Early long-term exposure with caffeine induces cross-sensitization to methylphenidate with involvement of DARPP-32 in adulthood of rats

Abstract

Chronic ingestion of caffeine causes dependence and sleep disturbance in children and adolescents. In rodents, the administration of caffeine may produce behavioral cross-sensitization to some psychostimulants, such as dopaminergic psychoactive drugs. Methylphenidate (MPH; Ritalin) is a psychostimulant used in pediatric- and adult human populations to manage the symptoms associated with attention-deficit hyperactivity disorder (ADHD). Previous studies have suggested that dopamine- and cAMP-regulated phosphoproteins of 32 kDa (DARPP-32) participate in the manifestation of behavioral activity following ingestion of caffeine or MPH. The aim of the present study was to evaluate whether long-term administration of low doses of caffeine in rodents during their adolescence induces cross-sensitization to MPH challenge in their adulthood and investigate the involvement of DARPP-32 in this model. Young rats (P25) consumed water or caffeine (0.3 g/L; mean consumption was 7.5 mg/day/kg) for 28 days. The caffeine consumption was then suspended for 14 days (washout period) when the animals received saline solution or MPH (1, 2, or 10 mg/kg) (P67) intraperitoneally. The locomotor activity of these rats was assessed using the open-field test, following which the immunocontent of DARPP-32 was evaluated in samples of their prefrontal cortex, striatum, or hippocampus. Rats chronically exposed to caffeine in their adolescent period and to inactive doses of MPH (1mg/kg) in adulthood showed augmented locomotor activity. The behavioral effect observed was accompanied by increased levels of DARPP-32 in the striatum and prefrontal cortex compared to control groups (saline or caffeine). However, no alteration caused by these treatments was noted in the hippocampus. In conclusion, chronic caffeine exposure induces likely long-term cross-sensitization to MPH in a DARPP-32-dependent pathway.

Effects of Adolescent Caffeine Consumption on Cocaine Sensitivity

“…The increases in total DARPP-32 expression in the NAc also suggest increased dopamine signaling in the NAc that is associated with heightened sensitivity and reward to cocaine (Fienberg et al, 1998;Zachariou et al, 2002). This finding corroborates with a recent study where adolescent caffeine exposure increased both methylphenidate-induced locomotion and total DARPP-32 expression (Boeck et al, 2009). Together, these findings suggest that chronic caffeine consumption during adolescence enhances dopamine receptor signaling in the NAc.…”

“…Chronic caffeine consumption produces tolerance to caffeine to a greater extent in adolescents compared with adults, suggesting that adolescent animals may exhibit greater brain changes associated with chronic caffeine consumption (Rhoads et al, 2011). Chronic caffeine exposure in adolescents also produces behavioral cross-sensitization with methylphenidate when tested in adulthood in the absence of caffeine (Boeck et al, 2009). Given the differences in sensitivity and susceptibility adolescents display to the behavioral changes produced by chronic caffeine exposure, we hypothesized that caffeine consumption during adolescence may enhance the behavioral sensitivity to cocaine by producing changes in protein expression and dopamine release within the NAc.…”

Nucleus accumbens lesions modulate the effects of methylphenidate

“…Other reports provide evidence alleging that treatment with MPD protects youths from substance abuse later in life [6,76]. In rats, it has also been shown that long-term exposure to caffeine during adolescence induces cross-sensitization to MPD during adulthood [7]. Past data suggests that the inconsistencies in these findings have resulted from a variety of factors, including differences in drug dosage, route of administration, time of administration, age, gender, and animal model used [3,4,20,80].…”

Concentration- and age-dependent effects of chronic caffeine on contextual fear conditioning in C57BL/6J mice

“…A preliminary dose analysis indicated that higher concentrations of caffeine were not well tolerated. Bottles were changed every 2-3 days as described previously (Boeck et al, 2009; da Silva et al, 2003). …”