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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

Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Room B109, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
Psychopharmacology (Impact Factor: 3.99). 10/2005; 181(3):537-49. DOI: 10.1007/s00213-005-0013-8
Source: PubMed

ABSTRACT 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 alpha2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects.
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.
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.
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.
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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    • "Indeed, recent studies have reported that pupil diameter tracks changes in the exploration-exploitation trade-off [Gilzenrat et al., 2010; Jepma and Nieuwenhuis, 2011] and the uncertainty associated with incoming taskrelevant information [Nassar et al., 2012; Preuschoff et al., 2011] in ways that are generally consistent with prominent accounts of LC-NA function [Aston-Jones and Cohen, 2005; Yu and Dayan, 2005]. However, the promise of these observations is tempered by the fact that, aside from indirect pharmacological manipulation [Hou et al., 2005] and an unpublished primate single-unit recording study [Rajkowski et al. 1993], no evidence actually exists to support an anatomical or functional connection between LC neurons and the pupil. "
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    • "However, R-MOD appears to activate LC activity in experimental animals and in humans, as shown by induction of Fos-like immunochemistry in the rat brain (Fiocchi et al. 2009) and stimulation of extracellular NE levels in the prefrontal cortex (along with DA) and rostromedial hypothalamus (de Saint Hilaire et al. 2001). Moreover, in a study on arousal and autonomic functions in humans (Hou et al. 2005), MOD was shown to activate noradrenergic neurons in the LC, without affecting extra-coerulear noradrenergic neurons, compared to clonidine. Hence, presently, it is unclear how MOD affects the noradrenergic system, as it does not appear to directly inhibit the reuptake of NE via the transporter, but "
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    • "While drugs targeted at α 2 -adrenoceptors are likely to have a direct effect on LC activity, a number of drugs may modify LC activity indirectly , by modulating excitatory and inhibitory inputs to the LC. Thus the wakefulness-promoting drug modafinil facilitates the acoustic startle response in humans (Samuels et al., 2007), probably by potentiating the dopaminergic excitation of LC neurones (Hou et al., 2005). Indeed, the activation of the LC by modafinil has been demonstrated by fMRI in human subjects (Minzenberg et al., 2008). "
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