Diurnal differences in sensitization to methylphenidate.

Using a computerized monitoring system, we investigated the development of motor sensitization to methylphenidate (MPD) in the rat, and determined whether sensitization was dependent on the time of drug administration. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days served as baseline for each rat, and on day 3 each rat received a saline injection. The locomotor response to 0.6, 2.5, or 10 mg/kg of MPD was tested on day 4, followed by 5 days of single injections of 2.5 mg/kg MPD (days 5-9). After 5 days without injection (days 10-14) rats were re-challenged (day 15) with the same doses they received on day 4. There were three separate challenge doses and four different times of administration: 08:00, 14:00, 20:00, or 02:00 h. Horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements were recorded. Sensitization to MPD was dependent on the time of administration, the motor index studied, and the challenge dose used. It was more pronounced for forward ambulation than for rearing, with no augmented response to stereotypic effects. The expression of the sensitized response was dose-dependent and mainly observed with the 0.6 and 2.5 mg/kg challenge dose groups. The development of sensitization to MPD was also time-dependent with the most robust sensitization occurring during the light phase, while no sensitization was observed during the middle of the dark phase. In addition, repeated MPD administration caused a significant increase in the amount of nocturnal forward ambulation that persisted long after cessation of drug treatment.