Depression-like deficits in rats improved by subchronic modafinil

Regenthal, Ralf; Koch, Holger; Kohler, Christian G.; Preiss, R; Krügel, Ute

doi:10.1007/s00213-009-1493-8

Cited by 32 publications

(17 citation statements)

References 73 publications

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“…Modafinil has been shown to exert antidepressive effects [4] and like other stimulants is an effective adjuvant for those experiencing only marginal improvement with serotonergic compounds [5], [6]. Classical psychostimulants, such as dextroamphetamine and methylphenidate exhibit dose-dependent biphasic effects on cognition—enhancing performance, learning and memory consolidation at moderate doses, but impairing cognitive function when used at high doses [7]–[9].…”

Section: Introductionmentioning

confidence: 99%

The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

2011

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Modafinil is a mild psychostimulant with pro-cognitive and antidepressant effects. Unlike many conventional stimulants, modafinil has little appreciable potential for abuse, making it a promising therapeutic agent for cocaine addiction. The chief molecular target of modafinil is the dopamine transporter (DAT); however, the mechanistic details underlying modafinil's unique effects remain unknown. Recent studies suggest that the conformational effects of a given DAT ligand influence the magnitude of the ligand's reinforcing properties. For example, the atypical DAT inhibitors benztropine and GBR12909 do not share cocaine's notorious addictive liability, despite having greater binding affinity. Here, we show that the binding mechanism of modafinil is different than cocaine and similar to other atypical inhibitors. We previously established two mutations (W84L and D313N) that increase the likelihood that the DAT will adopt an outward-facing conformational state—these mutations increase the affinity of cocaine-like inhibitors considerably, but have little or opposite effect on atypical inhibitor binding. Thus, a compound's WT/mutant affinity ratio can indicate whether the compound preferentially interacts with a more outward- or inward-facing conformational state. Modafinil displayed affinity ratios similar to those of benztropine, GBR12909 and bupropion (which lack cocaine-like effects in humans), but far different than those of cocaine, β-CFT or methylphenidate. Whereas treatment with zinc (known to stabilize an outward-facing transporter state) increased the affinity of cocaine and methylphenidate two-fold, it had little or no effect on the binding of modafinil, benztropine, bupropion or GBR12909. Additionally, computational modeling of inhibitor binding indicated that while β-CFT and methylphenidate stabilize an “open-to-out” conformation, binding of either modafinil or bupropion gives rise to a more closed conformation. Our findings highlight a mechanistic difference between modafinil and cocaine-like stimulants and further demonstrate that the conformational effects of a given DAT inhibitor influence its phenomenological effects.

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Section: Introductionmentioning

confidence: 99%

The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

2011

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“…[39] The mouse forced swimming test [45] and the tail suspension test [46] have been used to provide evidence of antidepressant activity for most approved antidepressants. Various agents such as modafinil, [47] ropinirole [41] and bromocriptine [42] that enhance dopamine transmission show antidepressant activity (i.e. decrease immobility time) in these animal models.…”

Section: Preclinical Evidencementioning

confidence: 99%

Aripiprazole as Adjunctive Therapy for Patients with Major Depressive Disorder

2011

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Aripiprazole was initially approved to treat schizophrenia and later approved for bipolar mania, as a monotherapy and an adjunctive therapy (manic or mixed episodes), and for irritability associated with autism. Aripiprazole is a partial agonist at dopamine D(2) and D(3) and serotonin 5-HT(1A) receptors, and is an antagonist at 5-HT(2A) receptors. This profile, and convincing preliminary data from small-scale studies, provided the rationale for the large-scale exploration of aripiprazole for unipolar depression. Recently, three 6-week, large-scale, randomized, double-blind, placebo-controlled clinical trials demonstrated clinically meaningful efficacy for aripiprazole as an adjunctive therapy to antidepressants for treating major depressive disorder (MDD). In November 2007, aripiprazole was approved by the US FDA as an adjunctive therapy to antidepressants for treating MDD, with support from two of the above-mentioned trials. In the trials, aripiprazole was demonstrated to be safe and well tolerated, and showed a minimal trend for weight gain over the course of a 6-week treatment. The incidence of akathisia was higher than that reported in studies of patients with schizophrenia; however, most cases were mild to moderate and infrequently lead to discontinuation (5/1090 from all three trials). This comprehensive review provides an overview of the data from all three 6-week studies (including a pooled analysis) and from an unpublished 52-week, open-label extension study, to inform physicians and facilitate reasonable treatment decisions. In addition, specific issues associated with the use of aripiprazole as an adjunctive therapy in patients with MDD, including possible early treatment effect, appropriate timing of therapy initiation, appropriate dosing and duration of treatment, possible differential effect on depressive subgroups and long-term tolerability, are also discussed.

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“…Likewise, modafinil, a nonamphetamine stimulant commonly prescribed for the treatment of narcolepsy and daytime sleepiness (Ballon and Feifel 2006;Becker et al 2004;McClellan and Spencer 1998;Thorpy et al 2003), has positive effects on ADHD symptoms (Rugino and Copley 2001;Taylor and Russo 2000;Turner et al 2004) and can enhance attentional and working memory performance in healthy participants (Baranski et al 2004;Dodds et al 2009;Müller et al 2004; Thomas and Kwong 2006;Turner et al 2003a;Wesensten 2006;Winder-Rhodes et al 2009; see Minzenberg and Carter 2008, for a review). Animal studies have also revealed improvement in depression-like attention deficits (Regenthal et al 2009). However, several studies found no effects on sustained attention, spatial span and higher-order executive functions (Müller et al 2004;Randall et al 2003Randall et al , 2005aTurner et al 2003b), whilst beneficial effects might be restricted to low-performing participants (Müller et al 2004;Randall et al 2005b).…”

Section: Introductionmentioning

confidence: 96%

Effects of modafinil and methylphenidate on visual attention capacity: a TVA-based study

et al. 2010

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This is the first pharmacological investigation demonstrating the usefulness of a TVA task for high-resolution and repeated cognitive parameter estimation after cognitive-enhancing medication. Our results confirm previous findings of attentional capacity improvements in low performers and extend the baseline dependency model to methylphenidate. Plasma level-dependent effects of psychostimulants can be modelled on an inverted U-shaped dose-response relationship, which is highly relevant to predict cognitive enhancing and detrimental effects of psychostimulants in patients with cognitive deficits (e.g., attention deficit hyperactivity disorder) and healthy volunteers (e.g., self-medicating academics).

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Depression-like deficits in rats improved by subchronic modafinil

Abstract: The improvement of impaired attentional and information-processing functions under depression-like conditions suggests a benefit of modafinil in treatment of cognitive residual symptoms in affective disorders.

Cited by 32 publications

References 73 publications

The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

Aripiprazole as Adjunctive Therapy for Patients with Major Depressive Disorder

Effects of modafinil and methylphenidate on visual attention capacity: a TVA-based study

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