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

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers
Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers
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 ?2-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.
modafinil, clonidine, central noradrenergic system, locus coeruleus, autonomic nervous system, arousal, pupillary control
0033-3158
537-549
Hou, R.H.
470bdcbc-93a9-4dad-aac5-26d455c34376
Freeman, C.
deca0fee-b76a-4fc2-a276-ecedf49c5a24
Langley, R.W.
579cc42e-972f-4422-952f-1c76ecc4b4e3
Szabadi, E.
cff688f8-264f-4ca3-a2c4-cb10930f1956
Bradshaw, C.M.
0baafd10-0e91-4113-b90b-27132bd77305
Hou, R.H.
470bdcbc-93a9-4dad-aac5-26d455c34376
Freeman, C.
deca0fee-b76a-4fc2-a276-ecedf49c5a24
Langley, R.W.
579cc42e-972f-4422-952f-1c76ecc4b4e3
Szabadi, E.
cff688f8-264f-4ca3-a2c4-cb10930f1956
Bradshaw, C.M.
0baafd10-0e91-4113-b90b-27132bd77305

Hou, R.H., Freeman, C., Langley, R.W., Szabadi, E. and Bradshaw, C.M. (2005) Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers. Psychopharmacology, 181 (3), 537-549. (doi:10.1007/s00213-005-0013-8). (PMID:15983798)

Record type: Article

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 ?2-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.

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More information

Published date: 2005
Keywords: modafinil, clonidine, central noradrenergic system, locus coeruleus, autonomic nervous system, arousal, pupillary control

Identifiers

Local EPrints ID: 181857
URI: http://eprints.soton.ac.uk/id/eprint/181857
ISSN: 0033-3158
PURE UUID: b9e91efb-e90d-4bc8-8e69-58fbdb7a678d
ORCID for R.H. Hou: ORCID iD orcid.org/0000-0001-6127-1478

Catalogue record

Date deposited: 18 May 2011 15:21
Last modified: 09 Jan 2022 03:25

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Contributors

Author: R.H. Hou ORCID iD
Author: C. Freeman
Author: R.W. Langley
Author: E. Szabadi
Author: C.M. Bradshaw

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