Corrigendum to “Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic–dopaminergic mechanism of action”

Department of Human Genetics, Emory University, Atlanta, GA 30322, United States.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 08/2008; 91(2):217-22. DOI: 10.1016/j.pbb.2008.07.014
Source: PubMed


Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine beta-hydroxylase knockout (Dbh -/-) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh -/- mice completely lack NE but have hypersensitive DA signaling. It was hypothesized that Dbh -/- mice would be unresponsive to modafinil if the compound acts primarily via NE, but would be hypersensitive to modafinil if it acts primarily via DA. Dbh -/- mice had increased sensitivity to the locomotor-activating and wake-promoting effects of modafinil. Paradoxically, the alpha1-adrenergic receptor antagonist, prazosin, attenuated the effects of modafinil in control mice, but not in Dbh -/- mice. Blockade of DA receptors with flupenthixol decreased modafinil-induced locomotion and wake in both control and Dbh -/- mice. These results suggest that both NE and DA are involved in the behavioral effects of modafinil in control mice, but the requirement for NE can be bypassed by hypersensitive DA signaling.

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    • "The non-amphetaminic mechanism of modafinil stimulatory potency was also shown in mice (Simon et al., 1995). On the other hand, a review compiling contemporary reports claims that modafinil complex action involves the inhibition of dopamine and noradrenaline transporters and the elevation of extracellular catecholamines, glutamate, gammaaminobutyric acid, histamine, and serotonin (Minzenberg and Carter, 2008; Mitchell et al., 2008). Modafinil is generally considered a safe drug with a minimum of adverse effects. "
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    ABSTRACT: The aim of the present study was to compare the behavioral effects of modafinil, an atypical psychostimulatory acting and cognitive-function improving drug, with the effects of the psychostimulants methamphetamine (MET) and MDMA (3,4-methylenedioxymethamphetamine, or "ecstasy") in a model of mouse agonistic behavior. This model enables the observation of ethologically well-defined sociable, timid, aggressive, and locomotor behavioral acts and postures. Singly-housed male mice (isolates) were separated into 4 groups. The observations were performed in 4 sessions, 1 week apart. In each interaction, singly-housed mice were paired with non-aggressive group-housed partners for 4 min in a neutral environment. The isolates received, in a Latin square design, either a) a vehicle or modafinil at doses 2.0, 10.0, or 50.0 mg/kg; or b) a vehicle or MET at doses 1.0, 5.0, or 10.0 mg/kg; or c) a vehicle or MDMA at doses 2.5, 10.0, or 30.0 mg/kg. The isolates were categorized as timid or aggressive according to their behavior in the control interaction (vehicle pre-treatment). Elements of locomotor, sociable, aggressive, and timid behavior were evaluated (one-way ANOVA). In the aggressive mice, no change in the sum of aggressive behavior was measured following modafinil administration, while both methamphetamine and MDMA produced dose-dependent inhibition of aggression (p<0.01). The substantial difference in the tested drug effects on agonistic behavior was an increased occurrence of sociable acts (p<0.01) accompanied by a simultaneous increase of timid acts (p<0.01) recorded after MDMA, but not after modafinil or methamphetamine administration. In the timid mice, at least some doses of modafinil decreased timidity (p<0.01) and increased aggression (p<0.01) with no effect on sociability. Administration of MDMA increased timid activities (p<0.01). Both MDMA and MET decreased sociability (p<0.01).
    Pharmacology Biochemistry and Behavior 05/2012; 102(2):215-23. DOI:10.1016/j.pbb.2012.04.013 · 2.78 Impact Factor
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    • "Specifically, modafinil may exert its effect by increasing electrical coupling across gap junctions between neurons.27 Potentiation of glutaminergic synapses on hypocretin/orexin neurons in the lateral hypothalamus28 together with effects on the GABA and monoaminergic systems are thought to mediate the wakefulness-promoting effects of modafinil and may also account for the observed clinical effect of armodafinil.29,30 In addition, although armodafinil is not a direct or indirect dopamine receptor agonist, it has been shown to bind to the dopamine transporter and inhibit dopamine reuptake.31,32 "
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    ABSTRACT: Excessive sleepiness (ES) is a major but underestimated public health concern associated with significant impairments in alertness/wakefulness and significant morbidity. The term ES has been used in the sleep medicine literature for years, but due to its nonspecific symptoms (ie tiredness or fatigue), it frequently goes unrecognized or is misdiagnosed in primary care. In some cases ES arises due to poor sleep habits or self-imposed sleep deprivation; however, ES is also a key component of a number of sleep/wake disorders and multiple medical and psychiatric disorders. Identification and treatment of ES is critical to improve the quality of life and well-being of patients and for the safety of the wider community. The inability of patients to recognize the nature, extent, and symptomatic profile of sleep/wake disorders requires vigilance on the part of healthcare professionals. Interventions to address ES and its associated impairments, treatment of the underlying sleep/wake disorder, and follow-up are a priority given the potential for serious consequences if left untreated. Wakefulness-promoting agents are available that treat ES associated with sleep/wake disorders. This review examines current approaches for managing this debilitating and potentially life-threatening condition, focusing on the place of armodafinil as a wakefulness-promoting agent.
    Neuropsychiatric Disease and Treatment 09/2010; 6:417-27. · 1.74 Impact Factor
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    • "Saline (0.9%) was then administered intraperitoneally and mice were observed by a trained experimenter for behavioral signs of sleep. Sleep was defined as 2 minutes of uninterrupted sleep behavior, and 75% of the next 10 minutes spent asleep (Mitchell et al., 2008). A single cohort of mice was tested at all time points. "
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    ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.
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