Effects of methylphenidate on the impairment of spontaneous alternation behavior in mice intermittently deprived of REM sleep.

ABSTRACT

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. We have previously shown that abnormal behaviors elicited by intermittent rapid eye movement (REM) sleep deprivation stress may fulfill the profile of a model of ADHD. It is well known that the impairment of spontaneous alternation behavior (SAB) in the Y-maze indicates inattentive features of ADHD model animals. On the other hand, it has been reported that nitric oxide (NO) in the hippocampus is required for SAB. In this study, using mice, we investigated whether intermittent REM sleep deprivation stress causes changes in SAB and the expression of NO synthase (NOS) mRNA and in the levels of NO metabolites in the hippocampus. Mice were deprived of REM sleep intermittently by the small-platform method (20 h/day) for 3 days. The SAB, the level of nitrite and expression of endothelial NOS (eNOS) and inducible NOS (iNOS) mRNA in the hippocampus, but not neuronal NOS (nNOS), were significantly decreased by intermittent REM sleep deprivation stress. The decreased levels of SAB, nitrite and iNOS mRNA were significantly increased by methylphenidate treatment, which is used clinically to treat ADHD symptoms. Moreover, these improvement effects of methylphenidate on SAB and the nitrite level were decreased by the administration of selective iNOS and eNOS inhibitors. However, the eNOS inhibitor decreased both nitrate and total NOx levels of the hippocampus in saline treated intermittent REM sleep-deprived mice. These results suggest that the impairment of SAB induced by intermittent REM sleep deprivation stress may serve as a model of the inattention symptom in ADHD. Further, the ameliorating effects of methylphenidate on the impairment of SAB may be mediated through NO production mainly by iNOS in the hippocampus of mice.