Original article| Volume 61, ISSUE 5, P577-581, March 01, 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


      Positron emission tomography (PET) studies of methamphetamine (METH) abusers suggest that psychotic symptoms of METH abusers may be attributable to the reduction of dopamine transporters (DAT) in the human brain. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with METH abuse.


      Using a PET study in conscious monkeys, we investigated whether the second generation antibiotic minocycline could protect against the reduction of DAT in monkeys treated with METH (2 mg/kg × 3, 3-hour intervals).


      Pretreatment and subsequent administration of minocycline significantly attenuated the reduction of DAT in the striatum of monkeys treated with METH. Furthermore, posttreatment and subsequent administration of minocycline also significantly attenuated the reduction of DAT. In contrast, repeated administration of minocycline alone did not alter the density of DAT in the striatum of monkeys treated with METH.


      Our findings suggest that minocycline protects against METH-induced neurotoxicity in the monkey brain. Therefore, minocycline is likely to be a promising therapeutic agent for the treatment of several symptoms associated with METH use in humans.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Aronson A.L.
        Pharmacotherapeutics of the newer tetracyclines.
        J Am Vet Med Assoc. 1980; 176: 1061-1068
        • Barza M.
        • Brown R.B.
        • Shanks C.
        • Gamble C.
        • Weinstein L.
        Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs.
        Antimicrob Agents Chemother. 1975; 8: 713-720
        • Blum D.
        • Chtarto A.
        • Tenenbaum L.
        • Brotchi J.
        • Levivier M.
        Clinical potential of minocycline for neurodegenerative disorders.
        Neurobiol Dis. 2004; 17: 359-366
        • Cadet J.L.
        • Jayanthi S.
        • Deng X.
        Speed kills: Cellular and molecular bases of methamphetamine-induced nerve terminal degeneration and neuronal apoptosis.
        FASEB J. 2003; 17: 1775-1788
        • Chen M.
        • Ona V.O.
        • Li M.
        • Ferrante R.J.
        • Fink K.B.
        • Zhu S.
        • et al.
        Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease.
        Nature Med. 2000; 6: 797-801
        • Creese I.
        • Burt D.R.
        • Snyder S.H.
        Dopamine receptor binding: Differentiation of agonist and antagonist states with [3H]dopamine and [3H]haloperidol.
        Life Sci. 1975; 17: 993-1002
        • Davidson C.
        • Gow A.J.
        • Lee T.H.
        • Ellinwood E.H.
        Methamphetamine neurotoxicity: Necrotic and apoptotic mechanisms and relevance to human abuse and treatment.
        Brain Res Brain Res Rev. 2001; 36: 1-22
        • Deng X.
        • Cai N.S.
        • McCoy M.T.
        • Chen W.
        • Trush M.A.
        • Cadet J.L.
        Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway.
        Neuropharmacology. 2002; 42: 837-845
        • Diguet E.
        • Fernagut P.O.
        • Wei X.
        • Du Y.
        • Rouland R.
        • Gross C.
        • et al.
        Deleterious effects of minocycline in animal models of Parkinson’s disease and Huntington’s disease.
        Eur J Neurosci. 2004; 19: 3266-3276
        • Domercq M.
        • Matute C.
        Neuroprotection by tetracyclines.
        Trends Pharmacol Sci. 2004; 25: 609-612
        • Du Y.
        • Ma Z.
        • Lin S.
        • Dodel R.C.
        • Gao F.
        • Bales K.R.
        • et al.
        Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease.
        Proc Natl Acad Sci U S A. 2001; 98: 14669-14674
        • Hanson G.R.
        • Rau K.S.
        • Fleckenstein A.E.
        The methamphetamine experience: A NIDA partnership.
        Neuropharmacology. 2004; 47: 92-100
        • Harada N.
        • Nishiyama S.
        • Satoh K.
        • Fukumoto D.
        • Kakiuchi T.
        • Tsukada H.
        Age-related changes in the striatal dopaminergic system in the living brain: A multiparametric PET study in conscious monkeys.
        Synapse. 2002; 45: 38-45
        • Hashimoto K.
        • Tsukada H.
        • Nishiyama S.
        • Fukumoto D.
        • Kakiuchi T.
        • Shimizu E.
        • et al.
        Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine.
        Neuropsychopharmacology. 2004; 29: 2018-2023
        • Jayanthi S.
        • Deng X.
        • Noailles P.A.
        • Ladenheim B.
        • Cadet J.L.
        Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades.
        FASEB J. 2004; 18: 238-251
        • Kaufman M.J.
        • Madras B.K.
        [3H]CFT ([3H]WIN 35,428) accumulation in dopamine regions of monkey brain: Comparison of a mature and an aged monkey.
        Brain Res. 1993; 611: 322-325
        • Kelly R.G.
        • Kanegis L.A.
        Metabolism and tissue distribution of radioisotopically labelled minocycline.
        Toxicol Appl Pharmacol. 1967; 11: 171-183
        • Konuma K.
        Use and abuse of amphetamines in Japan.
        in: Cho A.K. Segal D.S. Amphetamine and Its Analogs. Academic Press, San Diego1994: 415-435
        • Lammertsma A.
        • Hume S.
        Simplified reference tissue model for PET receptor studies.
        Neuroimage. 1996; 4: 153-158
        • London E.D.
        • Simon S.L.
        • Berman S.M.
        • Mandelkern M.A.
        • Lichtman A.M.
        • Bramen J.
        • et al.
        Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers.
        Arch Gen Psychiatry. 2004; 61: 73-84
        • Mortensen O.V.
        • Amara S.G.
        Dynamic regulation of the dopamine transporter.
        Eur J Pharmacol. 2003; 479: 159-170
        • National Institute on Drug Abuse
        Research Report Series.
        Methamphetamine Abuse and Addiction. National Clearinghouse on Alcohol and Drug Information, Rockville, MD2002 (NIH Publication No. 02-4210)
        • Nestler E.J.
        Molecular basis of long-term plasticity underlying addiction.
        Nat Rev Neurosci. 2001; 2: 119-128
        • Nestler E.J.
        From neurobiology to treatment: Progress against addiction.
        Nat Neurosci. 2002; 5: 1076-1079
        • Onoe H.
        • Inoue O.
        • Suzuki K.
        • Tsukada H.
        • Itoh T.
        • Mataga N.
        • et al.
        Ketamine increases the striatal N-[11C]methylspiperone binding in vivo: Positron emission tomography study using conscious rhesus monkey.
        Brain Res. 1994; 663: 191-198
        • Pierce R.C.
        • Kumaresan V.
        The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?.
        Neurosci Biobehav Rev. 2006; 30: 215-238
        • Sekine Y.
        • Iyo M.
        • Ouchi Y.
        • Matsunaga T.
        • Tsukada H.
        • Okada H.
        • et al.
        Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET.
        Am J Psychiatry. 2001; 158: 1206-1214
        • Sekine Y.
        • Minabe Y.
        • Ouchi Y.
        • Takei N.
        • Iyo M.
        • Nakamura K.
        • et al.
        Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms.
        Am J Psychiatry. 2003; 160: 1699-1701
        • Smith K.
        • Leyden J.J.
        Safety of doxycycline and minocycline: A systematic review.
        Clin Ther. 2005; 27: 1329-1342
        • Stirling D.P.
        • Koochesfahani K.M.
        • Steeves J.D.
        • Tetzlaff W.
        Minocycline as a neuroprotective agent.
        Neuroscientist. 2005; 11: 308-322
        • Takechi H.
        • Onoe H.
        • Imamura K.
        • Onoe K.
        • Kakiuchi T.
        • Nishiyama S.
        • et al.
        Brain activation study by use of positron emission tomography in unanesthetized monkeys.
        Neurosci Lett. 1994; 182: 279-282
        • Thomas D.M.
        • Walker P.D.
        • Benjamins J.A.
        • Geddes T.J.
        • Kuhn D.M.
        Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation.
        J Pharmacol Exp Ther. 2004; 311: 1-7
        • Tikka T.
        • Fiebich B.L.
        • Goldsteins G.
        • Keinanen R.
        • Koistinaho J.
        Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia.
        J Neurosci. 2001; 21: 2580-2588
        • Tsukada H.
        • Nishiyama S.
        • Kakiuchi T.
        • Ohba H.
        • Sato K.
        • Harada N.
        Ketamine alters the availability of striatal dopamine transporter as measured by [11C] β-CFT and [11C] β-CIT-FE in the monkey brain.
        Synapse. 2001; 42: 273-280
        • Volkow N.D.
        • Chang L.
        • Wang G.J.
        • Fowler J.S.
        • Leonido-Yee M.
        • Franceschi D.
        • et al.
        Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers.
        Am J Psychiatry. 2001; 158: 377-382
        • Wang X.
        • Zhu S.
        • Drozda M.
        • Zhang W.
        • Stavrovskaya I.G.
        • Cattaneo E.
        • et al.
        Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease.
        Proc Natl Acad Sci U S A. 2003; 100: 10483-10487
        • Watanabe M.
        • Okada H.
        • Shimizu K.
        • Omura T.
        • Yoshikawa E.
        • Kosugi T.
        • et al.
        A high resolution animal PET scanner using compact PS-PMT detectors.
        IEEE Trans Nucl Sci. 1997; 44: 1277-1282
        • Wilson J.M.
        • Kalasinsky K.S.
        • Levey A.I.
        • Bergeron C.
        • Reiber G.
        • Anthony R.M.
        • et al.
        Striatal dopamine nerve terminal markers in human, chronic methamphetamine users.
        Nat Med. 1996; 2: 699-703
        • Wu D.C.
        • Jackson-Lewis V.
        • Vila M.
        • Tieu K.
        • Teismann P.
        • Vadseth C.
        • et al.
        Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.
        J Neurosci. 2002; 22: 1763-1771
        • Yong V.W.
        • Wells J.
        • Giuliani F.
        • Casha S.
        • Power C.
        • Metz L.M.
        The promise of minocycline in neurology.
        Lancet Neurol. 2004; 3: 744-751
      1. Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, Iyo M, et al (in press): Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry.

        • Zhu S.
        • Stavrovskaya I.G.
        • Drozda M.
        • Kim B.Y.
        • Ona V.
        • Li M.
        • et al.
        Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice.
        Nature. 2002; 417: 74-78