Skip to main content

Advertisement

Log in

The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders

Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale and objectives

Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population.

Results and conclusions

MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  • Afifi AK (2003) The basal ganglia: a neural network with more than motor function. Semin Pediatr Neurol 10:3–10

    Article  PubMed  Google Scholar 

  • Akaoka H, Roussel B, Lin JS, Chouvet G, Jouvet M (1991) Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity. Neurosci Lett 123:20–22

    Article  PubMed  CAS  Google Scholar 

  • Alheid GF, Heimer L (1988) New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience 27:1–39

    Article  PubMed  CAS  Google Scholar 

  • Alvarez VA, Chow CC, Van Bockstaele EJ, Williams JT (2002) Frequency-dependent synchrony in locus ceruleus: role of electrotonic coupling. Proc Natl Acad Sci U S A 99:4032–4036

    Article  PubMed  CAS  Google Scholar 

  • Anderson AL, Li SH, Biswas K, McSherry F, Holmes T, Iturriaga E, Kahn R, Chiang N, Beresford T, Campbell J, Haning W, Mawhinney J, McCann M, Rawson R, Stock C, Weis D, Yu E, Elkashef AM (2012) Modafinil for the treatment of methamphetamine dependence. Drug Alcohol Depend 120:135–141

    Article  PubMed  CAS  Google Scholar 

  • Anderson AL, Reid MS, Li SH, Holmes T, Shemanski L, Slee A, Smith EV, Kahn R, Chiang N, Vocci F, Ciraulo D, Dackis C, Roache JD, Salloum IM, Somoza E, Urschel HC 3rd, Elkashef AM (2009) Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend 104:133–139

    Article  PubMed  CAS  Google Scholar 

  • Antonelli T, Ferraro L, Hillion J, Tomasini MC, Rambert FA, Fuxe K (1998) Modafinil prevents glutamate cytotoxicity in cultured cortical neurons. Neuroreport 9:4209–4213

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus–norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450

    Article  PubMed  CAS  Google Scholar 

  • Baranski JV, Pigeau R, Dinich P, Jacobs I (2004) Effects of modafinil on cognitive and meta-cognitive performance. Hum Psychopharmacol 19:323–332

    Article  PubMed  CAS  Google Scholar 

  • Batejat DM, Lagarde DP (1999) Naps and modafinil as countermeasures for the effects of sleep deprivation on cognitive performance. Aviat Space Environ Med 70:493–498

    PubMed  CAS  Google Scholar 

  • Beck P, Odle A, Wallace-Huitt T, Skinner RD, Garcia-Rill E (2008) Modafinil increases arousal determined by P13 potential amplitude: an effect blocked by gap junction antagonists. Sleep 31:1647–1654

    PubMed  Google Scholar 

  • Bentley P, Driver J, Dolan RJ (2011) Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging. Prog Neurobiol 94:360–388

    Article  PubMed  CAS  Google Scholar 

  • Beveridge TJ, Gill KE, Hanlon CA, Porrino LJ (2008) Review. Parallel studies of cocaine-related neural and cognitive impairment in humans and monkeys. Philos Trans R Soc Lond B Biol Sci 363:3257–3266

    Article  PubMed  Google Scholar 

  • Blandina P, Passani MB (2006) Central histaminergic system interactions and cognition. Exs 98:149–163

    PubMed  CAS  Google Scholar 

  • Boutrel B, Steiner N, Halfon O (2013) The hypocretins and the reward function: what have we learned so far? Front Behav Neurosci 7:59

    Article  PubMed  CAS  Google Scholar 

  • Bowers MS, Chen BT, Bonci A (2010) AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron 67:11–24

    Article  PubMed  CAS  Google Scholar 

  • Brabant C, Alleva L, Quertemont E, Tirelli E (2010) Involvement of the brain histaminergic system in addiction and addiction-related behaviors: a comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence. Prog Neurobiol 92:421–441

    Article  PubMed  CAS  Google Scholar 

  • Brady KT, Gray KM, Tolliver BK (2011) Cognitive enhancers in the treatment of substance use disorders: clinical evidence. Pharmacol Biochem Behav 99:285–294

    Article  PubMed  CAS  Google Scholar 

  • Brasil-Neto JP (2012) Learning, memory, and transcranial direct current stimulation. Front Psychiatry 3:80

    Article  PubMed  Google Scholar 

  • Brioni JD, McGaugh JL (1988) Post-training administration of GABAergic antagonists enhances retention of aversively motivated tasks. Psychopharmacology (Berl) 96:505–510

    Article  CAS  Google Scholar 

  • Brooks DJ (1995) The role of the basal ganglia in motor control: contributions from PET. J Neurol Sci 128:1–13

    Article  PubMed  CAS  Google Scholar 

  • Bubser M, Byun N, Wood MR, Jones CK (2012) Muscarinic receptor pharmacology and circuitry for the modulation of cognition. Handb Exp Pharmacol (208):121–166

  • Buguet A, Moroz DE, Radomski MW (2003) Modafinil—medical considerations for use in sustained operations. Aviat Space Environ Med 74:659–663

    PubMed  CAS  Google Scholar 

  • Cakic V (2009) Smart drugs for cognitive enhancement: ethical and pragmatic considerations in the era of cosmetic neurology. J Med Ethics 35:611–615

    Article  PubMed  CAS  Google Scholar 

  • Caldwell JA Jr, Caldwell JL, Smythe NK 3rd, Hall KK (2000) A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study. Psychopharmacology (Berl) 150:272–282

    Article  CAS  Google Scholar 

  • Campbell VC, Kopajtic TA, Newman AH, Katz JL (2005) Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. J Pharmacol Exp Ther 315:631–640

    Article  PubMed  CAS  Google Scholar 

  • Cao J, Prisinzano TE, Okunola OM, Kopajtic T, Shook M, Katz JL, Newman AH (2010) Structure–activity relationships at the monoamine transporters for a novel series of modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) analogues. ACS Med Chem Lett 2:48–52

    Article  PubMed  CAS  Google Scholar 

  • Cassel JC, Jeltsch H (1995) Serotonergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 69:1–41

    Article  PubMed  CAS  Google Scholar 

  • Chamberlain SR, Odlaug BL, Schreiber LR, Grant JE (2012) Association between tobacco smoking and cognitive functioning in young adults. Am J Addict 21(Suppl 1):S14–S19

    PubMed  Google Scholar 

  • Chatterjee A (2004) Cosmetic neurology: the controversy over enhancing movement, mentation, and mood. Neurology 63:968–974

    Article  PubMed  Google Scholar 

  • Chatterjee A (2007) Cosmetic neurology and cosmetic surgery: parallels, predictions, and challenges. Camb Q Healthc Ethics 16:129–137

    Article  PubMed  Google Scholar 

  • Chudasama Y, Robbins TW (2006) Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans. Biol Psychol 73:19–38

    Article  PubMed  CAS  Google Scholar 

  • Chung S, Hopf FW, Nagasaki H, Li CY, Belluzzi JD, Bonci A, Civelli O (2009) The melanin-concentrating hormone system modulates cocaine reward. Proc Natl Acad Sci U S A 106:6772–6777

    Article  PubMed  CAS  Google Scholar 

  • Cooper JR, Bloom FE, Roth RH (1996a) Dopamine. The biochemical basis of neuropharmacology. Oxford University Press, Oxford, pp 293–351

    Google Scholar 

  • Cooper JR, Bloom FE, Roth RH (1996b) Norepinephrine and epinephrine. The biochemical basis of neuropharmacology. Oxford University Press, Oxford, pp 226–292

    Google Scholar 

  • Coyle JT (1996) The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3:241–253

    Article  PubMed  CAS  Google Scholar 

  • Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP (2005) A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 30:205–211

    Article  PubMed  CAS  Google Scholar 

  • Dackis CA, Kampman KM, Lynch KG, Plebani JG, Pettinati HM, Sparkman T, O'Brien CP (2012) A double-blind, placebo-controlled trial of modafinil for cocaine dependence. J Subst Abuse Treat 43:303–312

    Article  PubMed  Google Scholar 

  • Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771–784

    Article  PubMed  CAS  Google Scholar 

  • De La Garza R 2nd, Zorick T, London ED, Newton TF (2010) Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers. Drug Alcohol Depend 106:173–180

    Article  PubMed  CAS  Google Scholar 

  • de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S (2001) Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport 12:3533–3537

    Article  PubMed  Google Scholar 

  • Dean AC, Sevak RJ, Monterosso JR, Hellemann G, Sugar CA, London ED (2011) Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. J Stud Alcohol Drugs 72:943–953

    PubMed  Google Scholar 

  • Deroche-Gamonet V, Darnaudery M, Bruins-Slot L, Piat F, Le Moal M, Piazza PV (2002) Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology (Berl) 161:387–395

    Article  CAS  Google Scholar 

  • Di Chiara G, Acquas E, Tanda G, Cadoni C (1993) Drugs of abuse: biochemical surrogates of specific aspects of natural reward? Biochem Soc Symp 59:65–81

    PubMed  Google Scholar 

  • Di Chiara G, Tanda G, Bassareo V, Pontieri F, Acquas E, Fenu S, Cadoni C, Carboni E (1999) Drug addiction as a disorder of associative learning. Role of nucleus accumbens shell/extended amygdala dopamine. Ann N Y Acad Sci 877:461–485

    Article  PubMed  Google Scholar 

  • Di Chiara G, Tanda G, Cadoni C, Acquas E, Bassareo V, Carboni E (1998) Homologies and differences in the action of drugs of abuse and a conventional reinforcer (food) on dopamine transmission: an interpretative framework of the mechanism of drug dependence. Adv Pharmacol 42:983–987

    Article  PubMed  Google Scholar 

  • Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK (2007) Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants. Eur J Pharmacol 568:112–123

    Article  PubMed  CAS  Google Scholar 

  • Durazzo TC, Meyerhoff DJ, Nixon SJ (2012) A comprehensive assessment of neurocognition in middle-aged chronic cigarette smokers. Drug Alcohol Depend 122:105–111

    Article  PubMed  Google Scholar 

  • Duteil J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E (1990) Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58

    Article  PubMed  CAS  Google Scholar 

  • Ellenbroek BA (2013) Histamine H3 receptors, The complex interaction with dopamine and its implications for addiction. Br J Pharmacol. doi:10.1111/bph.12221

  • Engber TM, Dennis SA, Jones BE, Miller MS, Contreras PC (1998a) Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine. Neuroscience 87:905–911

    Article  PubMed  CAS  Google Scholar 

  • Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV (1998b) Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil. Neurosci Lett 241:95–98

    Article  PubMed  CAS  Google Scholar 

  • Ersche KD, Turton AJ, Pradhan S, Bullmore ET, Robbins TW (2010) Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits. Biol Psychiatry 68:770–773

    Article  PubMed  Google Scholar 

  • Estrada A, Kelley AM, Webb CM, Athy JR, Crowley JS (2012) Modafinil as a replacement for dextroamphetamine for sustaining alertness in military helicopter pilots. Aviat Space Environ Med 83:556–564

    Article  PubMed  CAS  Google Scholar 

  • Evans WH, Boitano S (2001) Connexin mimetic peptides: specific inhibitors of gap-junctional intercellular communication. Biochem Soc Trans 29:606–612

    Article  PubMed  Google Scholar 

  • Faraone SV, Glatt SJ (2010) A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry 71:754–763

    Article  PubMed  Google Scholar 

  • Farrow TF, Hunter MD, Haque R, Spence SA (2006) Modafinil and unconstrained motor activity in schizophrenia: double-blind crossover placebo-controlled trial. Br J Psychiatry 189:461–462

    Article  PubMed  Google Scholar 

  • Fauchey V, Jaber M, Caron MG, Bloch B, Le Moine C (2000) Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter. Eur J Neurosci 12:19–26

    Article  PubMed  CAS  Google Scholar 

  • Fenton MC, Keyes K, Geier T, Greenstein E, Skodol A, Krueger B, Grant BF, Hasin DS (2012) Psychiatric comorbidity and the persistence of drug use disorders in the United States. Addiction 107:599–609

    Article  PubMed  Google Scholar 

  • Ferraro L, Antonelli T, Beggiato S, Cristina Tomasini M, Fuxe K, Tanganelli S (2013) The vigilance promoting drug modafinil modulates serotonin transmission in the rat prefrontal cortex and dorsal raphe nucleus. Possible relevance for its postulated antidepressant activity. Mini Rev Med Chem 13:478–492

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, Antonelli T, O'Connor WT, Tanganelli S, Rambert FA, Fuxe K (1997) Modafinil: an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry 42:1181–1183

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, Antonelli T, O'Connor WT, Tanganelli S, Rambert FA, Fuxe K (1998) The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission. Neurosci Lett 253:135–138

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, Antonelli T, Tanganelli S, O'Connor WT, Perez de la Mora M, Mendez-Franco J, Rambert FA, Fuxe K (1999) The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology 20:346–356

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, Fuxe K, Tanganelli S, Fernandez M, Rambert FA, Antonelli T (2000) Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil. Neuropharmacology 39:1974–1983

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, Fuxe K, Tanganelli S, Tomasini MC, Rambert FA, Antonelli T (2002) Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression. J Neurosci Res 68:107–112

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, O'Connor WT, Li XM, Rimondini R, Beani L, Ungerstedt U, Fuxe K, Tanganelli S (1996a) Evidence for a differential cholecystokinin-B and -A receptor regulation of GABA release in the rat nucleus accumbens mediated via dopaminergic and cholinergic mechanisms. Neuroscience 73:941–950

    Article  PubMed  CAS  Google Scholar 

  • Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K (1996b) The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor. Neurosci Lett 220:5–8

    Article  PubMed  CAS  Google Scholar 

  • Fiocchi EM, Lin YG, Aimone L, Gruner JA, Flood DG (2009) Armodafinil promotes wakefulness and activates Fos in rat brain. Pharmacol Biochem Behav 92:549–557

    Article  PubMed  CAS  Google Scholar 

  • Furey ML (2011) The prominent role of stimulus processing: cholinergic function and dysfunction in cognition. Curr Opin Neurol 24:364–370

    Article  PubMed  CAS  Google Scholar 

  • Garavan H, Hester R (2007) The role of cognitive control in cocaine dependence. Neuropsychol Rev 17:337–345

    Article  PubMed  Google Scholar 

  • Garcia-Rill E, Heister DS, Ye M, Charlesworth A, Hayar A (2007) Electrical coupling: novel mechanism for sleep–wake control. Sleep 30:1405–1414

    PubMed  Google Scholar 

  • Gerrard P, Malcolm R (2007) Mechanisms of modafinil: a review of current research. Neuropsychiatr Dis Treat 3:349–364

    PubMed  CAS  Google Scholar 

  • Getova D, Bowery NG (1998) The modulatory effects of high affinity GABA(B) receptor antagonists in an active avoidance learning paradigm in rats. Psychopharmacology (Berl) 137:369–373

    Article  CAS  Google Scholar 

  • Ghahremani DG, Tabibnia G, Monterosso J, Hellemann G, Poldrack RA, London ED (2011) Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals. Neuropsychopharmacology 36:950–959

    Article  PubMed  Google Scholar 

  • Gould TJ (2010) Addiction and cognition. Addict Sci Clin Pract 5:4–14

    PubMed  Google Scholar 

  • Gozzi A, Colavito V, Seke Etet PF, Montanari D, Fiorini S, Tambalo S, Bifone A, Zucconi GG, Bentivoglio M (2012) Modulation of fronto-cortical activity by modafinil: a functional imaging and fos study in the rat. Neuropsychopharmacology 37:822–837

    Article  PubMed  CAS  Google Scholar 

  • Graef S, Schonknecht P, Sabri O, Hegerl U (2011) Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings. Psychopharmacology (Berl) 215:205–229

    Article  CAS  Google Scholar 

  • Grahn JA, Parkinson JA, Owen AM (2009) The role of the basal ganglia in learning and memory: neuropsychological studies. Behav Brain Res 199:53–60

    Article  PubMed  Google Scholar 

  • Gu Q (2002) Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience 111:815–835

    Article  PubMed  CAS  Google Scholar 

  • Hart CL, Haney M, Vosburg SK, Rubin E, Foltin RW (2008) Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 33:761–768

    Article  PubMed  CAS  Google Scholar 

  • Havekes R, Abel T, Van der Zee EA (2011) The cholinergic system and neostriatal memory functions. Behav Brain Res 221:412–423

    Article  PubMed  CAS  Google Scholar 

  • He DS, Burt JM (2000) Mechanism and selectivity of the effects of halothane on gap junction channel function. Circ Res 86:E104–E109

    Article  PubMed  CAS  Google Scholar 

  • Heinzerling KG, Swanson AN, 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 Alcohol Depend 109:20–29

    Article  PubMed  CAS  Google Scholar 

  • Hester R, Lee N, Pennay A, Nielsen S, Ferris J (2010) The effects of modafinil treatment on neuropsychological and attentional bias performance during 7-day inpatient withdrawal from methamphetamine dependence. Exp Clin Psychopharmacol 18:489–497

    Article  PubMed  CAS  Google Scholar 

  • Hollander JA, Pham D, Fowler CD, Kenny PJ (2012) Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. Front Behav Neurosci 6:47

    Article  PubMed  CAS  Google Scholar 

  • Homayoun H, Moghaddam B (2010) Group 5 metabotropic glutamate receptors: role in modulating cortical activity and relevance to cognition. Eur J Pharmacol 639:33–39

    Article  PubMed  CAS  Google Scholar 

  • Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–159

    Article  PubMed  CAS  Google Scholar 

  • Hou RH, Freeman C, Langley RW, Szabadi E, Bradshaw CM (2005) Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers. Psychopharmacology (Berl) 181:537–549

    Article  CAS  Google Scholar 

  • Ishizuka T, Murakami M, Yamatodani A (2008) Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats. Eur J Pharmacol 578:209–215

    Article  PubMed  CAS  Google Scholar 

  • Ishizuka T, Murotani T, Yamatodani A (2010) Modanifil activates the histaminergic system through the orexinergic neurons. Neurosci Lett 483:193–196

    Article  PubMed  CAS  Google Scholar 

  • Ishizuka T, Murotani T, Yamatodani A (2012) Action of modafinil through histaminergic and orexinergic neurons. Vitam Horm 89:259–278

    Article  PubMed  CAS  Google Scholar 

  • Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A (2003) Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci Lett 339:143–146

    Article  PubMed  CAS  Google Scholar 

  • Jasinski DR (2000) An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 14:53–60

    Article  PubMed  CAS  Google Scholar 

  • Jasinski DR, Kovacevic-Ristanovic R (2000) Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy. Clin Neuropharmacol 23:149–156

    Article  PubMed  CAS  Google Scholar 

  • Jay TM (2003) Dopamine: a potential substrate for synaptic plasticity and memory mechanisms. Prog Neurobiol 69:375–390

    Article  PubMed  CAS  Google Scholar 

  • Jones SR, Gainetdinov RR, Hu XT, Cooper DC, Wightman RM, White FJ, Caron MG (1999) Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci 2:649–655

    Article  PubMed  CAS  Google Scholar 

  • Jupp B, Dalley JW (2013) Behavioral endophenotypes of drug addiction: etiological insights from neuroimaging studies. Neuropharmacology. doi:10.1016/j.neuropharm.2013.05.041

  • Kalechstein AD, De La Garza R 2nd, Newton TF (2010) Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment. Am J Addict 19:340–344

    PubMed  Google Scholar 

  • Kalechstein AD, Mahoney JJ 3rd, Yoon JH, Bennett R, De la Garza R 2nd (2013) Modafinil, but not escitalopram, improves working memory and sustained attention in long-term, high-dose cocaine users. Neuropharmacology 64:472–478

    Article  PubMed  CAS  Google Scholar 

  • Karlsson C, Zook M, Ciccocioppo R, Gehlert DR, Thorsell A, Heilig M, Cippitelli A (2012) Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors. Pharmacol Biochem Behav 102:400–406

    Article  PubMed  CAS  Google Scholar 

  • Klinkenberg I, Sambeth A, Blokland A (2011) Acetylcholine and attention. Behav Brain Res 221:430–442

    Article  PubMed  CAS  Google Scholar 

  • Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW (2010) Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci 30:7984–7992

    Article  PubMed  CAS  Google Scholar 

  • Koob GF (1999) The role of the striatopallidal and extended amygdala systems in drug addiction. Ann N Y Acad Sci 877:445–460

    Article  PubMed  CAS  Google Scholar 

  • Korotkova TM, Klyuch BP, Ponomarenko AA, Lin JS, Haas HL, Sergeeva OA (2007) Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors. Neuropharmacology 52:626–633

    Article  PubMed  CAS  Google Scholar 

  • Le Moal M, Koob GF (2007) Drug addiction: pathways to the disease and pathophysiological perspectives. Eur Neuropsychopharmacol 17:377–393

    Article  PubMed  CAS  Google Scholar 

  • Lee N, Pennay A, Hester R, McKetin R, Nielsen S, Ferris J (2013) A pilot randomised controlled trial of modafinil during acute methamphetamine withdrawal: feasibility, tolerability and clinical outcomes. Drug Alcohol Rev 32:88–95

    Article  PubMed  Google Scholar 

  • Leurs R, Smit MJ, Timmerman H (1995) Molecular pharmacological aspects of histamine receptors. Pharmacol Ther 66:413–463

    Article  PubMed  CAS  Google Scholar 

  • Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (1992) Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 591:319–326

    Article  PubMed  CAS  Google Scholar 

  • Lindsay SE, Gudelsky GA, Heaton PC (2006) Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother 40:1829–1833

    Article  PubMed  CAS  Google Scholar 

  • Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, Kopajtic T, Shi L, Katz JL, Tanda G, Newman AH (2012) R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry 72:405–413

    Article  PubMed  CAS  Google Scholar 

  • Luscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69:650–663

    Article  PubMed  CAS  Google Scholar 

  • Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ (2006) Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther 319:561–569

    Article  PubMed  CAS  Google Scholar 

  • Mahler SV, Hensley-Simon M, Tahsili-Fahadan P, Lalumiere RT, Thomas C, Fallon RV, Kalivas PW, Aston-Jones G (2012a) Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addict Biol. doi:10.1111/j.1369-1600.2012.00506.x

  • Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G (2012b) Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 198:79–121

    Article  PubMed  CAS  Google Scholar 

  • Makris AP, Rush CR, Frederich RC, Taylor AC, Kelly TH (2007) Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults. Exp Clin Psychopharmacol 15:123–133

    Article  PubMed  CAS  Google Scholar 

  • Malcolm R, Swayngim K, Donovan JL, DeVane CL, Elkashef A, Chiang N, Khan R, Mojsiak J, Myrick DL, Hedden S, Cochran K, Woolson RF (2006) Modafinil and cocaine interactions. Am J Drug Alcohol Abuse 32:577–587

    Article  PubMed  Google Scholar 

  • Malenka RC (1994) Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78:535–538

    Article  PubMed  CAS  Google Scholar 

  • Mann N, Bitsios P (2009) Modafinil treatment of amphetamine abuse in adult ADHD. J Psychopharmacol 23:468–471

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Raga J, Knecht C, Cepeda S (2008) Modafinil: a useful medication for cocaine addiction? Review of the evidence from neuropharmacological, experimental and clinical studies. Curr Drug Abuse Rev 1:213–221

    Article  PubMed  CAS  Google Scholar 

  • McGaugh J, Mancino MJ, Feldman Z, Chopra MP, Gentry WB, Cargile C, Oliveto A (2009) Open-label pilot study of modafinil for methamphetamine dependence. J Clin Psychopharmacol 29:488–491

    Article  PubMed  CAS  Google Scholar 

  • McNamara RK, Skelton RW (1996) Baclofen, a selective GABAB receptor agonist, dose-dependently impairs spatial learning in rats. Pharmacol Biochem Behav 53:303–308

    Article  PubMed  CAS  Google Scholar 

  • Meneses A (1999) 5-HT system and cognition. Neurosci Biobehav Rev 23:1111–1125

    Article  PubMed  CAS  Google Scholar 

  • Mignot E, Nishino S, Guilleminault C, Dement WC (1994) Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 17:436–437

    PubMed  CAS  Google Scholar 

  • Minzenberg MJ, Carter CS (2008) Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33:1477–1502

    Article  PubMed  CAS  Google Scholar 

  • Minzenberg MJ, Yoon JH, Carter CS (2011) Modafinil modulation of the default mode network. Psychopharmacology (Berl) 215:23–31

    Article  CAS  Google Scholar 

  • Monterosso JR, Aron AR, Cordova X, Xu J, London ED (2005) Deficits in response inhibition associated with chronic methamphetamine abuse. Drug Alcohol Depend 79:273–277

    Article  PubMed  Google Scholar 

  • Morein-Zamir S, Turner DC, Sahakian BJ (2007) A review of the effects of modafinil on cognition in schizophrenia. Schizophr Bull 33:1298–1306

    Article  PubMed  Google Scholar 

  • Muller U, Rowe JB, Rittman T, Lewis C, Robbins TW, Sahakian BJ (2013) Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. Neuropharmacology 64:490–495

    Article  PubMed  CAS  Google Scholar 

  • Muller U, Steffenhagen N, Regenthal R, Bublak P (2004) Effects of modafinil on working memory processes in humans. Psychopharmacology (Berl) 177:161–169

    Article  CAS  Google Scholar 

  • Munzar P, Tanda G, Justinova Z, Goldberg SR (2004) Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology 29:705–717

    Article  PubMed  CAS  Google Scholar 

  • Murillo-Rodriguez E, Haro R, Palomero-Rivero M, Millan-Aldaco D, Drucker-Colin R (2007) Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats. Behav Brain Res 176:353–357

    Article  PubMed  CAS  Google Scholar 

  • Myrick H, Malcolm R, Taylor B, LaRowe S (2004) Modafinil: preclinical, clinical, and post-marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry 16:101–109

    Article  PubMed  Google Scholar 

  • Nail-Boucherie K, Dourmap N, Jaffard R, Costentin J (1998) The specific dopamine uptake inhibitor GBR 12783 improves learning of inhibitory avoidance and increases hippocampal acetylcholine release. Brain Res Cogn Brain Res 7:203–205

    Article  PubMed  CAS  Google Scholar 

  • Nic Dhonnchadha BA, Kantak KM (2011) Cognitive enhancers for facilitating drug cue extinction: insights from animal models. Pharmacol Biochem Behav 99:229–244

    Article  PubMed  CAS  Google Scholar 

  • O'Brien CP, Charney DS, Lewis L, Cornish JW, Post RM, Woody GE, Zubieta JK, Anthony JC, Blaine JD, Bowden CL, Calabrese JR, Carroll K, Kosten T, Rounsaville B, Childress AR, Oslin DW, Pettinati HM, Davis MA, Demartino R, Drake RE, Fleming MF, Fricks L, Glassman AH, Levin FR, Nunes EV, Johnson RL, Jordan C, Kessler RC, Laden SK, Regier DA, Renner JA Jr, Ries RK, Sklar-Blake T, Weisner C (2004) Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action. Biol Psychiatry 56:703–713

    Article  PubMed  Google Scholar 

  • Partridge BJ, Bell SK, Lucke JC, Yeates S, Hall WD (2011) Smart drugs “as common as coffee”: media hype about neuroenhancement. PLoS One 6:e28416

    Article  PubMed  CAS  Google Scholar 

  • Passani MB, Giannoni P, Bucherelli C, Baldi E, Blandina P (2007) Histamine in the brain: beyond sleep and memory. Biochem Pharmacol 73:1113–1122

    Article  PubMed  CAS  Google Scholar 

  • Pierard C, Satabin P, Lagarde D, Barrere B, Guezennec CY, Menu JP, Peres M (1995) Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study. Brain Res 693:251–256

    Article  PubMed  CAS  Google Scholar 

  • Porter JN, Olsen AS, Gurnsey K, Dugan BP, Jedema HP, Bradberry CW (2011) Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory. J Neurosci 31:4926–4934

    Article  PubMed  CAS  Google Scholar 

  • Pulay AJ, Stinson FS, Dawson DA, Goldstein RB, Chou SP, Huang B, Saha TD, Smith SM, Pickering RP, Ruan WJ, Hasin DS, Grant BF (2009) Prevalence, correlates, disability, and comorbidity of DSM-IV schizotypal personality disorder: results from the wave 2 national epidemiologic survey on alcohol and related conditions. Prim Care Companion J Clin Psychiatry 11:53–67

    Article  PubMed  Google Scholar 

  • Raddatz R, Tao M, Hudkins RL (2010) Histamine H3 antagonists for treatment of cognitive deficits in CNS diseases. Curr Top Med Chem 10:153–169

    Article  PubMed  CAS  Google Scholar 

  • Randall DC, Shneerson JM, Plaha KK, File SE (2003) Modafinil affects mood, but not cognitive function, in healthy young volunteers. Hum Psychopharmacol 18:163–173

    Article  PubMed  CAS  Google Scholar 

  • Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE (2005) Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived? J Clin Psychopharmacol 25:175–179

    Article  PubMed  CAS  Google Scholar 

  • Rao Y, Liu ZW, Borok E, Rabenstein RL, Shanabrough M, Lu M, Picciotto MR, Horvath TL, Gao XB (2007) Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. J Clin Invest 117:4022–4033

    Article  PubMed  CAS  Google Scholar 

  • Rao Y, Lu M, Ge F, Marsh DJ, Qian S, Wang AH, Picciotto MR, Gao XB (2008) Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. J Neurosci 28:9101–9110

    Article  PubMed  CAS  Google Scholar 

  • Rasetti R, Mattay VS, Stankevich B, Skjei K, Blasi G, Sambataro F, Arrillaga-Romany IC, Goldberg TE, Callicott JH, Apud JA, Weinberger DR (2010) Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology 35:2101–2109

    Article  PubMed  CAS  Google Scholar 

  • Recinto P, Samant AR, Chavez G, Kim A, Yuan CJ, Soleiman M, Grant Y, Edwards S, Wee S, Koob GF, George O, Mandyam CD (2012) Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration. Neuropsychopharmacology 37:1275–1287

    Article  PubMed  CAS  Google Scholar 

  • Ricaurte GA, Markowska AL, Wenk GL, Hatzidimitriou G, Wlos J, Olton DS (1993) 3,4-Methylenedioxymethamphetamine, serotonin and memory. J Pharmacol Exp Ther 266:1097–1105

    PubMed  CAS  Google Scholar 

  • Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163:362–380

    Article  CAS  Google Scholar 

  • Robbins TW (2005) Chemistry of the mind: neurochemical modulation of prefrontal cortical function. J Comp Neurol 493:140–146

    Article  PubMed  CAS  Google Scholar 

  • Robertson P Jr, Hellriegel ET (2003) Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet 42:123–137

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal MH, Bryant SL (2004) Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clin Neuropharmacol 27:38–43

    Article  PubMed  CAS  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41

    Article  PubMed  CAS  Google Scholar 

  • Rush CR, Kelly TH, Hays LR, Baker RW, Wooten AF (2002a) Acute behavioral and physiological effects of modafinil in drug abusers. Behav Pharmacol 13:105–115

    Article  PubMed  CAS  Google Scholar 

  • Rush CR, Kelly TH, Hays LR, Wooten AF (2002b) Discriminative-stimulus effects of modafinil in cocaine-trained humans. Drug Alcohol Depend 67:311–322

    Article  PubMed  CAS  Google Scholar 

  • Sahakian BJ, Morein-Zamir S (2011) Neuroethical issues in cognitive enhancement. J Psychopharmacol 25:197–204

    Article  PubMed  Google Scholar 

  • Salo R, Nordahl TE, Possin K, Leamon M, Gibson DR, Galloway GP, Flynn NM, Henik A, Pfefferbaum A, Sullivan EV (2002) Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals. Psychiatry Res 111:65–74

    Article  PubMed  Google Scholar 

  • Sarter M, Paolone G (2011) Deficits in attentional control: cholinergic mechanisms and circuitry-based treatment approaches. Behav Neurosci 125:825–835

    Article  PubMed  CAS  Google Scholar 

  • Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB (2000) Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 20:8620–8628

    PubMed  CAS  Google Scholar 

  • Schmitt U, Hiemke C (2002) Tiagabine, a gamma-amino-butyric acid transporter inhibitor impairs spatial learning of rats in the Morris water-maze. Behav Brain Res 133:391–394

    Article  PubMed  CAS  Google Scholar 

  • Schnoll RA, Wileyto EP, Pinto A, Leone F, Gariti P, Siegel S, Perkins KA, Dackis C, Heitjan DF, Berrettini W, Lerman C (2008) A placebo-controlled trial of modafinil for nicotine dependence. Drug Alcohol Depend 98:86–93

    Article  PubMed  CAS  Google Scholar 

  • Seal KH, Cohen G, Waldrop A, Cohen BE, Maguen S, Ren L (2011) Substance use disorders in Iraq and Afghanistan veterans in VA healthcare, 2001–2010: implications for screening, diagnosis and treatment. Drug Alcohol Depend 116:93–101

    Article  PubMed  Google Scholar 

  • Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, Vandenhende F, Kielbasa W, Farde L, Innis RB, Halldin C (2006) Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2. Psychopharmacology (Berl) 188:119–127

    Article  CAS  Google Scholar 

  • Shearer J, Darke S, Rodgers C, Slade T, van Beek I, Lewis J, Brady D, McKetin R, Mattick RP, Wodak A (2009) A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction 104:224–233

    Article  PubMed  Google Scholar 

  • Sherin JE, Elmquist JK, Torrealba F, Saper CB (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 18:4705–4721

    PubMed  CAS  Google Scholar 

  • Simon P, Hemet C, Ramassamy C, Costentin J (1995) Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice. Eur Neuropsychopharmacol 5:509–514

    PubMed  CAS  Google Scholar 

  • Sirvio J, Riekkinen P Jr, Jakala P, Riekkinen PJ (1994) Experimental studies on the role of serotonin in cognition. Prog Neurobiol 43:363–379

    Article  PubMed  CAS  Google Scholar 

  • Smith A, Nutt D (1996) Noradrenaline and attention lapses. Nature 380:291

    Article  PubMed  CAS  Google Scholar 

  • Smythies J (2005a) Section II. The dopamine system. Int Rev Neurobiol 64:123–172

    Article  PubMed  Google Scholar 

  • Smythies J (2005b) Section III. The norepinephrine system. Int Rev Neurobiol 64:173–211

    Article  PubMed  Google Scholar 

  • Sofuoglu M, DeVito EE, Waters AJ, Carroll KM (2013) Cognitive enhancement as a treatment for drug addictions. Neuropharmacology 64:452–463

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Sewell RA (2009) Norepinephrine and stimulant addiction. Addict Biol 14:119–129

    Article  PubMed  CAS  Google Scholar 

  • Spencer TJ, Madras BK, Bonab AA, Dougherty DD, Clarke A, Mirto T, Martin J, Fischman AJ (2010) A positron emission tomography study examining the dopaminergic activity of armodafinil in adults using [11C]altropane and [11C]raclopride. Biol Psychiatry 68:964–970

    Article  PubMed  CAS  Google Scholar 

  • Stoops WW, Lile JA, Fillmore MT, Glaser PE, Rush CR (2005) Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration. Psychopharmacology (Berl) 182:186–193

    Article  CAS  Google Scholar 

  • Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349

    Article  PubMed  CAS  Google Scholar 

  • Sweeney CT, Sembower MA, Ertischek MD, Shiffman S, Schnoll SH (2013) Nonmedical use of prescription ADHD stimulants and preexisting patterns of drug abuse. J Addict Dis 32:1–10

    Article  PubMed  Google Scholar 

  • Tahsili-Fahadan P, Carr GV, Harris GC, Aston-Jones G (2010) Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism. Neuropsychopharmacology 35:2203–2210

    Article  PubMed  CAS  Google Scholar 

  • Tamminga CA (2006) The neurobiology of cognition in schizophrenia. J Clin Psychiatry 67:e11

    Article  PubMed  Google Scholar 

  • Tanda G, Kopajtic TA, Katz JL (2008) Cocaine-like neurochemical effects of antihistaminic medications. J Neurochem 106:147–157

    Article  PubMed  CAS  Google Scholar 

  • Tanda G, Pontieri FE, Frau R, Di Chiara G (1997) Contribution of blockade of the noradrenaline carrier to the increase of extracellular dopamine in the rat prefrontal cortex by amphetamine and cocaine. Eur J Neurosci 9:2077–2085

    Article  PubMed  CAS  Google Scholar 

  • Tanganelli S, Ferraro L, Bianchi C, Fuxe K (1994) 6-Hydroxy-dopamine treatment counteracts the reduction of cortical GABA release produced by the vigilance promoting drug modafinil in the awake freely moving guinea-pig. Neurosci Lett 171:201–204

    Article  PubMed  CAS  Google Scholar 

  • Tanganelli S, Fuxe K, Ferraro L, Janson AM, Bianchi C (1992) Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms. Naunyn Schmiedebergs Arch Pharmacol 345:461–465

    Article  PubMed  CAS  Google Scholar 

  • Tanganelli S, Perez de la Mora M, Ferraro L, Mendez-Franco J, Beani L, Rambert FA, Fuxe K (1995) Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins. Eur J Pharmacol 273:63–71

    Article  PubMed  CAS  Google Scholar 

  • Taylor FB, Russo J (2000) Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 10:311–320

    Article  PubMed  CAS  Google Scholar 

  • Terry AV Jr (2006) Muscarinic receptor antagonists in rats animal models of cognitive impairment. Taylor & Francis Group, LLC, Boca Raton

    Google Scholar 

  • Tiligada E, Kyriakidis K, Chazot PL, Passani MB (2011) Histamine pharmacology and new CNS drug targets. CNS Neurosci Ther 17:620–628

    Article  PubMed  CAS  Google Scholar 

  • Touret M, Sallanon-Moulin M, Fages C, Roudier V, Didier-Bazes M, Roussel B, Tardy M, Jouvet M (1994) Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain. Brain Res Mol Brain Res 26:123–128

    Article  PubMed  CAS  Google Scholar 

  • Turner D (2006) A review of the use of modafinil for attention-deficit hyperactivity disorder. Expert Rev Neurother 6:455–468

    Article  PubMed  CAS  Google Scholar 

  • Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003) Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl) 165:260–269

    CAS  Google Scholar 

  • Uguen M, Perrin D, Belliard S, Ligneau X, Beardsley PM, Lecomte JM, Schwartz JC (2013) Preclinical evaluation of the abuse potential of Pitolisant, a histamine H(3) receptor inverse agonist/antagonist compared with Modafinil. Br J Pharmacol 169:632–644

    Article  PubMed  CAS  Google Scholar 

  • Urbano FJ, Leznik E, Llinas RR (2007) Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling. Proc Natl Acad Sci U S A 104:12554–12559

    Article  PubMed  CAS  Google Scholar 

  • Verdejo-Garcia A, Contreras-Rodriguez O, Fonseca F, Cuenca A, Soriano-Mas C, Rodriguez J, Pardo-Lozano R, Blanco-Hinojo L, de Sola Llopis S, Farre M, Torrens M, Pujol J, de la Torre R (2012) Functional alteration in frontolimbic systems relevant to moral judgment in cocaine-dependent subjects. Addict Biol. doi:10.1111/j.1369-1600.2012.00472.x

  • Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang GJ, Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner 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: clinical implications. Jama 301:1148–1154

    Article  PubMed  CAS  Google Scholar 

  • Warot D, Corruble E, Payan C, Weil JS, Puech AJ (1993) Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 8:201–208

    Google Scholar 

  • Waters KA, Burnham KE, O'Connor D, Dawson GR, Dias R (2005) Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat. J Psychopharmacol 19:149–158

    Article  PubMed  CAS  Google Scholar 

  • Weisler RH, Pandina GJ, Daly EJ, Cooper K, Gassmann-Mayer C (2012) Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs 26:421–434

    Article  PubMed  CAS  Google Scholar 

  • Wesensten NJ (2006) Effects of modafinil on cognitive performance and alertness during sleep deprivation. Curr Pharm Des 12:2457–2471

    Article  PubMed  CAS  Google Scholar 

  • Whitmore J, Hickey P, Doan B, Harrison R, Kisner J, Beltran T, McQuade J, Fischer J, Marks F, Air Force Research Lab Brooks AFB TX Human Effectiveness DIR/Biodynamics and Protection Div (2006) A double-blind placebo-controlled investigation of the efficacy of modafinil for maintaining alertness and performance in sustained military ground operations. Technical report January 2003–November 2005. Available at http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=ADA454558

  • Wilens TE, Morrison NR, Prince J (2011) An update on the pharmacotherapy of attention-deficit/hyperactivity disorder in adults. Expert Rev Neurother 11:1443–1465

    Article  PubMed  Google Scholar 

  • Wise RA (2006) Role of brain dopamine in food reward and reinforcement. Philos Trans R Soc Lond B Biol Sci 361:1149–1158

    Article  PubMed  CAS  Google Scholar 

  • Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787–1794

    PubMed  CAS  Google Scholar 

  • Wong CG, Bottiglieri T, Snead OC 3rd (2003) GABA, gamma-hydroxybutyric acid, and neurological disease. Ann Neurol 54(Suppl 6):S3–S12

    Article  PubMed  CAS  Google Scholar 

  • Zarrindast MR (2006) Neurotransmitters and cognition. Exs 98:5–39

    PubMed  CAS  Google Scholar 

  • Zeng BY, Smith LA, Pearce RK, Tel B, Chancharme L, Moachon G, Jenner P (2004) Modafinil prevents the MPTP-induced increase in GABAA receptor binding in the internal globus pallidus of MPTP-treated common marmosets. Neurosci Lett 354:6–9

    Article  PubMed  CAS  Google Scholar 

  • Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (2009) Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil. J Pharmacol Exp Ther 329:738–746

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by the NIDA Intramural Research Program, NIH/DHHS.

Conflict of interest

All the authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gianluigi Tanda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mereu, M., Bonci, A., Newman, A.H. et al. The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacology 229, 415–434 (2013). https://doi.org/10.1007/s00213-013-3232-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3232-4

Keywords

Navigation