Age-dependent and multifaceted effects of methylphenidate in pre- and peri-adolescent rats.

Abstract

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder affecting approximately 9% of school-aged children. A number of therapeutic options exist to treat ADHD. One, methylphenidate (MPD), improves behavior of patients with ADHD in real life, as well as their performance in laboratory settings. Recent evidence indicates that MPD affects healthy humans in a manner similar to that in ADHD patients. However, data regarding the mechanisms and effects of MPD are inconsistent, particularly with respect to age groups (i.e., children, adolescents, adults). Using the rat as a model, we conducted several studies to clarify the effects of oral MPD on cognitive function, activity and anxiety during pre- and peri-adolescence in animals. A preliminary study revealed apparent age-dependent and multifaceted effects of oral MPD in pre- and peri-adolescent rats. There, we found that daily oral administration of MPD at 3 mg/kg resulted in: (1) improved performance from postnatal day (PND) 22 to 24 but impaired performance from PND 32-34; (2) increased locomotor activity and reduced anxiety-like behaviors at PND 22-23; and (3) improved performance in an attentional task. Moreover, we found that responses to oral MPD at 3 mg/kg varied among rats, specifically in locomotor activity and performance in the attention task. Here, we examined the following three hypotheses stemming from these preliminary data: (1) the effects of oral MPD at clinically-relevant doses on performance in cognitive tasks are age-dependent; (2) oral MPD alters anxiety-related behaviors and locomotor activity in an age-dependent manner, both of which contribute to the effects of MPD on performance in cognitive tasks; (3) individual responses to novelty (i.e., new environments) in rats predict individual behavioral responses to oral MPD, including cognitive performance, anxiety-like behaviors, and locomotor activity. To test our hypotheses, we tested drug-naive pre- and peri-adolescent rats over three age ranges (PND 23 to 28, PND 29 to 34 and PND 36 to 41) for (1) the effects of oral MPD in a radial arm maze (RAM) task; (2) the effects of oral MPD on anxiety-related behaviors and locomotor activity on the elevated plus-maze; and (3) interaction effects between treatment conditions and individual responses to novelty on measures from the behavioral tests. Plasma and brain levels of MPD were also measured to examine the absorption and metabolism of the drug across these age ranges. We found that (1) oral MPD at 3 mg/kg improved RAM performance during PND 36-41 but not during PND 23-28 and PND 29-34; (2) oral MPD at 3 mg/kg reduced anxiety-related behaviors across all ages and increased locomotor activity only on PND 24 and 37; and (3) the MPD-induced increase in locomotor activity correlated with individual response to novelty. Brain and plasma levels of MPD were highest on PND 24, lower on PND 30, and lowest on PND 37. In addition, the higher dose of oral MPD improved RAM performance significantly during PND 36-37. These results suggest that, during pre- and peri-adolescence: (1) oral MPD at a clinically-relevant dose produces multifaceted effects that change across ages, which together contribute to the improved performance on cognitive tasks; (2) these effects, according to known brain circuit information, are likely through independent circuits; and (3) the effects of oral MPD on cognitive performance vary according to the testing procedures and the state of maturation.