Abstract
Use of alcohol, cannabis and opioids is highly prevalent and is associated with global disease burden and high economic costs. The exact pathophysiology of abuse or addiction associated with these sedative substances is not completely understood, but previous research implicates the important role of the striatal dopamine system in the addiction process. Multiple studies investigated changes in the striatal dopamine systems of users of sedative substances, but currently these results are very heterogeneous. Therefore, we conducted a meta-analysis of in vivo neuroimaging studies investigating dopaminergic alterations in the striatum of users of alcohol, opioids or cannabis. Analyses for each substance were conducted separately for the availability of D2/D3 dopamine receptors, dopamine transporters and dopamine synthesis capacity. In total, 723 substance users and 752 healthy controls were included. The results indicated a significant lower striatal D2/D3 receptor availability in alcohol users compared to controls (g = 0.46) but no difference in dopamine transporter availability or dopamine synthesis capacity. Our analysis indicated that changes of dopamine receptors and transporters are moderated by the duration of abstinence. Comparing opioid users with controls revealed a significant lower D2/D3 receptor availability (g = 1.17) and a significantly lower transporter availability (g = 1.55) in opioid users. For cannabis users, there was no significant difference in receptor availability compared to controls and too few studies provided information on dopamine transporter availability or synthesis capacity. Our analysis provides strong evidence for a central role of the striatal dopamine system in use of alcohol or opioids. Further studies are needed to clarify the impact of the dopamine system in cannabis users.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
United Nations. Office on drugs and crime. World drug report 2017. Vienna: United Nations Publication; 2017.
World Health Organization. Global status report on alcohol and health 2014. Geneva: World Health Organization; 2014.
Degenhardt L, Charlson F, Mathers B, Hall WD, Flaxman AD, Johns N, et al. The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study. Addiction. 2014;109:1320–33.
Ashok AH, Mizuno Y, Volkow ND, Howes OD. Association of stimulant use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:511–9.
Di Chiara G, Bassareo V. Reward system and addiction: what dopamine does and doesn’t do. Curr Opin Pharmacol. 2007;7:69–76.
Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73.
Yager LM, Garcia AF, Wunsch AM, Ferguson SM. The ins and outs of the striatum: role in drug addiction. Neuroscience. 2015;301:529–41.
Laine TP, Ahonen A, Torniainen P, Heikkila J, Pyhtinen J, Rasanen P, et al. Dopamine transporters increase in human brain after alcohol withdrawal. Mol Psychiatry. 1999;4:189–91. 104-5
Repo E, Kuikka JT, Bergstrom KA, Karhu J, Hiltunen J, Tiihonen J. Dopamine transporter and D2-receptor density in late-onset alcoholism. Psychopharmacology. 1999;147:314–8.
Tiihonen J, Kuikka JT, Bergstrom KA, Karhu J, Viinamaki H, Lehtonen J, et al. Single-photon emission tomography imaging of monoamine transporters in impulsive violent behaviour. Eur J Nucl Med. 1997;24:1253–60.
Laine TP, Ahonen A, Rasanen P, Tiihonen J. Dopamine transporter density and novelty seeking among alcoholics. J Addict Dis. 2001;20:91–6.
Cosgrove KP, Krantzler E, Frohlich EB, Stiklus S, Pittman B, Tamagnan GD, et al. Dopamine and serotonin transporter availability during acute alcohol withdrawal: effects of comorbid tobacco smoking. Neuropsychopharmacology. 2009;34:2218–26.
Volkow ND, Wang GJ, Fowler JS, Logan J, Hitzemann R, Ding YS, et al. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res. 1996;20:1594–8.
Martinez D, Gil R, Slifstein M, Hwang D-R, Huang Y, Perez A, et al. Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry. 2005;58:779–86.
Volkow ND, Wang G-J, Maynard L, Fowler JS, Jayne B, Telang F, et al. Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study. Psychiatry Res. 2002;116:163–72.
Erritzoe D, Tziortzi A, Bargiela D, Colasanti A, Searle GE, Gunn RN, et al. In vivo imaging of cerebral dopamine D3 receptors in alcoholism. Neuropsychopharmacology. 2014;39:1703–12.
Guardia J, Catafau AM, Batlle F, Martin JC, Segura L, Gonzalvo B, et al. Striatal dopaminergic D(2) receptor density measured by (123)Iiodobenzamide SPECT in the prediction of treatment outcome of alcohol-dependent patients. Am J Psychiatry. 2000;157:127–9.
Tiihonen J, Vilkman H, Rasanen P, Ryynanen OP, Hakko H, Bergman J, et al. Striatal presynaptic dopamine function in type 1 alcoholics measured with positron emission tomography. Mol Psychiatry. 1998;3:156–61.
Kienast T, Schlagenhauf F, Rapp MA, Wrase J, Daig I, Buchholz H-G, et al. Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients. Pharmacopsychiatry. 2013;46:130–6.
Martinez D, Saccone PA, Liu F, Slifstein M, Orlowska D, Grassetti A, et al. Deficits in dopamine D(2) receptors and presynaptic dopamine in heroin dependence: commonalities and differences with other types of addiction. Biol Psychiatry. 2012;71:192–8.
Wang GJ, Volkow ND, Fowler JS, Logan J, Abumrad NN, Hitzemann RJ, et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology. 1997;16:174–82.
Zijlstra F, Booij J, van den Brink W, Franken IHA. Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males. Eur Neuropsychopharmacol. 2008;18:262–70.
Hou H, Yin S, Jia S, Hu S, Sun T, Chen Q, et al. Decreased striatal dopamine transporters in codeine-containing cough syrup abusers. Drug Alcohol Depend. 2011;118:148–51.
Shi J, Zhao L-Y, Copersino ML, Fang Y-X, Chen Y, Tian J, et al. PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users. Eur J Pharmacol. 2008;579:160–6.
Yeh TL, Chen KC, Lin S-H, Lee IH, Chen PS, Yao WJ, et al. Availability of dopamine and serotonin transporters in opioid-dependent users--a two-isotope SPECT study. Psychopharmacology. 2012;220:55–64.
Yuan J, Liu XD, Han M, Lv RB, Wang YK, Zhang GM, et al. Comparison of striatal dopamine transporter levels in chronic heroin-dependent and methamphetamine-dependent subjects. Addict Biol. 2015;22:229–34.
Albrecht DS, Skosnik PD, Vollmer JM, Brumbaugh MS, Perry KM, Mock BH, et al. Striatal D(2)/D(3) receptor availability is inversely correlated with cannabis consumption in chronic marijuana users. Drug Alcohol Depend. 2013;128:52–7.
Sevy S, Smith GS, Ma Y, Dhawan V, Chaly T, Kingsley PB, et al. Cerebral glucose metabolism and D2/D3 receptor availability in young adults with cannabis dependence measured with positron emission tomography. Psychopharmacology. 2008;197:549–56.
Volkow ND, Wang G-J, Telang F, Fowler JS, Alexoff D, Logan J, et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci USA. 2014;111:E3149–56.
Kuikka JT, Tiihonen J, Bergström KA, Karhu J, Räsänen P, Eronen M. Abnormal structure of human striatal dopamine re-uptake sites in habitually violent alcoholic offenders: a fractal analysis. Neurosci Lett. 1998;253:195–7.
Leroy C, Karila L, Martinot J-L, Lukasiewicz M, Duchesnay E, Comtat C, et al. Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study. Addict Biol. 2012;17:981–90.
Bloomfield MAP, Morgan CJA, Egerton A, Kapur S, Curran HV, Howes OD. Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol Psychiatry. 2014;75:470–8.
Hedges LV, Vevea JL. Fixed- and random-effects models in meta-analysis. Psychol Methods. 1998;3:486–504.
Raudenbusch S. Analysing effect sizes: random effects models. In: Cooper HM, Hedges LV, Valentine JC, editors. The handbook of research synthesis and meta-analysis. 2nd ed. New York: Russell Sage Foundation; 2009.
Viechtbauer W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 2010;36:1–48.
Core Team R. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2016.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.
Jia SW, Wang W, Liu Y, Wu ZM. Neuroimaging studies of brain corpus striatum changes among heroin-dependent patients treated with herbal medicine, U’finer capsule. Addict Biol. 2005;10:293–7.
Liu Y, Han M, Liu X, Deng Y, Li Y, Yuan J, et al. Dopamine transporter availability in heroin-dependent subjects and controls: longitudinal changes during abstinence and the effects of Jitai tablets treatment. Psychopharmacology. 2013;230:235–44.
Rominger A, Cumming P, Xiong G, Koller G, Boning G, Wulff M, et al. 18FFallypride PET measurement of striatal and extrastriatal dopamine D 2/3 receptor availability in recently abstinent alcoholics. Addict Biol. 2012;17:490–503.
Zaaijer ER, van Dijk L, Bruin K, de, Goudriaan AE, Lammers LA, Koeter MWJ, et al. Effect of extended-release naltrexone on striatal dopamine transporter availability, depression and anhedonia in heroin-dependent patients. Psychopharmacology. 2015;232:2597–607.
Tiihonen J, Kuikka J, Bergstrom K, Hakola P, Karhu J, Ryynanen OP, et al. Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics. Nat Med. 1995;1:654–7.
Tomasi D, Wang G-J, Volkow ND. Balanced modulation of striatal activation from D2 /D3 receptors in caudate and ventral striatum: disruption in cannabis abusers. Hum Brain Mapp. 2015;36:3154–66.
Rohatgi A. WebPlotDigitizer. 2016. http://arohatgi.info/WebPlotDigitizer. Accessed 20 Feb 2017.
Xu S, Liu Y, Li Y, Deng Y, Huang Y, Yuan J, et al. Longitudinal changes of dopamine transporters in heroin users during abstinence. Psychopharmacology. 2015;232:3391–401.
Spreckelmeyer KN, Paulzen M, Raptis M, Baltus T, Schaffrath S, van Waesberghe J, et al. Opiate-induced dopamine release is modulated by severity of alcohol dependence: an (18)Ffallypride positron emission tomography study. Biol Psychiatry. 2011;70:770–6.
Volkow ND, Wang G-J, Telang F, Fowler JS, Logan J, Jayne M, et al. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci. 2007;27:12700–6.
Nutt DJ, Lingford-Hughes A, Erritzoe D, Stokes PRA. The dopamine theory of addiction: 40 years of highs and lows. Nat Rev Neurosci. 2015;16:305–12.
Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–8.
Boileau I, Assaad J-M, Pihl RO, Benkelfat C, Leyton M, Diksic M, et al. Alcohol promotes dopamine release in the human nucleus accumbens. Synapse. 2003;49:226–31.
Heinz A, Siessmeier T, Wrase J, Hermann D, Klein S, Grusser SM, et al. Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am J Psychiatry. 2004;161:1783–9.
Thanos PK, Rivera SN, Weaver K, Grandy DK, Rubinstein M, Umegaki H, et al. Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. Life Sci. 2005;77:130–9.
Volkow ND, Wang G-J, Begleiter H, Porjesz B, Fowler JS, Telang F, et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. Arch Gen Psychiatry. 2006;63:999–1008.
Trifilieff P, Martinez D. Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity. Neuropharmacology. 2014;76 Pt B:498–509.
Volkow ND, Wiers CE, Shokri-Kojori E, Tomasi D, Wang G-J, Baler R. Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: studies with positron emission tomography. Neuropharmacology. 2017;122:175–88.
Heinz A, Siessmeier T, Wrase J, Buchholz HG, Grunder G, Kumakura Y, et al. Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined 18FDOPA and 18FDMFP PET study in detoxified alcoholic patients. Am J Psychiatry. 2005;162:1515–20.
Karrer TM, Josef AK, Mata R, Morris ED, Samanez-Larkin GR. Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis. Neurobiol Aging. 2017;57:36–46.
Martinez D, Orlowska D, Narendran R, Slifstein M, Liu F, Kumar D, et al. Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers. Biol Psychiatry. 2010;67:275–8.
Wiers CE, Towb PC, Hodgkinson CA, Shen P-H, Freeman C, Miller G, et al. Association of genetic ancestry with striatal dopamine D2/D3 receptor availability. Mol Psychiatry. 2017.
Volkow ND, Wang G-J, Telang F, Fowler JS, Logan J, Wong C, et al. Sleep deprivation decreases binding of 11Craclopride to dopamine D2/D3 receptors in the human brain. J Neurosci. 2008;28:8454–61.
Wiers CE, Cabrera EA, Tomasi D, Wong CT, Demiral ŞB, Kim SW, et al. Striatal dopamine D2/D3 receptor availability varies across smoking status. Neuropsychopharmacology. 2017;42:2325–2332.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012;69:776–86.
Kambeitz J, Abi-Dargham A, Kapur S, Howes OD. Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. Br J Psychiatry. 2014;204:420–9.
Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22:666–79.
Cosgrove KP, Tellez-Jacques K, Pittman B, Petrakis I, Baldwin RM, Tamagnan G, et al. Dopamine and serotonin transporter availability in chronic heroin users: a (1)(2)(3)Ibeta-CIT SPECT imaging study. Psychiatry Res. 2010;184:192–5.
Urban NBL, Slifstein M, Thompson JL, Xu X, Girgis RR, Raheja S, et al. Dopamine release in chronic cannabis users: a 11craclopride positron emission tomography study. Biol Psychiatry. 2012;71:677–83.
Bortz J, Schuster C. Statistik für human- und Sozialwissenschaftler. 7th ed. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg; 2010.
Funding and disclosure
FK and LP are employed and funded by the German Federal Ministry of Health (Project ZMVI1-2516DSM216).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Kamp, F., Proebstl, L., Penzel, N. et al. Effects of sedative drug use on the dopamine system: a systematic review and meta-analysis of in vivo neuroimaging studies. Neuropsychopharmacol 44, 660–667 (2019). https://doi.org/10.1038/s41386-018-0191-9
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41386-018-0191-9
This article is cited by
-
Addiction and the Capability to Abstain
Res Publica (2024)
-
Long-term alcohol consumption alters dorsal striatal dopamine release and regulation by D2 dopamine receptors in rhesus macaques
Neuropsychopharmacology (2021)
-
Neuroimaging the Neuropathogenesis of HIV
Current HIV/AIDS Reports (2021)
-
A wireless, implantable optoelectrochemical probe for optogenetic stimulation and dopamine detection
Microsystems & Nanoengineering (2020)
-
Vapor Cannabis Exposure Promotes Genetic Plasticity in the Rat Hypothalamus
Scientific Reports (2019)
