Abstract
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.
Highlights
Modafinil (2-(benzhydrylsulfinyl)acetamide) is a mild psychostimulant-like agent that increases wakefulness, improves attention and enhances performance in a variety of cognitive tasks [1,2,3]
Modafinil and other compounds—representing different chemical classes of dopamine transporter (DAT) ligands (Fig. 2)—were assayed for their ability to inhibit [3H]CFT binding to WT or mutant DATs expressed in whole HEK293 cells
Recent broad-spectrum receptor screening assays have identified the DAT as the only protein target displaying significant (,10 mM) affinity for modafinil ( Madras et al (2006) showed that modafinil inhibits noradrenaline uptake by the NET, albeit with an IC50 value of
Summary
Modafinil (2-(benzhydrylsulfinyl)acetamide) is a mild psychostimulant-like agent that increases wakefulness, improves attention and enhances performance in a variety of cognitive tasks [1,2,3]. 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 [7,8,9]. Modafinil attenuates craving for cocaine during drug withdrawal and has been shown to decrease selfadministration of smoked cocaine base (crack) in habitual crack users [14,15]. A recent study of modafinil selfadministration in human cocaine addicts demonstrated that modafinil was not administered more frequently than placebo, nor did it occasion cocaine-like subjective effects [16]
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