (Andersen, 2005;Torres-Reveron and DowEdwards, 2005;Wooters et al, 2006).…”

“Laughing” rats and the evolutionary antecedents of human joy?

“…It is certainly possible that many children are given such drugs partly because they reduce disorderly behaviors, and at time bladder control problems, that arise from playful urges [58,86], but we must be concerned whether such long-term drug treatments have deleterious consequences on brain development [52]. One major concern is the issue of psychostimulant sensitization, which can lead to longterm behavioral changes in animals which might not be deemed desirable [53,91], including increased drug seeking tendencies [10,44]. Indeed, using our 50-kHz laughter measure, we have found evidence for sensitization.…”

Amphetamine, but not methylphenidate, increases ethanol intake in adolescent male, but not in female, rats

“…The studies that assessed the effects of exposure to MPH during adolescence have also produced inconsistent results. MPH treatment during adolescence reduced subsequent CPP by cocaine (Andersen, Arvanitogiannis, Pliakas, LeBlanc, & Carlezon, 2002) yet enhanced cocaine‐induced motor activity and self‐administration (Brandon, Marinelli, Baker, & White, 2001). In another study, adolescent male Wistar rats that had been given MPH (orally from PD 27–33) did not exhibit behavioral sensitization when challenged with either MPH (1.0 or 10.0 mg/kg) or nicotine (0.4 mg/kg; Justo, Carneiro‐de‐Oliveira, Delucia, Aizenstein, & Planeta, 2010).…”