Juvenile methylphenidate exposure and factors that influence incentive processing

Abstract

Methylphenidate (MPH) is one of the few psychotropic agents approved for use in pediatric populations, underscoring the importance of elucidating any long-term consequences following exposure to this agent. Here, we examined the influence of several variables (i.e. age of assessment, age of exposure, sex, route of administration) on the effect of chronic low-dose MPH (2 mg/kg, twice daily) exposure on place conditioning to cocaine. Juvenile exposure to MPH, but not later exposure, resulted in aversions to cocaine-paired environments when assessed in young adult male rats, but not those entering adolescence. Juvenile MPH enhanced place preferences for cocaine-paired environments in female adolescent rats. The route of administration (i.p. injection or oral ingestion) did not produce enduring differential effects on behavior, and D-MPH was confirmed as the active enantiomer. These observations add to the growing literature on the enduring effects of MPH exposure, and highlight the need for more research in females.

Fig. 1

Schematic of ages of drug administration and test periods. Rats were administered VEH or MPH (2 mg/kg, twice daily) during a 15-day period.

Fig. 2

Age of exposure influenced the effects of MPH on cocaine-induced place conditioning, when assessed 25 days following treatment (F_{2, 46} = 3.05, p = 0.05). Age also influenced conditioned preferences for cocaine-paired environments in general, as displayed by the VEH-exposed groups. *p<0.001, t tests comparing postconditioning values between VEH- and MPH-exposed groups.

Fig. 3

Age of assessment influenced the apparent effect of juvenile MPH exposure on subsequent place conditioning to cocaine. Compared to VEH-treated subjects, which formed preferences for environments associated with 10 mg/kg cocaine regardless of age (* p < 0.05), juvenile MPH-exposed rats displayed neither preferences nor aversions to cocaine-paired environments when tested 5 days following exposure, at P 40 (adolescence). However, when tested 25 days after exposure at P 60 (young adulthood), rats displayed significant aversions to the cocaine-paired environment (* p < 0.05).

Fig. 4

Juvenile exposure to MPH produces sex-dependent effects on conditioning to cocaine-associated environments (F_{1, 79} = 10.27, p < 0.002). a Prior to place conditioning, P 40 males spent equal amounts of time in the saline- or drug-paired environment (p > 0.5). After place conditioning, VEH rats demonstrated significant place preferences for environments associated with 10 and 20 mg/kg cocaine (* p < 0.05, t tests before and after conditioning). MPH male rats, however, formed neither a preference nor aversion to cocaine-associated environments at the 10 mg/kg dose. b In contrast, females exposed to MPH preferred the environment conditioned to 5 and 20 mg/kg cocaine (* p < 0.05, ** p < 0.01; 10 mg/kg: p = 0.08), whereas VEH-exposed females significantly preferred only the 20 mg/kg cocaine-associated environment relative to preconditioning baselines (t tests).

Fig. 5

The route of MPH administration did not significantly influence the effect of MPH exposure on subsequent place conditioning. Intraperitoneal injection and ingestion both resulted in similar aversions (* p < 0.05) to cocaine-paired environments when tested in young adulthood, compared to preferences displayed in VEH-treated subjects (* p < 0.05). Oral gavage, however, resulted in diminished effects in both VEH- and MPH-treated subjects.

Fig. 6

The enduring effects of d,l-MPH are mediated by the d enantiomer. A significant drug × conditioning interaction (F_{2, 26} = 6.04, p < 0.008) indicated that the enantiomers (l-MPH, d,l-MPH, and d-MPH) had differential effects on place conditioning to cocaine-associated environments. Place preferences for cocaine-associated environments were comparable for the VEH-and l-MPH-exposed groups when tested at P 60 (postconditioning comparison: p > 0.8). Conversely, place aversions were similar between the d,l-MPH- and d-MPH-exposed groups (p > 0.8). * p < 0.05, t tests for pre- versus postconditioning to 10 mg/kg cocaine within each exposure group.