Action of modafinil on increased motivation (study).
The mean (SD) reductions in [11C]raclopride and [11C]cocaine BPND after modafinil were similar to those reported for a 20-mg oral dose of methylphenidate in normal volunteers, which corresponded to about 5% (6%) for raclopride28 and to about 54% (5%) for [11C]cocaine.27 This indicates that modafinil at therapeutic doses produces elevations in brain dopamine through blockade of dopamine transporters, which are similar to those produced by therapeutic doses of methylphenidate. Even though modafinil’s affinity for dopamine transporters is low relative to methylphenidate (6.390 μM vs 0.025 μM14), the therapeutic doses are much higher for modafinil (200 mg) than for methylphenidate (20 mg).
Two doses of modafinil (200 mg and 400 mg) were evaluated, but neither the plasma modafinil concentrations nor the dopamine transporter blockade or dopamine changes differed between the 2 doses, which may reflect the relatively small sample of the study. The lack of a dose effect is also confounded by the large participant variability in modafinil’s plasma concentrations (particularly for 1 participant in the 400-mg dose group) (Figure 2), which predicted the level of dopamine transporter occupancy (Figure 3).
The variability in plasma modafinil concentration is likely to reflect variability in metabolism of modafinil. Neither modafinil’s plasma concentration nor the level of dopamine transporter occupancy correlated with the dopamine changes. We had reported a similar finding with methylphenidate in which a correlation was found between plasma concentration and dopamine transporter occupancy, but neither plasma concentration nor dopamine transporter occupancy correlated with dopamine changes.32 This reflects that although plasma (and presumably brain) modafinil levels proportionally compete with [11C]cocaine for binding to the dopamine transporters, decreases in [11C]raclopride binding are a function of changes in extracellular dopamine, which are determined not only by dopamine transporter blockade but also by dopamine cell firing. For the same level of dopamine transporter blockade, dopamine changes will be greater when the activity of dopamine cells is high than when it is low.
Stimulant medications act as wake-promoting agents by increasing dopamine (as well as norepinephrine) in brain.6 Modafinil was developed with an expectation that a medication could have a nondopaminergic target for its wake-promoting effects. However, the current findings in humans, along with preclinical studies,9,10 documenting the indispensable role of dopamine in the wake-promoting effects of modafinil, support modafinil’s dopamine-enhancing effects as a mechanism for its therapeutic actions.
The dopamine-enhancing effects of modafinil in the nucleus accumbens may help explain reports of its abuse, since this pharmacological effect is considered crucial for drug reinforcement.33 Indeed, modafinil was shown to be self-administered in monkeys previously trained to self-administer cocaine,34 and in humans modafinil can act as a reinforcer under conditions of behavioral demand.35 However, modafinil is much less potent as a reinforcer than stimulant drugs, and reports of modafinil abuse are rare and much less frequent than those for stimulant drugs.36 Nonetheless, considering the broadening use of modafinil and the results in this study showing that it increases dopamine in the nucleus accumbens at therapeutic doses, its potential for abuse should not be disregarded.
In this study, modafinil’s binding to dopamine transporters overlapped with the binding site of cocaine. This could account for the findings that modafinil interfered with the behavioral effects of cocaine.37 Indeed pilot studies have reported some beneficial effects of modafinil in the treatment of cocaine addiction.38
The [11C]raclopride method does not allow the exclusion of the possibility that decreases reflect down-regulation of D2/D3 receptors and changes in affinity39 rather than dopamine increases. Since microdialysis studies9,11–13 have shown that modafinil increases dopamine in striatum (including nucleus accumbens), this suggests that the findings in this study reflect dopamine increases. The small sample size of the study did not provide sufficient statistical power to detect dose effects. Only healthy young men were tested, which may limit generalizability to other populations. This study did not use a complete placebo design but rather used a placebo to compare the effects of modafinil on each radiotracer, which required that the placebo be given first and the modafinil second, so the possibility of an order effect cannot be ruled out. The order of modafinil doses tested was not randomized; instead the first 5 participants were tested with 200 mg and the subsequent 5 with 400 mg. However, it is unlikely that this affected the results obtained. This study did not measure a clinical outcome, so further studies are necessary to assess this.Go to:
In this pilot study, modafinil acutely increased dopamine levels and blocked dopamine transporters in the human brain. Because drugs that increase dopamine have the potential for abuse, and considering the increasing use of modafinil for multiple purposes, these results suggest that risk for addiction in vulnerable persons merits heightened awareness.Go to:
Financial Disclosures: None reported.
Funding/Support: This research was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the US Department of Energy with infrastructure support from its Office of Biological and Environmental Research. Support was also provided by grant K05DA020001 (J.S.F.) from the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism Intramural research program, grant F32EB997320 (J.M.H.) from the National Institute of Biomedical Imaging and Bioengineering, and grant MO1RR10710 from the General Research Clinical Centers. A Goldhaber distinguished fellowship provided support for Dr Hooker.
Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.Go to:
Author Contributions: Dr Volkow had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Drs Volkow and Fowler contributed equally to this work.
Study concept and design: Volkow, Fowler, Wang.
Acquisition of data: Telang, Wang, Jayne, Hubbard, Carter, Warner, King, Shea, Xu, Muench, Apelskog-Torres.
Analysis and interpretation of data: Volkow, Fowler, Logan, Alexoff, Zhu, Hooker, Wong.
Drafting of the manuscript: Volkow, Fowler, Alexoff, Telang, Wang, Jayne, Hooker, Wong, Hubbard, Carter, Warner, King, Shea, Xu, Muench, Apelskog-Torres.
Critical revision of the manuscript for important intellectual content: Volkow, Fowler, Logan, Zhu.
Statistical analysis: Zhu.
Obtained funding: Volkow, Fowler.
Administrative, technical, or material support: Telang, Wang, Jayne, Hubbard, Carter, Apelskog-Torres.
Study supervision: Volkow, Fowler, Wang.
Previous Presentation: Presented at the 55th Annual Society of Nuclear Medicine meeting; June 16, 2008; New Orleans, Louisiana.
Additional Contributions: David Schlyer, PhD, and Michael Schueller, PhD, Brookhaven National Laboratory, assisted with cyclotron operations. Joan Terry, and Hai-Dee Lee, MS, Brookhaven National Laboratory, assisted with clinical research center operations. Nikhil Pujari, BS, State University of New York at Stony Brook, helped with the image analysis, and Linda Thomas, BS, National Institutes of Health, provided editorial assistance. None received compensation outside of their salaries. We thank the individuals who volunteered for these studies, who each received a volunteer fee.Go to:
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