Skip to main content

Advertisement

SpringerLink
Log in

Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Minocycline, a tetracycline antibiotic, interacts with brain glutamate and dopamine neurotransmission. In preclinical studies, minocycline attenuated amphetamine-induced acute dopamine release and subsequent behavioral sensitization. The goal of this study was to determine minocycline’s effects on the acute physiological, behavioral, and subjective responses to dextroamphetamine (DAMP) in healthy volunteers.

Methods

Ten healthy volunteers participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects had a 5-day treatment period with either minocycline (200 mg/day) or placebo and then were crossed over for 5 days of the other treatment. After 2 days of taking the study medication, on days 3 and 4, subjects were randomly assigned to double-blind acute challenge with either 20 mg/70 kg DAMP or placebo DAMP (randomly labeled as drug A or B) and then crossed over to the other challenge. On day 5 (experimental session 3), subjects had the opportunity to self-administer either placebo or DAMP capsules by working on a progressive ratio computer task.

Results

Minocycline attenuated DAMP-induced subjective rewarding effects but did not change DAMP choice behavior. Minocycline treatment speeded reaction times on a Go No-Go task and reduced plasma cortisol levels.

Conclusions

These findings warrant further studies examining the potential use of minocycline for stimulant addiction.

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

Access this article

Log in via an institution

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
Fig. 4

Similar content being viewed by others

References

  • Bardo MT (1998) Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Crit Rev Neurobiol 12:37–67

    CAS  PubMed  Google Scholar 

  • Brauer LH, de Wit H (1996) Subjective responses to d-amphetamine alone and after pimozide pretreatment in normal, healthy volunteers. Biol Psychiatry 39:26–32

    Article  CAS  PubMed  Google Scholar 

  • Chaves C, Marque CR, Trzesniak C, Machado de Sousa JP, Zuardi AW, Crippa JA, Dursun SM, Hallak JE (2009) Glutamate-N-methyl-d-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update. Braz J Med Biol Res 42:1002–1014

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Uz T, Manev H (2009) Minocycline affects cocaine sensitization in mice. Neurosci Lett 452:258–261

    Article  CAS  PubMed  Google Scholar 

  • Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20: RC89 (1–5)

    Google Scholar 

  • Di Ciano P, Everitt BJ (2001) Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 25:341–360

    Article  PubMed  Google Scholar 

  • Dudish-Poulsen SA, Hatsukami DK (1997) Dissociation between subjective and behavioral responses after cocaine stimuli presentations. Drug Alcohol Depend 47:1–9

    Article  PubMed  Google Scholar 

  • Fillmore MT, Rush CR, Marczinski CA (2003) Effects of d-amphetamine on behavioral control in stimulant abusers: the role of prepotent response tendencies. Drug Alcohol Depend 71:143–152

    Article  CAS  PubMed  Google Scholar 

  • Fujita Y, Ishima T, Kunitachi S, Hagiwara H, Zhang L, Iyo M, Hashimoto K (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline. Prog Neuropsychopharmacol Biol Psychiatry 32:336–339

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez JC, Egea J, Del Carmen GM, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J, Hernandez-Guijo JM (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26:2481–2495

    Article  PubMed  Google Scholar 

  • Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6:1045–1053

    Article  CAS  PubMed  Google Scholar 

  • Grady TA, Broocks A, Canter SK, Pigott TA, Dubbert B, Hill JL, Murphy DL (1996) Biological and behavioral responses to d-amphetamine, alone and in combination with the serotonin3 receptor antagonist ondansetron, in healthy volunteers. Psychiatry Res 64:1–10

    Article  CAS  PubMed  Google Scholar 

  • Haney M, Spealman R (2008) Controversies in translational research: drug self-administration. Psychopharmacology (Berl) 199:403–419

    Article  CAS  Google Scholar 

  • Hashimoto K (2009) Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 61:105–123

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Iyo M (2007) Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: a positron emission tomography study in conscious monkeys. Biol Psychiatry 61:577–581

    Article  CAS  PubMed  Google Scholar 

  • Imbesi M, Uz T, Manev R, Sharma RP, Manev H (2008) Minocycline increases phosphorylation and membrane insertion of neuronal GluR1 receptors. Neurosci Lett 447:134–137

    Article  CAS  PubMed  Google Scholar 

  • Itzhak Y, Ali SF (2006) Role of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs. Pharmacol Ther 109:246–262

    Article  CAS  PubMed  Google Scholar 

  • Jonas M, Cunha BA (1982) Minocycline. Ther Drug Monit 4:137–145

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW (2007) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neurosci 9:389–397

    PubMed  Google Scholar 

  • Kim SS, Kong PJ, Kim BS, Sheen DH, Nam SY, Chun W (2004) Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Arch Pharm Res 27:314–318

    Article  CAS  PubMed  Google Scholar 

  • Knackstedt LA, Kalivas PW (2009) Glutamate and reinstatement. Curr Opin Pharmacol 9:59–64

    Article  CAS  PubMed  Google Scholar 

  • Kofman O, Klein E, Newman M, Hamburger R, Kimchi O, Nir T, Shimon H, Belmaker RH (1990) Inhibition by antibiotic tetracyclines of rat cortical noradrenergic adenylate cyclase and amphetamine-induced hyperactivity. Pharmacol Biochem Behav 37:417–424

    Article  CAS  PubMed  Google Scholar 

  • Kofman O, van Embden S, Alpert C, Fuchs I (1993) Central and peripheral minocycline suppresses motor activity in rats. Pharmacol Biochem Behav 44:397–402

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (1992) Neural mechanisms of drug reinforcement. Ann NY Acad Sci 654:171–191

    Article  CAS  PubMed  Google Scholar 

  • Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M (2007) Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69:1404–1410

    Article  CAS  PubMed  Google Scholar 

  • Leigh PN, Meininger V, Bensimon G, Cudkowicz M, Robberecht W (2008) Minocycline for patients with ALS. Lancet Neurol 7:119–120, author reply 120-1

    Article  PubMed  Google Scholar 

  • Levkovitz Y, Levi U, Braw Y, Cohen H (2007) Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia. Brain Res 1154:154–162

    Article  CAS  PubMed  Google Scholar 

  • Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S (2009) A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 71:138–149

    Article  PubMed  Google Scholar 

  • Martin WR, Sloan JW, Sapira JD, Jasinski DR (1971) Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 12:245–258

    Google Scholar 

  • McNair D, Lorr M, Dropperman L (1971) Manual for profile of mood states. Educational and industrial testing services, Educational and industrial testing services

  • Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, Ibi D, Kim HC, Yamada K (2008) Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology (Berl) 196:233–241

    Article  CAS  Google Scholar 

  • Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, Olivera-Lopez JI, Jaramillo-Jaimes MT (2008) Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry 32:380–386

    Article  CAS  PubMed  Google Scholar 

  • Munzar P, Li H, Nicholson KL, Wiley JL, Balster RL (2002) Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats. Psychopharmacology (Berl) 160:331–336

    Article  CAS  Google Scholar 

  • Patchev VK, Karalis K, Chrousos GP (1994) Effects of excitatory amino acid transmitters on hypothalamic corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) release in vitro: implications in pituitary-adrenal regulation. Brain Res 633:312–316

    Article  CAS  PubMed  Google Scholar 

  • PDR (2009) Physicians’ Desk Reference: PDR. Medical Economics Data, Medical Economics Data

  • Robertson IH, Manly T, Andrade J, Baddeley BT, Yiend J (1997) ‘Oops!’: performance correlates of everyday attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 35:747–758

    Article  CAS  PubMed  Google Scholar 

  • Sadowski T, Steinmeyer J (2001) Minocycline inhibits the production of inducible nitric oxide synthase in articular chondrocytes. J Rheumatol 28:336–340

    CAS  PubMed  Google Scholar 

  • Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–677

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Waters AJ, Mooney M, Kosten T (2008a) Riluzole and d-amphetamine interactions in humans. Prog Neuropsychopharmacol Biol Psychiatry 32:16–22

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Poling J, Waters A, Sewell A, Hill K, Kosten T (2008b) Disulfiram enhances subjective effects of dextroamphetamine in humans. Pharmacol Biochem Behav 90:394–398

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Waters AJ, Mooney M, O’Malley SS (2009) Minocycline reduced craving for cigarettes but did not affect smoking or intravenous nicotine responses in humans. Pharmacol Biochem Behav 92:135–140

    Article  CAS  PubMed  Google Scholar 

  • Stoops WW, Glaser PE, Fillmore MT, Rush CR (2004) Reinforcing, subject-rated, performance and physiological effects of methylphenidate and d-amphetamine in stimulant abusing humans. J Psychopharmacol 18:534–543

    Google Scholar 

  • Stoops WW, Lile JA, Fillmore MT, Glaser PE, Rush CR (2005) Reinforcing effects of methylphenidate: influence of dose and behavioral demands following drug administration. Psychopharmacology (Berl) 177:349–355

    Google Scholar 

  • Tanibuchi Y, Shimagami M, Fukami G, Sekine Y, Iyo M, Hashimoto K (2010) A case of methamphetamine use disorder treated with the antibiotic drug minocycline. Gen Hosp Psychiatry (in press)

  • The NINDS NET-PD Investigators (2006) A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66:664–671

    Article  Google Scholar 

  • Thomas MJ, Kalivas PW, Shaham Y (2008) Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol 154:327–342

    Article  CAS  PubMed  Google Scholar 

  • Tidey JW, O’Neill SC, Higgins ST (2000) d-Amphetamine increases choice of cigarette smoking over monetary reinforcement. Psychopharmacology (Berl) 153:85–92

    Article  CAS  Google Scholar 

  • Tzschentke TM (2001) Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Prog Neurobiol 63:241–320

    Article  CAS  PubMed  Google Scholar 

  • Tzschentke TM, Schmidt WJ (2003) Glutamatergic mechanisms in addiction. Mol Psychiatry 8:373–382

    Article  CAS  PubMed  Google Scholar 

  • Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587

    Article  CAS  PubMed  Google Scholar 

  • Vezina P, Queen AL (2000) Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area. Psychopharmacology (Berl) 151:184–191

    Article  CAS  Google Scholar 

  • Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Dewey SL, Pappas N (1997) Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386:830–833

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, Iyo M, Hashimoto K (2006) Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry 30:1381–1393

    Article  CAS  PubMed  Google Scholar 

  • Ziegler DR, Cullinan WE, Herman JP (2005) Organization and regulation of paraventricular nucleus glutamate signaling systems: N-methyl-d-aspartate receptors. J Comp Neurol 484:43–56

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the Veterans Administration Mental Illness Research, Education and Clinical Center (MIRECC), and National Institute on Drug Abuse (NIDA) grants P50-DA12762, K05-DA0454 (TK), K02-DA021304 (MS), and K01-DA-019446 (MM).

We would like to thank Ellen Mitchell, R.N. and Stacy Minnix for the technical assistance.

Conflict of interest

Dr. Kosten is in the Speakers Bureau of Reckitt. He served as a consultant for Celtic, Alkermes, Synosia, Catalyst, and Gerson Lerman and has ownership interests with Pfizer and Johnson & Johnson. Dr. Mooney has received research grants from Pfizer. None of the products of these companies are associated with this work. The other authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Psychiatry and VA Connecticut Healthcare System, School of Medicine, Yale University, 950 Campbell Ave., Bldg. 36/116A4, West Haven, CT, 06516, USA

    Mehmet Sofuoglu

  2. Department of Psychiatry, School of Medicine, University of Minnesota, Minneapolis, MN, USA

    Marc Mooney

  3. Baylor College of Medicine, Houston, TX, USA

    Thomas Kosten

  4. Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Andrew Waters

  5. Chiba University Center for Forensic Mental Health, Inohana, Chiba, Japan

    Kenji Hashimoto

Authors
  1. Mehmet Sofuoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc Mooney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Kosten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew Waters
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenji Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehmet Sofuoglu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sofuoglu, M., Mooney, M., Kosten, T. et al. Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacology 213, 61–68 (2011). https://doi.org/10.1007/s00213-010-2014-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-2014-5

Keywords

Search

Navigation