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Modafinil Pharmacology: A Practitioner's Review of Neurochemical Actions and Cognitive Effects

How modafinil's weak dopamine transporter inhibition combines with orexin, histamine, glutamate, and GABA modulation to produce wake-promoting and cognitive-enhancing effects without the abuse liability of classical psychostimulants.

Author Shane Hellmrich Studied health promotion, Curtin University
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Suggested citation Hellmrich, S. (2026). Modafinil pharmacology: A practitioner's review of neurochemical actions and cognitive effects. BuyModa. Retrieved from https://buymoda.net/research/modafinil-pharmacology/

Modafinil's wake-promoting and cognitive-enhancing effects originate from a mechanism distinct from classical psychostimulants: weak dopamine transporter (DAT) inhibition combined with concerted modulation of orexin, histamine, noradrenergic, glutamatergic, and GABAergic systems (Mereu et al., 2013; Hersey et al., 2021). Unlike amphetamine, which reverses DAT transport to flood synapses with dopamine, modafinil binds DAT with comparatively low affinity (Mignot et al., 1994; Volkow et al., 2009) and does not produce the marked nucleus accumbens dopamine elevations associated with addictive psychostimulants (Shuman et al., 2009; Wuo-Silva et al., 2019). This regional specificity, particularly the preferential modulation of prefrontal catecholamines, accounts for both modafinil's cognitive benefits in attention and working memory (Bisagno et al., 2016) and its substantially lower abuse liability (Hersey et al., 2021; Olive et al., 2011).

Methodology

This article combines a narrative literature review with original practitioner observations. The literature component synthesises peer-reviewed neuropharmacology, pharmacology, and clinical psychiatry research published between 1994 and 2022, identified through PubMed and Google Scholar searches using the terms "modafinil mechanism", "modafinil dopamine transporter", "modafinil orexin", "modafinil GABA glutamate", and "modafinil cognitive enhancement". Inclusion criteria for the literature component: peer-reviewed primary research, systematic reviews, and meta-analyses examining modafinil's neurochemical actions or cognitive effects in human or animal models. The reference list comprises 60 primary and review sources.

The practitioner observation component draws on personal records of modafinil and armodafinil purchasing, dosing, and product evaluation between 2014 and 2026, across vendors shipping to the United States, Australia, the United Kingdom, Canada, and the European Union, and across multiple manufacturers including Sun Pharmaceutical Industries (Modalert, Modvigil) and HAB Pharma (Modafil MD). These observations are single-operator and longitudinal, not controlled experimental data, and are presented in dedicated callout blocks throughout the page rather than mixed with the literature claims.

Summary of effects across neurotransmitter systems

The table below summarises modafinil's documented effects on each major neurotransmitter system, the brain regions implicated, and the behavioural outcome each contributes to. Each row is supported by the literature reviewed in the sections that follow.

System Effect Primary regions Behavioural outcome
Dopamine Weak DAT inhibition; raises extracellular dopamine Prefrontal cortex (preferential); nucleus accumbens (limited) Attention, motivation, wakefulness
Norepinephrine NET inhibition; modulates α1-adrenoceptors Locus coeruleus, cortex Arousal, vigilance
Orexin / hypocretin Activates orexin neurons (c-Fos expression) Lateral hypothalamus Wake-promotion, sleep-wake stability
Histamine Indirect activation, dependent on intact orexin signalling Tuberomammillary nucleus Wake-promotion, locomotor activity
Glutamate Increases extracellular release; raises glutamine synthetase activity Dorsal striatum, hippocampus, thalamus, diencephalon Excitatory tone, alertness
GABA Reduces outflow Cortex, striatum, posterior hypothalamus Disinhibition of arousal centres
Source: BuyModa, 2026, synthesised from Hersey et al. (2021), Olive et al. (2011), Qu et al. (2008), Volkow et al. (2009), and additional sources cited below.

Dopaminergic and noradrenergic systems

The primary mechanism of modafinil involves the modulation of catecholamines. Modafinil binds directly to the dopamine transporter and the norepinephrine transporter (Qu et al., 2008), and in the human brain it occupies DAT to increase extracellular dopamine concentrations (Volkow et al., 2009). Unlike amphetamine and methamphetamine, which reverse DAT transport and act as monoamine releasers, modafinil functions as a weak inhibitor (Olive et al., 2011; Żółkowska et al., 2009). Its DAT affinity is low (Mignot et al., 1994), and substantial transporter occupancy requires relatively high plasma concentrations (Garza et al., 2009).

This atypical interaction with DAT is mechanistically distinct from cocaine-like inhibitors (Schmitt & Reith, 2011, 2012). Modafinil reaches lower maximal dopamine levels in the nucleus accumbens than cocaine (Løland et al., 2012), is not self-administered by rodents under standard conditions (Haile et al., 2012), and does not function as a reinforcer in cocaine-using volunteers (Vosburg et al., 2009). These features collectively support its evaluation as a candidate pharmacotherapy for cocaine and methamphetamine use disorders (Anderson et al., 2011; Heinzerling et al., 2010; Martínez-Raga et al., 2008; Roberts et al., 2020). Counter-evidence does exist: dose-dependent locomotor activation, conditioned place preference, and behavioural sensitisation have been observed in some rodent paradigms (Nguyen et al., 2010; Paterson et al., 2010; Wuo-Silva et al., 2016, 2019), and case reports of modafinil dependence have been published (Alaçam et al., 2018; Kim, 2012). However, the abuse liability remains substantially lower than that of amphetamines (Tsapakis et al., 2020; Uguen et al., 2013).

Noradrenergic transmission contributes to modafinil's behavioural profile alongside dopamine. Studies in dopamine β-hydroxylase knockout mice indicate a dual noradrenergic-dopaminergic mechanism (Mitchell et al., 2008; Mitchell & Weinshenker, 2009), and α1B-adrenoceptor activity has been implicated in memory effects following sleep deprivation (Piérard et al., 2007). DAT gene deletion in mice abolishes modafinil-induced wakefulness (Wisor et al., 2001), confirming DAT as essential, while leaving room for parallel noradrenergic contributions.

Practitioner observation: peripheral effects and post-dose recovery. [SHANE: 3 to 5 sentences on the subjective profile of modafinil compared to caffeine or any classic stimulant exposure you have observation data for. Specifically: presence or absence of peripheral effects (heart rate, hand tremor, vasoconstriction sensation), subjective onset character (gradual vs. abrupt), and the post-dose recovery profile (presence or absence of a crash). This is the most-cited type of practitioner data in journalism on this drug class because the "no peripheral activation" claim from the academic literature is otherwise unverifiable to a non-clinical reader. Frame as observational, single-operator, 2014 to 2026. Do not generalise to all users.]

Orexin and histamine pathways

Modafinil activates the orexin (hypocretin) system, which is central to sleep-wake regulation. Administration increases c-Fos expression in orexin-containing hypothalamic neurons (Hersey et al., 2021; Scammell et al., 2000), and this activation is required for downstream histaminergic effects in the tuberomammillary nucleus (Hersey et al., 2021; Qu et al., 2008). Reductions in histamine, or loss of histamine neurons, blunt modafinil's wakefulness-promoting and locomotor effects (Hersey et al., 2021; Lin et al., 2007; Parmentier et al., 2007).

Glutamatergic synapses on hypocretin/orexin neurons are potentiated by modafinil (Rao et al., 2007, 2008), and electrotonic coupling through gap junctions has been proposed as an additional mechanism contributing to network-level arousal effects (Diaper et al., 2013; Siegel, 2008; Tanda et al., 2020). The convergence of orexin activation, histaminergic disinhibition, and gap-junction coupling distinguishes modafinil's wake-promoting mechanism from monoamine-release-driven stimulants (Boutrel & Koob, 2004; García-Rill et al., 2012).

GABA and glutamate modulation

Modafinil shifts the excitatory-inhibitory balance toward arousal. Extracellular glutamate is increased in the dorsal striatum, hippocampus, thalamus, and diencephalon (Ferraro et al., 1997; Olive et al., 2011), and the activity of glutamine synthetase, the enzyme that converts glutamate to glutamine for storage, rises in parallel (Hersey et al., 2021). Concurrent reductions in GABA outflow have been documented in the cortex, striatum, and posterior hypothalamus, with the latter contributing to wakefulness by disinhibiting tuberomammillary neurons that drive cortical arousal (Olive et al., 2011; Qu et al., 2008; Scammell et al., 2000).

Glutamatergic modulation also appears central to modafinil's effects on drug-seeking behaviour. Increased extrasynaptic glutamate concentration in the nucleus accumbens has been linked to attenuation of cocaine reinstatement and reduced relapse in psychostimulant addiction models (Gass & Olive, 2007; Jensen et al., 2022; Mahler et al., 2012; Scofield & Kalivas, 2014; Xi & Gardner, 2008). This pathway operates partly independently of modafinil's dopaminergic actions and is one reason atypical DAT inhibitors are being developed as candidate therapies for substance use disorders (Cao et al., 2016; Reith et al., 2014; Tunstall et al., 2017).

Cognitive effects and clinical applications

Beyond wake-promotion, modafinil produces measurable cognitive effects, particularly on tasks dependent on prefrontal cortical function. Working memory, sustained attention, and executive planning improvements are reported most consistently in sleep-deprived and clinical populations (Becker et al., 2021; Roberts et al., 2020). The mechanism is thought to involve preferential elevation of catecholamines in the prefrontal cortex, with dopaminergic D1 and D2 receptor signalling essential to the arousal effect (Huang, 2010; Qu et al., 2008; Young & Geyer, 2010).

Modafinil is used off-label for cognitive dysfunction in psychiatric disorders including schizophrenia, ADHD, and treatment-resistant depression (Tsapakis et al., 2020; Volkow et al., 2009; Yamada et al., 2019). It has shown benefit for object recognition deficits and prefrontal ERK signalling in methamphetamine-exposed mice (González et al., 2014, 2017), and chronic administration ameliorates depressive-like behaviour and hippocampal plasticity impairments in a surgical mouse model of menopause (Yan et al., 2021). Some evidence suggests neuroprotective effects through reduction of cytotoxicity and free radicals induced by sleep deprivation (Olive et al., 2011), although these findings remain preliminary. Effects on cognitive conflict processing in healthy adults are mediated by enhanced inferior frontal gyrus activation and its communication with the dorsomedial prefrontal cortex (Li et al., 2020), consistent with the prefrontal-preferential mechanism described above.

Practitioner observation: tolerance and dependence over 11 years. [SHANE: 4 to 6 sentences on the 11-year tolerance and dependence pattern from longitudinal personal use. Specifically: did you observe escalating dose requirements over time, did you observe physical or psychological dependence, did you observe withdrawal on cessation, did you observe habituation in subjective sharpness without dose escalation? Frame honestly. If the observation is "no detectable tolerance, no dependence, no withdrawal," say so plainly. Note that academic literature on tolerance is short-window and small-sample; long-window single-operator data is the gap your observation fills. Frame as observational, not as a clinical claim.]

Practical implications: pharmacology and generic equivalence

The pharmacology described above assumes pharmaceutical-grade product as supplied for clinical research, almost always Provigil-labelled product manufactured by Cephalon (now Teva). Most users sourcing modafinil through online pharmacies receive generic versions manufactured in India by Sun Pharmaceutical Industries (Modalert, Modvigil) or HAB Pharma (Modafil MD), among others. The published mechanism is dose-dependent in a conventional sense: more drug at the receptor produces more catecholamine elevation, more orexin and histaminergic activation, and more wake-promotion, up to receptor saturation. There is no special pharmacology that would make brand-name product behave differently from a chemically equivalent generic.

Two predictions follow. If a generic is bioequivalent to the reference product (similar API content, similar dissolution profile, similar peak plasma concentration), the cognitive and wake-promoting effects should be indistinguishable from the reference. If a generic is sub-bioequivalent (lower API content per labelled dose, slower or incomplete dissolution, degraded API from improper storage), the pharmacology predicts attenuated or delayed effects. The published literature does not address how often online-pharmacy generics deviate from bioequivalence, in what direction, or whether deviations correlate with manufacturer, batch, packaging, or storage conditions, because the academic studies were conducted on standardised pharmaceutical-grade product.

Practitioner observation: batch and manufacturer variability, 2014 to 2026. [SHANE: 5 to 8 sentences on observed batch-to-batch and manufacturer-to-manufacturer variability across 11 years and across multiple shipping destinations. Specifically: which manufacturers consistently produced product matching expected onset and duration, which produced inconsistent results, and any documented changes (packaging shifts, pill markings, colour changes, scoring differences) that correlated with observed effect changes. Reference Sun Pharma (Modalert, Modvigil) and HAB Pharma (Modafil MD) by name where you have data. This is the single most-original observation in the document and the strongest candidate for journalist citation, because the academic literature cannot answer the question "does the generic I bought online behave like Provigil?" Frame as observational, single-operator, longitudinal, not as a clinical or regulatory claim. This block is also the natural bridge to /our-testing-process/ when that asset publishes.]

Limitations

The literature component of this article is a narrative review, not a systematic meta-analysis. Most mechanism findings derive from rodent and primate models; human PET imaging confirms DAT occupancy in vivo (Volkow et al., 2009) but full mechanistic translation to human cognition remains incomplete. Cognitive enhancement effects observed in healthy adults are smaller and more variable than effects in sleep-deprived or clinically affected populations (Roberts et al., 2020). Several mechanistic findings remain contested, including the relative contributions of dopaminergic versus noradrenergic and glutamatergic pathways to wakefulness (Mitchell et al., 2008; Wisor et al., 2001), and the extent to which abuse-liability data from rodent paradigms generalise to humans (Wuo-Silva et al., 2016). The practitioner observations are single-operator and longitudinal, not controlled experimental data; they are intended to add real-world context that the academic literature on pharmaceutical-grade product cannot provide, not to substitute for it. This article does not constitute medical advice and is not a substitute for consultation with a qualified clinician.

References

  • Aggarwal, S., & Mortensen, O. V. (2017). Overview of monoamine transporters. Current Protocols in Pharmacology, 79(1). https://doi.org/10.1002/cpph.32
  • Alaçam, H., Başay, Ö., Tümkaya, S., Mart, M., & Kar, G. (2018). Modafinil dependence: A case with attention-deficit/hyperactivity disorder. Psychiatry Investigation, 15(4), 424–427. https://doi.org/10.30773/pi.2016.10.25
  • Anderson, A., Li, S.-H., Biswas, K., McSherry, F., Holmes, T. H., Iturriaga, E., Kahn, R., Chiang, N., Beresford, T. P., Campbell, J., Haning, W., Mawhinney, J., McCann, M., Rawson, R. A., Stock, C., Weis, D., Yu, E., & Elkashef, A. (2011). Modafinil for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 120, 135–141. https://doi.org/10.1016/j.drugalcdep.2011.07.007
  • Becker, M., Repantis, D., Dresler, M., & Kühn, S. (2021). Cognitive enhancement: Effects of methylphenidate, modafinil and caffeine on latent memory and resting state functional connectivity in healthy adults. medRxiv. https://doi.org/10.1101/2021.11.07.21266019
  • Bisagno, V., González, B., & Urbano, F. J. (2016). Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits. Pharmacological Research, 109, 108–118. https://doi.org/10.1016/j.phrs.2016.01.013
  • Black, S. W., Yamanaka, A., & Kilduff, T. S. (2015). Challenges in the development of therapeutics for narcolepsy. Progress in Neurobiology, 152, 89–113. https://doi.org/10.1016/j.pneurobio.2015.12.002
  • Boutrel, B., & Koob, G. F. (2004). What keeps us awake: The neuropharmacology of stimulants and wakefulness promoting medications. Sleep, 27(6), 1181–1194. https://doi.org/10.1093/sleep/27.6.1181
  • Cao, J., Slack, R. D., Bakare, O. M., Burzynski, C., Rais, R., Slusher, B. S., Kopajtic, T., Bonifazi, A., Ellenberger, M. P., Yano, H., He, Y., Bi, G.-H., Xi, Z., Løland, C. J., & Newman, A. H. (2016). Novel and high affinity 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues as atypical dopamine transporter inhibitors. Journal of Medicinal Chemistry, 59(23), 10676–10691. https://doi.org/10.1021/acs.jmedchem.6b01373
  • Diaper, A., Law, F., & Melichar, J. (2013). Pharmacological strategies for detoxification. British Journal of Clinical Pharmacology, 77(2), 302–314. https://doi.org/10.1111/bcp.12245
  • Esposito, R., Cilli, F., Pieramico, V., Ferretti, A., Macchia, A., Tommasi, M., Saggino, A., Ciavardelli, D., Manna, A., Navarra, R., Cieri, F., Stuppia, L., Tartaro, A., & Sensi, S. L. (2013). Acute effects of modafinil on brain resting state networks in young healthy subjects. PLoS ONE, 8(7). https://doi.org/10.1371/journal.pone.0069224
  • Ferraro, L., Antonelli, T., Beggiato, S., Tomasini, M. C., Fuxé, K., & Tanganelli, S. (2013). The vigilance promoting drug modafinil modulates serotonin transmission in the rat prefrontal cortex and dorsal raphe nucleus. Mini-Reviews in Medicinal Chemistry, 13(4), 478–492. https://doi.org/10.2174/1389557511313040002
  • Ferraro, L., Antonelli, T., O'Connor, W. T., Tanganelli, S., Rambert, F. A., & Fuxé, K. (1997). The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. NeuroReport, 8(13), 2883–2887. https://doi.org/10.1097/00001756-199709080-00016
  • García-Rill, E., Kezunovic, N., Hyde, J., Simon, C., Beck, P., & Urbano, F. J. (2012). Coherence and frequency in the reticular activating system (RAS). Sleep Medicine Reviews, 17(3), 227–238. https://doi.org/10.1016/j.smrv.2012.06.002
  • Garza, R. D. L., Zorick, T., London, E. D., & Newton, T. F. (2009). Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers. Drug and Alcohol Dependence, 106, 173–180. https://doi.org/10.1016/j.drugalcdep.2009.08.013
  • Gass, J. T., & Olive, M. F. (2007). Glutamatergic substrates of drug addiction and alcoholism. Biochemical Pharmacology, 75(1), 218–265. https://doi.org/10.1016/j.bcp.2007.06.039
  • González, B., Jayanthi, S., Gómez, N., Torres, O. V., Sosa, M. H., Bernardi, A., Urbano, F. J., García-Rill, E., Cadet, J. L., & Bisagno, V. (2017). Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 82, 1–11. https://doi.org/10.1016/j.pnpbp.2017.12.009
  • González, B., Raineri, M., Cadet, J. L., García-Rill, E., Urbano, F. J., & Bisagno, V. (2014). Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice. Neuropharmacology, 87, 188–197. https://doi.org/10.1016/j.neuropharm.2014.02.002
  • Haile, C. N., Mahoney, J. J., Newton, T. F., & Garza, R. D. L. (2012). Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: Focus on dopamine, norepinephrine and glutamate. Pharmacology & Therapeutics, 134(2), 260–277. https://doi.org/10.1016/j.pharmthera.2012.01.010
  • Heinzerling, K. G., Swanson, A.-N., Kim, S., Cederblom, L., Moe, A., Ling, W., & Shoptaw, S. (2010). Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 109, 20–29. https://doi.org/10.1016/j.drugalcdep.2009.11.023
  • Hersey, M., Bacon, A. K., Bailey, L. G., Coggiano, M. A., Newman, A. H., Leggio, L., & Tanda, G. (2021). Psychostimulant use disorder, an unmet therapeutic goal: Can modafinil narrow the gap? Frontiers in Neuroscience, 15. https://doi.org/10.3389/fnins.2021.656475
  • Howell, L. L., & Negus, S. S. (2014). Monoamine transporter inhibitors and substrates as treatments for stimulant abuse. Advances in Pharmacology, 129–176. https://doi.org/10.1016/b978-0-12-420118-7.00004-4
  • Huang, Z. (2010). Mechanism profile for arousal effects of modafinil. Zhongguo Linchuang Yaolixue Yu Zhiliaoxue.
  • Jensen, K. L., Jensen, S. B., & Madsen, K. L. (2022). A mechanistic overview of approaches for the treatment of psychostimulant dependence. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.854176
  • Keighron, J. D., Quarterman, J. C., Cao, J., DeMarco, E. M., Coggiano, M. A., Gleaves, A., Slack, R. D., Zanettini, C., Newman, A. H., & Tanda, G. (2019). Effects of (R)-modafinil and modafinil analogues on dopamine dynamics assessed by voltammetry and microdialysis in the mouse nucleus accumbens shell. ACS Chemical Neuroscience, 10(4), 2012–2021. https://doi.org/10.1021/acschemneuro.8b00340
  • Kim, D. (2012). Practical use and risk of modafinil, a novel waking drug. Environmental Health and Toxicology, 27. https://doi.org/10.5620/eht.2012.27.e2012007
  • Lazarus, M., Chen, J., Urade, Y., & Huang, Z. (2013). Role of the basal ganglia in the control of sleep and wakefulness. Current Opinion in Neurobiology, 23(5), 780–785. https://doi.org/10.1016/j.conb.2013.02.001
  • Li, J., Yang, X., Zhou, F., Liu, C., Wei, Z., Xin, F., Daumann, B., Daumann, J., Kendrick, K. M., & Becker, B. (2020). Modafinil enhances cognitive, but not emotional conflict processing via enhanced inferior frontal gyrus activation and its communication with the dorsomedial prefrontal cortex. Neuropsychopharmacology, 45(6), 1026–1033. https://doi.org/10.1038/s41386-020-0625-z
  • Lin, J., Dauvilliers, Y., Arnulf, I., Bastuji, H., Anaclet, C., Parmentier, R., Kocher, L., Yanagisawa, M., Lehert, P., Ligneau, X., Perrin, D., Robert, P., Roux, M., Lecomte, J.-M., & Schwartz, J. (2007). An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients. Neurobiology of Disease, 30(1), 74–83. https://doi.org/10.1016/j.nbd.2007.12.003
  • Løland, C. J., Mereu, M., Okunola, O. M., Cao, J., Prisinzano, T. E., Mazier, S., Kopajtic, T., Shi, L., Katz, J. L., Tanda, G., & Newman, A. H. (2012). R-Modafinil (armodafinil): A unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biological Psychiatry, 72(5), 405–413. https://doi.org/10.1016/j.biopsych.2012.03.022
  • Mahler, S. V., Hensley-Simon, M. E., Tahsili-Fahadan, P., LaLumiere, R. T., Thomas, C. A., Fallon, R. V., Kalivas, P. W., & Aston-Jones, G. (2012). Modafinil attenuates reinstatement of cocaine seeking: Role for cystine-glutamate exchange and metabotropic glutamate receptors. Addiction Biology, 19(1), 49–60. https://doi.org/10.1111/j.1369-1600.2012.00506.x
  • Martínez-Raga, J., Knecht, C., & Cepeda, S. (2008). Modafinil: A useful medication for cocaine addiction? Review of the evidence from neuropharmacological, experimental and clinical studies. Current Drug Abuse Reviews, 1(2), 213–221. https://doi.org/10.2174/1874473710801020213
  • Mereu, M., Bonci, A., Newman, A. H., & Tanda, G. (2013). The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacology, 229(3), 415–434. https://doi.org/10.1007/s00213-013-3232-4
  • Mereu, M., Chun, L. E., Prisinzano, T. E., Newman, A. H., Katz, J. L., & Tanda, G. (2016). The unique psychostimulant profile of (±)-modafinil: Investigation of behavioral and neurochemical effects in mice. European Journal of Neuroscience, 45(1), 167–174. https://doi.org/10.1111/ejn.13376
  • Mignot, E., Nishino, S., Guilleminault, C., & Wc, D. (1994). Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep, 17(5), 436–437. https://doi.org/10.1093/sleep/17.5.436
  • Miller, D. K., Dopheide, M. M., Rodvelt, K. R., Schachtman, T. R., & Morgan, R. E. (2007). The behavioral and neurochemical effects of modafinil are mediated by the dopamine transporter. The FASEB Journal, 21(6). https://doi.org/10.1096/fasebj.21.6.a787-c
  • Mitchell, H. A., Bogenpohl, J. W., Liles, L. C., Epstein, M. P., Bozyczko-Coyne, D., Williams, M., & Weinshenker, D. (2008). Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action. Pharmacology Biochemistry and Behavior, 91(2), 217–222. https://doi.org/10.1016/j.pbb.2008.07.014
  • Mitchell, H. A., & Weinshenker, D. (2009). Good night and good luck: Norepinephrine in sleep pharmacology. Biochemical Pharmacology, 79(6), 801–809. https://doi.org/10.1016/j.bcp.2009.10.004
  • Morgan, P., Angarita, G. A., Canavan, S. V., Pittman, B., Oberleitner, L., Malison, R. T., Mohsenin, V., Hodges, S. E., Easton, C. J., McKee, S. A., Bessette, A., & Forselius, E. (2016). Modafinil and sleep architecture in an inpatient-outpatient treatment study of cocaine dependence. Drug and Alcohol Dependence, 160, 49–56. https://doi.org/10.1016/j.drugalcdep.2015.12.004
  • Nguyen, T., Tian, Y., You, I., Lee, S., & Jang, C. (2010). Modafinil-induced conditioned place preference via dopaminergic system in mice. Synapse, 65(8), 733–741. https://doi.org/10.1002/syn.20892
  • Olive, M. F., Cleva, R. M., Kalivas, P. W., & Malcolm, R. (2011). Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacology Biochemistry and Behavior, 100(4), 801–810. https://doi.org/10.1016/j.pbb.2011.04.015
  • Parmentier, R., Anaclet, C., Guhennec, C., Brousseau, E., Bricout, D., Giboulot, T., Bozyczko-Coyne, D., Spiegel, K., Ohtsu, H., Williams, M., & Lin, J. (2007). The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochemical Pharmacology, 73(8), 1157–1171. https://doi.org/10.1016/j.bcp.2007.01.002
  • Paterson, N. E., Fedolak, A., Olivier, B., Hanania, T., Ghavami, A., & Caldarone, B. J. (2010). Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents. Pharmacology Biochemistry and Behavior, 95(4), 449–456. https://doi.org/10.1016/j.pbb.2010.03.006
  • Piérard, C., Liscia, P., Philippin, J.-N., Mons, N., Lafon, T., Chauveau, F., VanBeers, P., Drouet, I., Serra, A. C., & Jouanin, J.-C. (2007). Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice. Pharmacology Biochemistry and Behavior, 88(1), 55–63. https://doi.org/10.1016/j.pbb.2007.07.006
  • Qu, W., Huang, Z., Xu, X., Matsumoto, N., & Urade, Y. (2008). Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. Journal of Neuroscience, 28(34), 8462–8469. https://doi.org/10.1523/jneurosci.1819-08.2008
  • Rao, Y., Hon, L., Borók, E., Rabenstein, R. L., Shanabrough, M., Lü, M., Picciotto, M. R., Horváth, T. L., & Gao, X. (2007). Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. Journal of Clinical Investigation, 117(12), 4022–4033. https://doi.org/10.1172/jci32829
  • Rao, Y., Lü, M., Ge, F., Marsh, D. J., Qian, S., Wang, A. H., Picciotto, M. R., & Gao, X. (2008). Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. Journal of Neuroscience, 28(37), 9101–9110. https://doi.org/10.1523/jneurosci.1766-08.2008
  • Reith, M. E. A., Blough, B. E., Hong, W., Jones, K. T., Schmitt, K. C., Baumann, M. H., Partilla, J. S., Rothman, R. B., & Katz, J. L. (2014). Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug and Alcohol Dependence, 147, 1–19. https://doi.org/10.1016/j.drugalcdep.2014.12.005
  • Robbins, T. W., & Arnsten, A. F. T. (2009). The neuropsychopharmacology of fronto-executive function: Monoaminergic modulation. Annual Review of Neuroscience, 32(1), 267–287. https://doi.org/10.1146/annurev.neuro.051508.135535
  • Roberts, C., Jones, A., Sumnall, H., Gage, S. H., & Montgomery, C. (2020). How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine. European Neuropsychopharmacology, 38, 40–62. https://doi.org/10.1016/j.euroneuro.2020.07.002
  • Scammell, T. E., Estabrooke, I. V., McCarthy, M. T., Chemelli, R. M., Yanagisawa, M., Miller, M. S., & Saper, C. B. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. Journal of Neuroscience, 20(22), 8620–8628. https://doi.org/10.1523/jneurosci.20-22-08620.2000
  • Schmitt, K. C., & Reith, M. E. A. (2011). The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS ONE, 6(10). https://doi.org/10.1371/journal.pone.0025790
  • Schmitt, K. C., & Reith, M. E. A. (2012). Correction: The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS ONE, 7(1). https://doi.org/10.1371/annotation/ba711a7c-13fb-4d18-89a8-28dcc68fcd04
  • Schwartz, J., & Roth, T. (2008). Neurophysiology of sleep and wakefulness: Basic science and clinical implications. Current Neuropharmacology, 6(4), 367–378. https://doi.org/10.2174/157015908787386050
  • Scofield, M. D., & Kalivas, P. W. (2014). Astrocytic dysfunction and addiction. The Neuroscientist, 20(6), 610–622. https://doi.org/10.1177/1073858413520347
  • Shorter, D., & Kosten, T. R. (2011). Novel pharmacotherapeutic treatments for cocaine addiction. BMC Medicine, 9(1). https://doi.org/10.1186/1741-7015-9-119
  • Shuman, T., Wood, S., & Anagnostaras, S. (2009). Modafinil and memory: Effects of modafinil on Morris water maze learning and Pavlovian fear conditioning. Behavioral Neuroscience, 123(2), 257–266. https://doi.org/10.1037/a0014366
  • Siegel, J. M. (2008). Gaps that wake you up. Sleep, 31(12), 1625–1626. https://doi.org/10.1093/sleep/31.12.1625
  • Tanda, G., Mereu, M., Hiranita, T., Jordan, C. J., Chun, L. E., Lopez, J. P., Coggiano, M. A., Quarterman, J. C., Bi, G., Keighron, J. D., Xi, Z., Katz, J. L., & Newman, A. H. (2020). Gap junctions modulate the effects of modafinil on cocaine self-administration behavior in a dopamine-independent fashion in rats. The FASEB Journal, 34, 1–1. https://doi.org/10.1096/fasebj.2020.34.s1.04150
  • Tsapakis, E.-M., Preti, A., Mintzas, M. D., & Fountoulakis, K. N. (2020). Adjunctive treatment with psychostimulants and stimulant-like drugs for resistant bipolar depression: A systematic review and meta-analysis. CNS Spectrums, 26(6), 625–636. https://doi.org/10.1017/s109285292000156x
  • Tunstall, B. J., Ho, C. P., Cao, J., Vendruscolo, J. C. M., Schmeichel, B. E., Slack, R. D., Tanda, G., Gadiano, A. J., Rais, R., Slusher, B. S., Koob, G. F., Newman, A. H., & Vendruscolo, L. F. (2017). Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats. Neuropharmacology, 131, 96–103. https://doi.org/10.1016/j.neuropharm.2017.12.006
  • Uguen, M., Perrin, D., Belliard, S., Ligneau, X., Beardsley, P. M., Lecomte, J., & Jc, S. (2013). Preclinical evaluation of the abuse potential of pitolisant, a histamine H3 receptor inverse agonist/antagonist compared with modafinil. British Journal of Pharmacology, 169(3), 632–644. https://doi.org/10.1111/bph.12149
  • Volkow, N. D., Fowler, J. S., Logan, J., Alexoff, D., Zhu, W., Telang, F., Wang, G., Jayne, M., Hooker, J. M., Wong, C., Hubbard, B., Carter, P., Warner, D. D., King, P., Shea, C., Xu, Y., Muench, L., & Apelskog-Torres, K. (2009). Effects of modafinil on dopamine and dopamine transporters in the male human brain. JAMA, 301(11), 1148. https://doi.org/10.1001/jama.2009.351
  • Vosburg, S. K., Hart, C. L., Haney, M., Rubin, E., & Foltin, R. W. (2009). Modafinil does not serve as a reinforcer in cocaine abusers. Drug and Alcohol Dependence, 106, 233–236. https://doi.org/10.1016/j.drugalcdep.2009.09.002
  • Wisor, J. P. (2013). Modafinil as a catecholaminergic agent: Empirical evidence and unanswered questions. Frontiers in Neurology, 4. https://doi.org/10.3389/fneur.2013.00139
  • Wisor, J. P., Nishino, S., Sora, I., Uhl, G. H., Mignot, E., & Edgar, D. M. (2001). Dopaminergic role in stimulant-induced wakefulness. Journal of Neuroscience, 21(5), 1787–1794. https://doi.org/10.1523/jneurosci.21-05-01787.2001
  • Wuo-Silva, R., Fukushiro, D. F., Hollais, A. W., Santos-Baldaia, R., Mári-Kawamoto, E., Berro, L. F., Yokoyama, T. S., Lopes-Silva, L. B., Bizerra, C. S., Procópio-Souza, R., Hashiguchi, D., Figueiredo, L. A., Costa, J. L., Frussa-Filho, R., & Longo, B. M. (2016). Modafinil induces rapid-onset behavioral sensitization and cross-sensitization with cocaine in mice: Implications for the addictive potential of modafinil. Frontiers in Pharmacology, 7. https://doi.org/10.3389/fphar.2016.00420
  • Wuo-Silva, R., Fukushiro-Lopes, D. F., Fialho, B. P., Hollais, A. W., Santos-Baldaia, R., Marinho, E. A. V., Mári-Kawamoto, E., Yokoyama, T. S., Lopes-Silva, L. B., Berro, L. F., Frussa-Filho, R., & Longo, B. M. (2019). Participation of dopamine D1 and D2 receptors in the rapid-onset behavioral sensitization to modafinil. Frontiers in Pharmacology, 10. https://doi.org/10.3389/fphar.2019.00211
  • Xi, Z., & Gardner, E. L. (2008). Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Current Drug Abuse Reviews, 1(3), 303–327. https://doi.org/10.2174/1874473710801030303
  • Yamada, Y., Inagawa, T., Sueyoshi, K., Sugawara, N., Ueda, N., Omachi, Y., Hirabayashi, N., Madoka, M., & Sumiyoshi, T. (2019). Social cognition deficits as a target of early intervention for psychoses: A systematic review. Frontiers in Psychiatry, 10. https://doi.org/10.3389/fpsyt.2019.00333
  • Yan, Y.-D., Chen, Y., Wang, C.-Y., Ye, C.-B., Hu, Z., Behnisch, T., Huang, Z., & Yang, S.-R. (2021). Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause. Translational Psychiatry, 11(1). https://doi.org/10.1038/s41398-021-01229-6
  • Young, J. W., & Geyer, M. A. (2010). Action of modafinil: Increased motivation via the dopamine transporter inhibition and D1 receptors? Biological Psychiatry, 67(8), 784–787. https://doi.org/10.1016/j.biopsych.2009.12.015
  • Żółkowska, D., Jain, R., Rothman, R. B., Partilla, J. S., Roth, B. L., Setola, V., Prisinzano, T. E., & Baumann, M. H. (2009). Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil. Journal of Pharmacology and Experimental Therapeutics, 329(2), 738–746. https://doi.org/10.1124/jpet.108.146142

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