Research reportMethylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat
Introduction
Methylphenidate (Ritalin) is the most widely prescribed psychomotor stimulant, and due to the relatively long duration of treatment, most of the research conducted on methylphenidate (MPD) in humans has centered on its possible abuse potential, and its side effects 6, 14, 30. Of the MPD studies conducted in animals 10, 33, 34, 45, only a few have investigated the effects of acute and chronic exposure to this drug on motor behavior 1, 31, 48. Chronic intermittent administration of other psychomotor stimulants, such as amphetamines and cocaine, can produce both behavioral sensitization 19, 32, 37, 41and tolerance 8, 11to their locomotor and stereotypic effects in animals.
Moreover, most studies of the behavioral effects of acute and/or chronic administration of stimulants in the rat have been conducted during the light cycle (i.e., the sleep time of the rat) with little attention given to other times of the day (24 h), even though motor behavior varies considerably throughout the light/dark cycle 13, 15, 35. Many drugs, including stimulants, have been shown to vary in their pharmacokinetics and their efficacy throughout the day 42, 43, 49. Even the neurotransmitters involved in the motor effects of stimulants exhibit circadian variations, with fluctuations in dopamine levels as well as in dopamine, α, and β-adrenergic receptor densities in the rat brain 2, 16, 17, 18, 28, 29, which may result in differences in the motor response of animals to stimulants throughout the day. Consequently, variation within and among laboratories regarding the time at which a drug is administered may lead to variability in acute effects, as well as differences in the outcome of chronic administration of stimulants.
The present study was initiated to investigate whether differences in the time of acute MPD administration may cause changes in its effect on motor activity. The effect of MPD on locomotor and stereotypic behavior at the beginning and middle of the light and dark phase was investigated under conditions designed to minimize variability between studies. A computerized animal activity monitoring (CAAM) system 5, 13was used to measure multiple indices of locomotor activity continuously in the rats' home cages. The initial studies focused on: (1) determining whether the motor indices used in monitoring the animals display a stable hourly and daily baseline of activity over the course of the experiment (4 days); (2) investigating relationships between locomotor and stereotypic behavior throughout the light/dark cycle during the normal state and after drug administration; (3) comparing the dose–response relationship for MPD at the four different times of the day; and (4) determining whether there are any persistent alterations in the circadian pattern of locomotor activity after a single administration of MPD.
Section snippets
Materials and methods
Male Sprague–Dawley rats (n=172) weighing 180–225 g were housed in the experiment room in groups of four at an ambient temperature of 21±2°C and relative humidity of 37–42%. Animals were maintained on a 12:12 light/dark schedule (light on at 07:00) for a minimum of 5 to 7 days before experimentation in order to internally synchronize their neuroendocrine systems. On the last day of acclimatization, rats were weighed and individually housed in the experimental cages, and allowed a minimum of 12
Time control
The horizontal activity during the light phase (12 h) and dark phase (12 h), as well as the hourly pattern of activity (24 h) are shown in Fig. 1. Similar observations were obtained for the other indices (TD, VA, SA, and NOS). Baseline activity was stable during both the light and dark phase (Fig. 1A and B). The hourly histogram (Fig. 1C) revealed a clear difference in activity between the rats' inactive (light phase) and active (dark phase) periods, with a consistent circadian rhythm of
Discussion
The main objective of this investigation was to determine whether the dose-related effects of MPD are different during the active (dark phase) and rest (light phase) periods. The only previous comparison of stimulant effects in the light and dark phase was done with amphetamine, and used continuous, rather than acute, drug administration [16].
Stimulants, including MPD, increase two different aspects of motor activity: locomotor and stereotypic behavior 9, 37, 46. Some investigators have
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