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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    ABSTRACT: The locus coeruleus-noradrenergic (LC–NA) neuromodulatory system has been implicated in a broad array of cognitive processes, yet scope for investigating this system’s function in humans is currently limited by an absence of reliable non-invasive measures of LC activity. Although pupil diameter has been employed as a proxy measure of LC activity in numerous studies, empirical evidence for a relationship between the two is lacking. In the present study, we sought to rigorously probe the relationship between pupil diameter and BOLD activity localized to the human LC. Simultaneous pupillometry and fMRI revealed a relationship between continuous pupil diameter and BOLD activity in a dorsal pontine cluster overlapping with the LC, as localized via neuromelanin-sensitive structural imaging and an LC atlas. This relationship was present both at rest and during performance of a twostimulus oddball task, with and without spatial smoothing of the fMRI data, and survived retrospective image correction for physiological noise. Furthermore, the spatial extent of this pupil/LC relationship guided a volume-of-interest analysis in which we provide the first demonstration in humans of a fundamental characteristic of animal LC activity: phasic modulation by oddball stimulus relevance. Taken together, these findings highlight the potential for utilizing pupil diameter to achieve a more comprehensive understanding of the role of the LC–NA system in human cognition.
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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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    ABSTRACT: Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population. MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.
    Psychopharmacology 08/2013; 229(3). DOI:10.1007/s00213-013-3232-4 · 3.99 Impact Factor
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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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    ABSTRACT: The locus coeruleus is activated by noxious stimuli, and this activation leads to inhibition of perceived pain. As two physiological reflexes, the acoustic startle reflex and the pupillary light reflex, are sensitive to noxious stimuli, this sensitivity, at least to some extent, may be mediated by the locus coeruleus. The acoustic startle reflex, contraction of a large body of skeletal muscles in response to a sudden loud acoustic stimulus, can be enhanced by both directly (“sensitization”) and indirectly (“fear conditioning”) applied noxious stimuli. The enhancement of the startle response by conditioned fear (“fear-potentiated startle”) involves the activation of the amygdala. The locus coeruleus may also be involved in both sensitization and fear potentiation: pain signals activate the locus coeruleus both directly and indirectly via the amygdala, which results in enhanced motoneurone activity, leading to an enhanced muscular response. The light reflex response is constriction of the pupil evoked by a light stimulus. The pupil is dilated by the sympathetic and constricted by the parasympathetic output to the iris. The locus coeruleus contributes to the sympathetic outflow to the iris and attenuates the parasympathetic output by inhibiting the Edinger-Westphal nucleus, the preganglionic cholinergic nucleus in the light reflex pathway. Noxious stimulation results in pupil dilation (“reflex dilation”), without any change in the light reflex response, consistent with sympathetic activation via the locus coeruleus. Conditioned fear, on the other hand, results in the attenuation of the light reflex response (“fear-inhibited light reflex”), consistent with the inhibition of the parasympathetic light reflex via the locus coeruleus. Directly applied pain and fear conditioning may affect different populations of autonomic neurones in the locus coeruleus, directly applied pain activating sympathetic and fear conditioning parasympathetic premotor neurones.
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