Skip to main content
    • Aa
    • Aa
  • The International Journal of Neuropsychopharmacology, Volume 15, Issue 7
  • August 2012, pp. 919-929

Chronic modafinil effects on drug-seeking following methamphetamine self-administration in rats

  • Carmela M. Reichel (a1) and Ronald E. See (a1)
  • DOI:
  • Published online: 28 June 2011

Acute administration of the cognitive enhancing drug, modafinil (Provigil®), reduces methamphetamine (Meth) seeking following withdrawal from daily self-administration. However, the more clinically relevant effects of modafinil on Meth-seeking after chronic treatment have not been explored. Here, we determined the impact of modafinil on Meth-seeking after chronic daily treatment during extinction or abstinence following Meth self-administration. Rats self-administered intravenous Meth during daily 2-h sessions for 14 d, followed by extinction sessions or abstinence. During this period, rats received daily injections of vehicle, 30, or 100 mg/kg modafinil and were then tested for Meth-seeking via cue, Meth-primed, and context-induced reinstatement at early and late withdrawal time-points. We found that chronic modafinil attenuated relapse to a Meth-paired context, decreased conditioned cue-induced and Meth-primed reinstatement, and resulted in enduring reductions in Meth-seeking even after discontinuation of treatment. Additionally, we determined that only a very high dose of modafinil (300 mg/kg) during maintenance of self-administration had an impact on Meth intake. These results validate and extend clinical and preclinical findings that modafinil may be a viable treatment option for Meth addiction.

Corresponding author
Address for correspondence: Dr C. M. Reichel, Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. Tel.: 843-792-4272Fax: 843-792-4423Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

RE Bernardi , JR Lewis , KM Lattal , SP Berger (2009). Modafinil reinstates a cocaine conditioned place preference following extinction in rats. Behavior Brain Research 204, 250253.

ME Bouton (2002). Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biological Psychiatry 52, 976986.

CA Conklin (2006). Environments as cues to smoke: implications for human extinction-based research and treatment. Experimental and Clinical Psychopharmacology 14, 1219.

CA Dackis , KG Lynch , E Yu , FF Samaha , (2003). Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug and Alcohol Dependence 70, 2937.

M Davis , K Ressler , BO Rothbaum , R Richardson (2006). Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biological Psychiatry 60, 369375.

R De La Garza , T Zorick , E London , T Newton (2009). Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers. Drug and Alcohol Dependence 106, 173180.

V Deroche-Gamonet , M Darnaudéry , L Bruins-Slot , F Piat , (2002). Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology 161, 387395.

MM Dopheide , RE Morgan , KR Rodvelt , TR Schachtman , (2007). Modafinil evokes striatal [3H]dopamine release and alters the subjective properties of stimulants. European Journal of Pharmacology 568, 112123.

L Ferraro , T Antonelli , WT O'Connor , S Tanganelli , (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. Neuroscience Letters 253, 135138.

RA Fuchs , RK Branham , RE See (2006). Different neural substrates mediate cocaine seeking after abstinence vs. extinction training: a critical role for the dorsolateral caudate-putamen. Journal of Neuroscience 26, 35843588.

M Gasior , JM Witkin , SR Goldberg , P Munzar (2004). Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats. European Journal of Pharmacology 494, 183189.

MB Gatch , M Selvig , MJ Forster (2005). GABAergic modulation of the discriminative stimulus effects of methamphetamine. Behavioural Pharmacology 16, 261266.

DG Ghahremani , G Tabibnia , J Monterosso , G Hellemann , (2011). Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals. Neuropsychopharmacology 36, 950959.

LH Gold , RL Balster (1996). Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology 126, 286292.

JW Grimm , BT Hope , RA Wise , Y Shaham (2001). Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412, 141142.

KG Heinzerling , A-N Swanson , S Kim , L Cederblom , (2010). Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence. Drug and Alcohol Dependence 109, 2029.

AD Kalechstein , R De La Garza , TF Newton (2010). Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment. American Journal of Addiction 19, 340344.

PW Kalivas (2009). The glutamate homeostasis hypothesis of addiction. Nature Reviews Neuroscience 10, 561572.

L Karila , A Weinstein , H-J Aubin , A Benyamina , (2010). Pharmacological approaches to methamphetamine dependence: a focused review. British Journal of Clinical Pharmacology 69, 578592.

LA Knackstedt , K Moussawi , R Lalumiere , M Schwendt , (2010). Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. Journal of Neuroscience 30, 79847992.

J-H Lee , H Kwon , J Choi , B-H Yang (2007). Cue-exposure therapy to decrease alcohol craving in virtual environment. Cyberpsychology and Behavior 10, 617623.

W Ling , R Rawson , S Shoptaw , W Ling (2006). Management of methamphetamine abuse and dependence. Current Psychiatry Report 8, 345354.

BK Madras , Z Xie , Z Lin , A Jassen , (2006). Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. Journal of Pharmacology and Experimental Therapeutics 319, 561569.

R Malcolm , S Book , D Moak , L Devane , (2002). Clinical applications of modafinil in stimulant abusers: low abuse potential. American Journal of Addiction 11, 247249.

MAE Marissen , IHA Franken , P Blanken , W van den Brink , (2007). Cue exposure therapy for the treatment of opiate addiction: results of a randomized controlled clinical trial. Psychotherapy and Psychosomatics 76, 97–105.

J McGaugh , MJ Mancino , Z Feldman , MP Chopra , (2009). Open-label pilot study of modafinil for methamphetamine dependence. Journal of Clinical Psychopharmacology 29, 488491.

MJ Minzenberg , CS Carter (2008). Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33, 14771502.

P Munzar , SR Goldberg (1999). Noradrenergic modulation of the discriminative-stimulus effects of methamphetamine in rats. Psychopharmacology 143, 293301.

P Munzar , SR Goldberg (2000). Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats. Psychopharmacology 148, 209216.

P Munzar , G Tanda , Z Justinova , SR Goldberg (2004). Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology 29, 705717.

JL Newman , SS Negus , A Lozama , TE Prisinzano , (2010). Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys. Experimental and Clinical Psychopharmacology 18, 395408.

C O'Brien (2006) Drug addiction and drug abuse. In: LL Brunton , J Lazo , KL Parker (Eds), Goodman and Gilman's The Pharmacological Basis of Therapeutics (pp. 607627). New York: McGraw-Hill.

MW Otto , SA Safren , MH Pollack (2004). Internal cue exposure and the treatment of substance use disorders: lessons from the treatment of panic disorder. Journal of Anxiety Disorders 18, 6987.

NE Paterson , A Fedolak , B Olivier , T Hanania , (2010). Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents. Pharmacology Biochemistry and Behavior 95, 449456.

GJ Quirk , D Mueller (2008). Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 5672.

CM Reichel , RA Bevins (2009). Forced abstinence model of relapse to study pharmacological treatments of substance use disorder. Current Drug Abuse Reviews 2, 184194.

CM Reichel , K Moussawi , PH Do , PW Kalivas , (2011). Chronic N-acetylcysteine during abstinence or extinction following cocaine self-administration produces enduring reductions in drug-seeking. Journal of Pharmacology and Experimental Therapeutics 337, 487493.

CM Reichel , RE See (2010). Modafinil effects on reinstatement of methamphetamine seeking in a rat model of relapse. Psychopharmacology 210, 337346.

CM Reichel , JL Wilkinson , RA Bevins (2007). Methamphetamine functions as a positive and negative drug feature in a Pavlovian appetitive discrimination task. Behavioural Pharmacology 18, 755765.

KJ Ressler , BO Rothbaum , L Tannenbaum , P Anderson , (2004). Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Archives of General Psychiatry 61, 11361144.

ME Rose , JE Grant (2008). Pharmacotherapy for methamphetamine dependence: a review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions. Annals of Clinical Psychiatry 20, 145155.

CR Rush , TH Kelly , LR Hays , AF Wooten (2002). Discriminative-stimulus effects of modafinil in cocaine-trained humans. Drug and Alcohol Dependence 67, 311322.

R Salo , TE Nordahl , Y Natsuaki , MH Leamon , (2007). Attentional control and brain metabolite levels in methamphetamine abusers. Biological Psychiatry 61, 12721280.

M Schwendt , A Rocha , R See , A Pacchioni , (2009). Extended methamphetamine self-administration in rats results in a selective reduction of dopamine transporter levels in the prefrontal cortex and dorsal striatum not accompanied by marked monoaminergic depletion. Journal of Pharmacology and Experimental Therapeutics 331, 555.

DW Self (2004). Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology 47 (Suppl. 1), 242255.

Y Shaham , U Shalev , L Lu , H De Wit , (2003). The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168, 3–20.

J Shearer , S Darke , C Rodgers , T Slade , (2009). A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction 104, 224233.

MA Sutton , EF Schmidt , K-H Choi , CA Schad , (2003). Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421, 7075.

P Tahsili-Fahadan , GV Carr , GC Harris , G Aston-Jones (2010). Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism. Neuropsychopharmacology 35, 22032210.

SAM van Vliet , SAM van Vlieta , ELA Blezer , MJ Jongsma , (2008). Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy. Brain Research 1189, 219228.

FJ Vocci , NM Appel (2007). Approaches to the development of medications for the treatment of methamphetamine dependence. Addiction 102 (Suppl. 1), 96106.

ND Volkow , JS Fowler , J Logan , D Alexoff , (2009). Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. Journal of the American Medical Association 301, 11481154.

SK Vosburg , CL Hart , M Haney , E Rubin , (2009). Modafinil does not serve as a reinforcer in cocaine abusers. Drug and Alcohol Dependence 106, 233236.

N Yahyavi-Firouz-Abadi , RE See (2009). Anti-relapse medications: preclinical models for drug addiction treatment. Pharmacology & Therapeutics 124, 235247.

AR Zavala , S Biswas , RE Harlan , JL Neisewander (2007). Fos and glutamate AMPA receptor subunit coexpression associated with cue-elicited cocaine-seeking behavior in abstinent rats. Neuroscience 145, 438452.

D Zolkowska , R Jain , RB Rothman , JS Partilla , (2009). Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil. Journal of Pharmacology and Experimental Therapeutics 329, 738746.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Image

Reichel Supplementary Image 4
Reichel Supplementary Image 4

 Unknown (9.5 MB)
9.5 MB
Supplementary Images Legend

Reichel Supplementary Images Legend
Reichel Supplementary Images Legend

 Unknown (78 KB)
78 KB
Supplementary Image 3

Reichel Supplementary Image 3
Reichel Supplementary Image 3

 Unknown (17.2 MB)
17.2 MB
Supplementary Image 1

Reichel Supplementary Image 1
Reichel Supplementary Image 1

 Unknown (6.3 MB)
6.3 MB
Supplementary Image 2

Reichel Supplementary Image 2
Reichel Supplementary Image 2

 Unknown (11.7 MB)
11.7 MB