Psychopharmacology

, Volume 181, Issue 3, pp 537–549

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers

  • R. H. Hou
  • C. Freeman
  • R. W. Langley
  • E. Szabadi
  • C. M. Bradshaw
Original Investigation

Abstract

Rationale

Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be “switched off” by the α2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects.

Objective

The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers.

Methods

Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary “fatigue waves” (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons.

Results

Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions.

Conclusions

Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.

Keywords

Modafinil Clonidine Central noradrenergic system Locus coeruleus Autonomic nervous system Arousal Pupillary control 

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • R. H. Hou
    • 1
  • C. Freeman
    • 1
  • R. W. Langley
    • 1
  • E. Szabadi
    • 1
  • C. M. Bradshaw
    • 1
  1. 1.Psychopharmacology Section, Division of PsychiatryUniversity of NottinghamNottinghamUK

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