Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors
Introduction
Modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal, Provigil] is a wake-promoting substance used for the treatment of excessive sleepiness associated with narcolepsy (Mignot and Nishino, 2005), multiple sclerosis (Kraft and Bowen, 2005) and Parkinson's disease (Nieves and Lang, 2002, Ferraro et al., 1998). Further therapeutic potential of modafinil includes attention-deficit disorder (Swanson et al., 2006), cocaine dependence and withdrawal (Vocci and Elkashef, 2005), postanesthetic sedation and depression (for review see Ballon and Feifel, 2006). The mechanism of action of modafinil is controversial. Early studies have indicated that modafinil acts different from established psychostimulants (Akaoka et al., 1991, Lin et al., 1992) and possesses only minimal potential for abuse (Scammell and Matheson, 1998, Jasinski, 2000, Deroche-Gamonet et al., 2002). Several hypotheses were suggested for the mechanism of modafinil action by in vivo and in vitro studies. Modafinil can increase serotonin release (Ferraro et al., 2000, Ferraro et al., 2002), decrease GABA release and enhance glutamate release in various brain regions (Ferraro et al., 1997, Ferraro et al., 1998, Ferraro et al., 1999), and activate orexin-containing hypothalamic neurons (Chemelli et al., 1999). Studies employing pharmacological tools or genetic ablation of α-1B-adrenoreceptors suggested that modafinil increases wakefulness by activating central noradrenergic transmission (Duteil et al., 1990, Lin et al., 1992, Stone et al., 2002). This hypothesis left several questions unresolved, mainly why modafinil does not affect the peripheral sympathetic system (Duteil et al., 1990) and why in narcoleptic patients modafinil effectively treats excessive daytime sleepiness but fails to prevent the loss of muscle tone that occurs during cataplexy. On the other hand, a number of studies indicate that modafinil interacts with the dopamine system. In an elegant study by Wisor and Eriksson (2005) pharmacological elimination of the noradrenaline transporter-bearing forebrain projections in mice did not influence the efficacy of modafinil action; at the same time evidence was obtained that dopamine-dependent adrenergic signaling is important for the wake-promoting action of modafinil. In another study Wisor et al. (2001) reported that deletion of the DA transporter (DAT) gene in mice causes a 20% increase in wakefulness; moreover wake -promoting effects of classical stimulants (such as amphetamine) and modafinil are abolished. Dopamine-specific reuptake blockers can promote wakefulness in normal and narcoleptic animals better than noradrenaline-selective blockers (Nishino and Mignot, 1997). The action of modafinil seems to be distinct from these drugs of abuse with respect to addiction potential (Nishino et al., 1998, Jasinski, 2000). In contrast to amphetamine, modafinil did not influence the firing pattern of DA neurons (VTA) of anesthetized rat (Akaoka et al., 1991). The action of amphetamine in vivo was attributed to enhanced catecholaminergic function and inhibition of DA neurons, while modafinil demanded α1- and β-adrenoreceptor activity (Lin et al., 1992). On the other hand blockade of catecholamine synthesis with the tyrosine hydroxylase inhibitor α-methyl-dl-p-tyrosine methyl ester (αMPT) abolished the amphetamine, but not the modafinil, action (Lin et al., 1992). This finding is difficult to interpret if the action of modafinil is restricted to the blockade of dopamine uptake (Wisor et al., 2001, Wisor and Eriksson, 2005). We investigated now the modafinil action on DA neurons recorded in brain slices in situ and in acute isolation. We demonstrate D2-receptor-mediated inhibition on VTA and SN dopaminergic, but not GABAergic neurons.
Section snippets
Slice preparation
Coronal brain slices were prepared from 3–4-week-old male Wistar rats. All experiments were conducted in compliance with German law and with the approval of the Bezirksregierung Duesseldorf. The animals were quickly decapitated and the brain transferred to a modified artificial cerebrospinal fluid (ACSF), in which all NaCl had been replaced by 207 mM sucrose (Aghajanian and Rasmussen, 1989). 400-μm-thick slices were cut at the level of the rostral VTA (−5.4 to −6.0 mm from Bregma using a
Results
Bath application of modafinil (20 μM) inhibited all dopaminergic neurons to 68.6 ± 5.1% of control in VTA (n = 7) and to 61.0 ± 6.0% in SN (n = 3, Fig. 1A,C). Effects of modafinil on DA neurons from both neuronal groups were similar. Bath application of modafinil (20 and 50 μM) did not affect the membrane potential or firing rate of GABAergic VTA neurons (n = 6). The inhibitory action of modafinil on midbrain DA neurons resembled that of amphetamine-like psychostimulants, in keeping with recent results on
Discussion
We demonstrate a direct inhibition of midbrain dopaminergic neurons by modafinil. This action does not involve the adrenergic system, but is related to D2-receptor-activation. Considering all available publications on modafinil actions in the brain we suggest that D2-like receptors are the major if not unique target of modafinil. These findings are relevant for understanding the dopaminergic control of sleep–wake regulation.
A number of studies have pointed out the importance of dopamine
Acknowledgements
We thank Annette Scherer and Claudia Wittrock for their excellent technical assistance. These investigations have been supported by European Community, Fifth Framework Program Grant QLRT 826, Graduiertenkolleg 320, Federation pour la Recherche sur le Cerveau (Paris, France for J.S.L.) and a stipend from Schering AG (for T.M.K.).
References (55)
- et al.
Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity
Neurosci. Lett.
(1991) - et al.
Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation
Cell
(1999) - et al.
Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals
Eur. J. Pharmacol.
(1990) - et al.
Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine
Neuroscience
(1998) - et al.
The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission
Neurosci. Lett.
(1998) - et al.
The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade
Neuropsychopharmacology
(1999) - et al.
Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil
Neuropharmacology
(2000) From waking to sleeping: neuronal and chemical substrates
Trends Pharmacol. Sci.
(2005)- et al.
G protein-coupled inward rectifier modulated by dopamine agonists in cultured substantia nigra neurons
Neuroscience
(1995) - et al.
Neurotoxic N-methyl-D-aspartate lesion of the ventral midbrain and mesopontine junction alters sleep-wake organization
Neuroscience
(1999)
Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat
Brain Res.
Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and walking in the rat
Brain Res.
Pharmacological aspects of human and canine narcolepsy
Prog. Neurobiol.
Dopaminergic ventral tegmental neurons modulated by methylphenidate
Life Sci.
Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil
Neuroscience
Intracellular studies in the facial nucleus illustrating a simple new method for obtaining viable motoneurons in adult rat brain slices
Synapse
A systematic review of modafinil: potential clinical uses and mechanisms of action
J. Clin. Psychiatry
What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications
Sleep
Electrophysiological effects of cocaethylene, cocaine, and ethanol on dopaminergic neurons of the ventral tegmental area
J. Pharmacol. Exp. Ther.
Study of the addictive potential of modafinil in naive and cocaine-experienced rats
Psychopharmacology (Berl.)
Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates
J. Neurosci.
Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area
J. Neurosci.
The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus
Neuroreport
Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression
J. Neurosci. Res.
Identification of sleep-promoting neurons in vitro
Nature
Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study
Sleep
Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro
J. Neurosci.
Cited by (0)
- 1
Present address: Clinical Neurobiology, University Hospital for Neurology, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
- 2
These authors contributed equally to the study.