Skip to main content

Advertisement

SpringerLink
Log in

Longitudinal changes of dopamine transporters in heroin users during abstinence

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

Abstract

Rationale

Chronic exposure to heroin results in decreased dopamine transporter levels. Jitai tablets, a traditional Chinese medicine, have been effective at increasing striatal dopamine transporter availability after 6 months of treatment. However, it remains unknown how long the heroin-induced impairment persists and whether dopamine transporter can be normalized following long-term abstinence or treatment.

Objectives

This study was to evaluate the time course of dopamine transporter changes in heroin users undergoing long-term abstinence and treatment with Jitai tablets for 1 year.

Methods

Single-photon emission computed tomography using [99mTc]TRODAT-1 was performed on 64 heroin users and 20 healthy subjects to assess striatal dopamine transporter availability at baseline, 3, 6, and 12 months. Heroin users were randomly assigned to treatment with either placebo or Jitai tablets. Depression and anxiety scores were measured before each imaging session.

Results

Compared with healthy controls, significant reduction in dopamine transporter availability was found in heroin users at baseline in both the right (by ∼31.6 %) and left striatum (by ∼33.2 %). At 6 months, dopamine transporter availability was significantly higher in Jitai tablet-treated group than placebo group in the bilateral striatum (p < 0.01). At 12 months, dopamine transporter levels in both groups were upregulated substantially from baseline but still not recovered to normal levels in the left striatum (p < 0.05). Depression and anxiety scores significantly decreased at 3, 6, and 12 months (p < 0.05).

Conclusions

Our results confirmed that heroin abuse induces pronounced, long-term reduction in dopamine transporter. Treatment with Jitai tablets appears to stimulate recovery.

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

Similar content being viewed by others

References

  • Adams JB, Pyke RE, Costa J, Cutler NR, Schweizer E, Wilcox CS, Wisselink PG, Greiner M, Pierce MW, Pande AC (1995) A double-blind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder. J Clin Psychopharmacol 15:428–434

    Article  CAS  PubMed  Google Scholar 

  • Beveridge TJR, Smith HR, Nader MA, Porrino LJ (2009) Abstinence from chronic cocaine self-administration alters striatal dopamine systems in rhesus monkeys. Neuropsychopharmacology 34:1162–1171

    Article  CAS  PubMed  Google Scholar 

  • Bustamante JC, Barros-Loscertales A, Costumero V, Fuentes-Claramonte P, Rosell-Negre P, Ventura-Campos N, Llopis JJ, Avila C (2014) Abstinence duration modulates striatal functioning during monetary reward processing in cocaine patients. Addict Biol 19:885–894

    Article  PubMed  Google Scholar 

  • Chang SC (1995) The method of space-time conservation element and solution element—a new approach for solving the Navier–Stokes and Euler equations. J Comput Phys 119:295–324

    Article  Google Scholar 

  • Chu HY, Jin GZ, Friedman E, Zhen XC (2008) Recent development in studies of tetrahydroprotoberberines: mechanism in antinociception and drug addiction. Cell Mol Neurobiol 28:491–499

    Article  CAS  PubMed  Google Scholar 

  • Cosgrove KP, Tellez-Jacques K, Pittman B, Petrakis I, Baldwin RM, Tamagnan G, Seibyl J, Kosten T, Staley JK (2010) Dopamine and serotonin transporter availability in chronic heroin users: a I-123 beta-CIT SPECT imaging study. Psychiatry Res Neuroimaging 184:192–195

    Article  CAS  PubMed  Google Scholar 

  • Di Chiara G, Bassareo V (2007) Reward system and addiction: what dopamine does and doesn’t do (vol 7, pg 69, 2007). Curr Opin Pharmacol 7:233–233

    Article  Google Scholar 

  • Dichiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278

    Article  CAS  Google Scholar 

  • Gainetdinov RR, Jones SR, Fumagalli F, Wightman RM, Caron MG (1998) Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis. Brain Res Rev 26:148–153

    Article  CAS  PubMed  Google Scholar 

  • Gao JL, Tu SA, Liu J, Zhang JM, Huang YY, Han M, Liang JH (2014) An-jun-ning, a traditional herbal formula, attenuates spontaneous withdrawal symptoms via modulation of the dopamine system in morphine-dependent rats. BMC Complement Altern Med. doi:10.1186/1472-6882-14-308

    Google Scholar 

  • Gerra G, Zaimovic A, Zambelli U, Delsignore R, Baroni MC, Laviola G, Macchia T, Brambilla F (2000) Neuroendocrine correlates of depression in abstinent heroin-dependent subjects. Psychiatry Res 96:221–234

    Article  CAS  PubMed  Google Scholar 

  • Goeldner C, Lutz PE, Darcq E, Halter T, Clesse D, Ouagazzal AM, Kieffer BL (2011) Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine. Biol Psychiatry 69:236–244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gonzalez G, Oliveto A, Kosten TR (2002) Treatment of heroin (diamorphine) addiction—current approaches and future prospects. Drugs 62:1331–1343

    Article  CAS  PubMed  Google Scholar 

  • Hamilton M (1959) The assessment of anxiety-states by rating. Br J Med Psychol 32:50–55

    Article  CAS  PubMed  Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hao SQ, Zhao M, Zhang RW, Zhang JC, Zhang J, Feng XS (2013) The effectiveness comparison of Jitai tablets versus methadone in community-based drug treatment: a 1-year follow-up study. Addict Behav 38:2596–2600

    Article  PubMed  Google Scholar 

  • Hartz DT, Frederick-Osborne SL, Galloway GP (2001) Craving predicts use during treatment for methamphetamine dependence: a prospective, repeated-measures, within-subject analysis. Drug Alcohol Depend 63:269–276

    Article  CAS  PubMed  Google Scholar 

  • Heinz A, Goldman D, Gallinat J, Schumann G, Puls L (2004) Pharmacogenetic insights to monoaminergic dysfunction in alcohol dependence. Psychopharmacology 174:561–570

    Article  CAS  PubMed  Google Scholar 

  • Jia SW, Wang W, Liu Y, Wu ZM (2005) Neuroimaging studies of brain corpus striatum changes among heroin-dependent patients treated with herbal medicine, U’finer (TM) capsule. Addict Biol 10:293–297

    Article  CAS  PubMed  Google Scholar 

  • Kabir MA, Goh KL, Kamal SMM, Khan MMH (2013) Tobacco smoking and its association with illicit drug use among young men aged 15–24 years living in urban slums of Bangladesh. PLoS One. doi:10.1371/journal.pone.0068728

    Google Scholar 

  • Kim H, Kang J, Oh K (1995) Inhibition by ginseng total saponin of the development of morphine reverse tolerance ad dopamine receptor supersensitivity in mice. Gen Pharmacol Vasc S 26:1071–1076

    Article  CAS  Google Scholar 

  • Kin HS, Kang JG, Oh KW (1995) Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice. Gen Pharmacol 26:1071–1076

    Article  CAS  PubMed  Google Scholar 

  • Kish SJ, Kalasinsky KS, Derkach P, Schmunk GA, Guttman M, Ang L, Adams V, Furukawa Y, Haycock JW (2001) Striatal dopaminergic and serotonergic markers in human heroin users. Neuropsychopharmacology 24:561–567

    Article  CAS  PubMed  Google Scholar 

  • Kung MP, Stevenson DA, Plossl K, Meegalla SK, Beckwith A, Essman WD, Mu M, Lucki I, Kung HF (1997) Tc-99m TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent. Eur J Nucl Med 24:372–380

    CAS  PubMed  Google Scholar 

  • Laakso A, Bergman J, Haaparanta M, Vilkman H, Solin O, Syvalahti E, Hietala J (2001) Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia. Schizophrenia Res 52:115–120

    Article  CAS  Google Scholar 

  • Laine TPJ, Ahonen A, Torniainen P, Heikkila J, Pyhtinen J, Rasanen P, Niemela O, Hillbom M (1999) Dopamine transporters increase in human brain after alcohol withdrawal. Mol Psychiatr 4:189–191

    Article  CAS  Google Scholar 

  • Lee B, Kwon S, Yeom M, Shim I, Lee H, Hahm DH (2011) Wild ginseng attenuates repeated morphine-induced behavioral sensitization in rats. J Microbiol Biotechnol 21:757–765

    Article  PubMed  Google Scholar 

  • Lee B, Yang CH, Hahm DH, Lee HJ, Han SM, Kim KS, Shim I (2008) Inhibitory effects of ginseng total saponins on behavioral sensitization and dopamine release induced by cocaine. Biol Pharm Bull 31:436–441

    Article  CAS  PubMed  Google Scholar 

  • Leri F, Tremblay A, Sorge RE, Stewart J (2004) Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use. Neuropsychopharmacology 29:1312–1320

    Article  CAS  PubMed  Google Scholar 

  • Leroy C, Karila L, Martinot JL, Lukasiewicz M, Duchesnay E, Comtat C, Dolle F, Benyamina A, Artiges E, Ribeiro MJ, Reynaud M, Trichard C (2012) Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study. Addict Biol 17:981–990

    Article  CAS  PubMed  Google Scholar 

  • Li SX, Shi J, Epstein DH, Wang X, Zhang XL, Bao YP, Zhang D, Zhang XY, Kosten TR, Lu L (2009) Circadian alteration in neurobiology during 30 days of abstinence in heroin users. Biol Psychiatry 65:905–912

    Article  CAS  PubMed  Google Scholar 

  • Liang C-S, Ho P-S, Yen C-H, Yeh Y-W, Kuo S-C, Huang C-C, Chen C-Y, Shih M-C, Ma K-H, Huang S-Y (2014) Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study. Addict Biol. doi:10.1111/adb.12203

    PubMed  Google Scholar 

  • Lin SH, Chen KC, Lee SY, Chiu NT, Lee IH, Chen PS, Yeh TL, Lu RB, Chen CC, Liao MH, Yang YK (2015) The association between heroin expenditure and dopamine transporter availability—a single-photon emission computed tomography study. Psychiatry Res Neuroimaging 231:292–297

    Article  PubMed  Google Scholar 

  • Liu J, Gao JL, Tu SA, Xu SS, Liu Y, Shang WH, Gu CX, Huang YY, Han M (2014) Neuroprotective effects of Jitai tablet, a traditional Chinese medicine, on the MPTP-induced acute model of Parkinson’s disease: involvement of the dopamine system. Evid-Based Complement Altern Med. doi:10.1155/2014/542383

    Google Scholar 

  • Liu TT, Shi J, Epstein DH, Bao YP, Lu L (2009) A meta-analysis of Chinese herbal medicine in treatment of managed withdrawal from heroin. Cell Mol Neurobiol 29:17–25

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu Y, Han M, Liu XD, Deng YP, Li Y, Yuan J, Lv RB, Wang YK, Zhang GM, Gao JL (2013) Dopamine transporter availability in heroin-dependent subjects and controls: longitudinal changes during abstinence and the effects of Jitai tablets treatment. Psychopharmacology 230:235–244

    Article  CAS  PubMed  Google Scholar 

  • Malison RT, Best SE, van Dyck CH, McCance EF, Wallace EA, Laruelle M, Baldwin RM, Seibyl JP, Price LH, Kosten TR, Innis RB (1998) Elevated striatal dopamine transporters during acute cocaine abstinence as measured by I-123 beta-CIT SPECT. Am J Psychiat 155:832–834

    CAS  PubMed  Google Scholar 

  • McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with C-11 WIN-35,428. J Neurosci 18:8417–8422

    CAS  PubMed  Google Scholar 

  • Renoir T, Pang TY, Lanfumey L (2012) Drug withdrawal-induced depression: serotonergic and plasticity changes in animal models. Neurosci Biobehav Rev 36:696–726

    Article  CAS  PubMed  Google Scholar 

  • Rouge-Pont F, Usiello A, Benoit-Marand M, Gonon F, Piazza PV, Borrelli E (2002) Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors. J Neurosci 22:3293–3301

    CAS  PubMed  Google Scholar 

  • Sayette MA, Shiffman S, Tiffany ST, Niaura RS, Martin CS, Shadel WG (2000) The measurement of drug craving. Addiction 95:S189–S210

    Article  PubMed Central  PubMed  Google Scholar 

  • Shi J, Li SX, Zhang XL, Wang X, Le Foll B, Zhang XY, Kosten TR, Lu L (2009) Time-dependent neuroendocrine alterations and drug craving during the first month of abstinence in heroin addicts. Am J Drug Alcohol Abuse 35:267–272

    Article  PubMed  Google Scholar 

  • Shi J, Zhao LY, Copersino ML, Fang YX, Chen Y, Tian A, Deng YP, Shuai YH, Jin J, Lu L (2008) PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users. Eur J Pharmacol 579:160–166

    Article  CAS  PubMed  Google Scholar 

  • Tomer R, Goldstein RZ, Wang GJ, Wong C, Volkow ND (2008) Incentive motivation is associated with striatal dopamine asymmetry. Biol Psychol 77:98–101

    Article  PubMed Central  PubMed  Google Scholar 

  • Tsukada H, Harada N, Nishiyama S, Ohba H, Kakiuchi T (2000) Cholinergic neuronal modulation alters dopamine D-2 receptor availability in vivo by regulating receptor affinity induced by facilitated synaptic dopamine turnover: positron emission tomography studies with microdialysis in the conscious monkey brain. J Neurosci 20:7067–7073

    CAS  PubMed  Google Scholar 

  • UNODC (2012) World Drug Report 2012. United Nations

  • UNODC (2014) World Drug Report 2014. United Nations

  • UNODC/WHO (2013) Opioid overdose: preventing and reducing opioid overdose mortality. United Nations

  • Varrone A, Dickson JC, Tossici-Bolt L, Sera T, Asenbaum S, Booij J, Kapucu OL, Kluge A, Knudsen GM, Koulibaly PM, Nobili F, Pagani M, Sabri O, Vander Borght T, Van Laere K, Tatsch K (2013) European multicentre database of healthy controls for I-123 FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis. Eur J Nucl Med Mol Imaging 40:213–227

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J (2001a) Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci 21:9414–9418

    CAS  PubMed  Google Scholar 

  • Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, Miller EN (2001b) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiat 158:377–382

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ, Logan J, Schlyer D, Macgregor R, Hitzemann R, Wolf AP (1994) Decreased dopamine transporters with age in healthy-human subjects. Ann Neurol 36:237–239

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R, Shea CE (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827–830

    Article  CAS  PubMed  Google Scholar 

  • Wang S-P, Liu L, Wang L-L, Jiang P, Zhang J-Q, Zhang W-D, Liu R-H (2010) Screening and analysis of the multiple absorbed bioactive components and metabolites in rat plasma after oral administration of Jitai tablets by high-performance liquid chromatography/diode-array detection coupled with electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrometry 24:1641–1652

    Article  CAS  Google Scholar 

  • Wang SP, Liu L, Wang LL, Hu YH, Zhang WD, Liu RH (2012) Structural characterization and identification of major constituents in Jitai tablets by high-performance liquid chromatography/diode-array detection coupled with electrospray ionization tandem mass spectrometry. Molecules 17:10470–10493

    Article  CAS  PubMed  Google Scholar 

  • Watkins SS, Koob GF, Markou A (2000) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res Off J Soc Res Nicotine Tob 2:19–37

    Article  CAS  Google Scholar 

  • Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2:699–703

    Article  CAS  PubMed  Google Scholar 

  • Xiong JG, Xiao ZX, Li J, Qin DS, Min MS, Yang JH, Wang YH, Yan L, Shu QL (2002) Clinical effect of Jitai tablet combined with lofexidine in the treatment of heroin dependence. Chin J Drug Depend 10:290–292

    Google Scholar 

  • Xu G, Duan L, Wang Z, Liu R, Lu X, Wang Z, Tu Q, Sun G, Wang P, Cai Z (2000) A double-blind clinical trial of Jitai tablets vs Lofexidine in the treatment of heroin withdrawal symptoms. Chin J Drug Depend 9:273–277

    CAS  Google Scholar 

  • Yang Z, Shao YC, Li SJ, Qi JL, Zhang MJ, Hao W, Jin GZ (2008) Medication of l-tetrahydropalmatine significantly ameliorates opiate craving and increases the abstinence rate in heroin users: a pilot study. Acta Pharmacol Sin 29:781–788

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yeh TL, Chen KC, Lin SH, Lee IH, Chen PS, Yao WJ, Lee SY, Yang YK, Lu RB, Liao MH, Chiu NT (2012) Availability of dopamine and serotonin transporters in opioid-dependent users—a two-isotope SPECT study. Psychopharmacology 220:55–64

    Article  CAS  PubMed  Google Scholar 

  • Yuan J, Lv RB, Brasic JR, Han M, Liu XD, Wang YK, Zhang GM, Liu CJ, Li Y, Deng YP (2014) Dopamine transporter dysfunction in Han Chinese people with chronic methamphetamine dependence after a short-term abstinence. Psychiatry Res Neuroimaging 221:92–96

    Article  PubMed  Google Scholar 

  • Zihong LI, Yuanxing T, Shengzhong HUA, Ying W (2007) Efficacy of Jitai for protracted withdrawal symptoms in heroin dependent patients. Chin J Drug Depend 16:284–287

    Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Key Technology R&D Program of China (2008BA149B04 and 2008BA149B01) and the China National Science Foundation (81173139). The authors thank Daqing Shi, Zhijun Zheng, Hua Zhou, Mei Wen, and Zhihui Ni for patient care and Xianhui Qin for advice on statistics. The authors are particularly grateful to Pingrang Shen for her coordination and help. The study was approved by the Shanghai Mental Health Center in China.

Conflict of interest

All authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, China

    Shasha Xu, Ying Liu, Zhirui Guo & Mei Han

  2. Department of Nuclear Medicine, Huashan Hospital, Fudan University, Shanghai, China

    Shasha Xu, Jie Yuan, Rongbin Lv, Yuankai Wang, Guangming Zhang & Xingdang Liu

  3. Shanghai Center of Biomedicine Development, Shanghai, China

    Shasha Xu & Daxu Fu

  4. Drug Rehabilitation Center, Shanghai, China

    Yu Li

  5. National Institute on Drug Dependence, Peking University, Beijing, China

    Yangping Deng

  6. PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA

    Yiyun Huang

Authors
  1. Shasha Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yangping Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yiyun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rongbin Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuankai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guangming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhirui Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mei Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xingdang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Daxu Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mei Han, Xingdang Liu or Daxu Fu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, S., Liu, Y., Li, Y. et al. Longitudinal changes of dopamine transporters in heroin users during abstinence. Psychopharmacology 232, 3391–3401 (2015). https://doi.org/10.1007/s00213-015-3992-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-3992-0

Keywords

Search

Navigation