Elsevier

Brain Research

Volume 777, Issues 1–2, 28 November 1997, Pages 1-12
Brain Research

Research report
Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat

https://doi.org/10.1016/S0006-8993(97)00880-9Get rights and content

Abstract

The dose–response relationship and time course of effect on motor activity after a single dose of methylphenidate given at different times of the light/dark cycle was investigated using a computerized infrared activity analysis system. After 5 to 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate at 08:00, 14:00, 20:00, or 02:00. Recording was then resumed for an additional 36 to 48 hours. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements. Saline and 0.6 mg/kg did not alter motor activity, but 2.5, 10 and 40 mg/kg significantly increased (P<0.01) motor activity. The time to the maximum effect and the duration of effect increased with dose. Ten mg/kg had the most robust effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. A single injection of methylphenidate had only transient effects. The locomotor stimulating effects of the lower doses were similar whether given during the light or dark phase, despite the large diurnal variations in baseline activity between the activity phases. The stereotypic effects of the highest dose of methylphenidate, however, varied between the light and dark phase, with a smaller stereotypic effect during the dark phase when compared to administration during the light phase.

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

References (49)

  • P.H. Kelly et al.

    Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum

    Brain Res.

    (1975)
  • M.G. Kolta et al.

    Time course of the development of the enhanced behavioral and biochemical responses to amphetamine after pretreatment with amphetamine

    Neuropharmacology

    (1985)
  • C.G. McNamara et al.

    A comparison of the motor-activating effects of acute and chronic exposure to amphetamine and methylphenidate

    Pharmacol. Biochem. Behav.

    (1993)
  • L.R. Nelson et al.

    Enhanced stereotypies after repeated injections but not continuous amphetamines

    Neuropharmacology

    (1978)
  • M.P. Paulus et al.

    Three independent factors characterize spontaneous rat motor activity

    Behav. Brain Res.

    (1993)
  • G.V. Rebec et al.

    Critical issues in assessing the behavioral effects of amphetamine

    Neurosci. Biobehav. Rev.

    (1984)
  • T.E. Robinson et al.

    Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis

    Brain Res. Rev.

    (1986)
  • D.S. Segal et al.

    Long term administration of d-amphetamine: Progressive augmentation of motor activity and stereotype

    Pharmac. Biochem. Behav.

    (1974)
  • I. Creese et al.

    The role of the forebrain dopamine systems in amphetamine-induced stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine

    Psychopharmacologia

    (1974)
  • W. Eichlseder

    Ten years of experience with 1,000 hyperactive children in a private practice

    Pediatrics

    (1985)
  • G.D. Ellison et al.

    Continuous amphetamine intoxication: an animal model of the acute psychotic episode

    Psychol. Med.

    (1983)
  • A.M. Ernst et al.

    Site of action of dopamine and apomorphine in compulsive gnawing behaviour in rats

    Experienta

    (1966)
  • R.M. Ferris et al.

    Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradol on the uptake of l-[3H]norepinephrine and [3H]dopamine by synaptic vesicles from rat whole brain, striatum and hypothalamus

    J. Pharmacol. Exp. Ther.

    (1979)
  • M.W. Fischman, Cocaine and the amphetamines, In H. Y. Meltzer (Ed.), Psychopharmacology: The third generation of...
  • Cited by (0)

    View full text