Abstract
Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stress-induced relapse. Our goal was to investigate changes in kappa-opioid receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist [11C]GR103545. Subjects with cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administration sessions in the laboratory as follows: (1) choice sessions following a cold pressor test, to induce stress, and (2) binge dosing of cocaine. This allowed us investigate the following: (1) the association between KOR binding and a laboratory model of stress-induced relapse and (2) the change in KOR binding following a 3-day cocaine binge, which is thought to represent a change in endogenous dynorphin. A group of matched healthy controls was included to investigate between group differences in KOR availability. A significant association between [11C]GR103545 binding and cocaine self-administration was seen: greater KOR availability was associated with more choices for cocaine. In addition, the 3-day cocaine binge significantly reduced [11C]GR103545 binding by 18% in the striatum and 14% across brain regions. No difference in [11C]GR103545 binding was found between the CUD subjects and matched controls. In the context of previous studies, these findings add to the growing evidence that pharmacotherapies targeting the KOR have the potential to significantly impact treatment development for cocaine-use disorder.
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
Koob GF. Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology. 2009;56:18–31.
Trifilieff P, Martinez D. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence. Front Psychiatry. 2013;4:44.
Shippenberg TS, Herz A. Differential effects of mu and kappa opioid systems on motivational processes. NIDA Res Monogr. 1986;75:563–6.
Sivam SP. Cocaine selectively increases striatonigral dynorphin levels by a dopaminergic mechanism. J Pharmacol Exp Ther. 1989;250:818–24.
Smiley PL, Johnson M, Bush L, Gibb JW, Hanson GR. Effects of cocaine on extrapyramidal and limbic dynorphin systems. J Pharmacol Exp Ther. 1990;253:938–43.
Daunais JB, Roberts DC, McGinty JF. Cocaine self-administration increases preprodynorphin, but not c-fos, mRNA in rat striatum. Neuroreport. 1993;4:543–6.
Daunais JB, Roberts DC, McGinty JF. Short-term cocaine self administration alters striatal gene expression. Brain Res Bull. 1995b;37:523–7.
Jenab S, Festa ED, Russo SJ, Wu HB, Inturrisi CE, Quinones-Jenab V. MK-801 attenuates cocaine induction of c-fos and preprodynorphin mRNA levels in Fischer rats. Brain Res Mol Brain Res. 2003;117:237–9.
Schlussman SD, Zhang Y, Yuferov V, LaForge KS, Ho A, Kreek MJ. Acute ‘binge’ cocaine administration elevates dynorphin mRNA in the caudate putamen of C57BL/6J but not 129/J mice. Brain Res. 2003;974:249–53.
Schlussman SD, Zhou Y, Bailey A, Ho A, Kreek MJ. Steady-dose and escalating-dose “binge” administration of cocaine alter expression of behavioral stereotypy and striatal preprodynorphin mRNA levels in rats. Brain Res Bull. 2005;67:169–75.
Spangler R, Ho A, Zhou Y, Maggos CE, Yuferov V, Kreek MJ. Regulation of kappa opioid receptor mRNA in the rat brain by “binge’ pattern cocaine administration and correlation with preprodynorphin mRNA. Brain Res Mol Brain Res. 1996;38:71–6.
Spangler R, Unterwald E, Kreek M. Binge cocaine administration induces a sustained increase of prodynorphin mRNA in rat caudate-putamen. Brain Res Mol Brain Res. 1993;19:323–7.
Zhou Y, Spangler R, Schlussman SD, Yuferov VP, Sora I, Ho A, et al. Effects of acute “binge” cocaine on preprodynorphin, preproenkephalin, proopiomelanocortin, and corticotropin-releasing hormone receptor mRNA levels in the striatum and hypothalamic-pituitary-adrenal axis of mu-opioid receptor knockout mice. Synapse. 2002;45:220–9.
Daunais JB, McGinty JF. Cocaine binges differentially alter striatal preprodynorphin and zif/268 mRNAs. Brain Res Mol Brain Res. 1995a;29:201–10.
Daunais JB, McGinty JF. The effects of D1 or D2 dopamine receptor blockade on zif/268 and preprodynorphin gene expression in rat forebrain following a short-term cocaine binge. Brain Res Mol Brain Res. 1996;35:237–48.
Hurd YL, Herkenham M. Molecular alterations in the neostriatum of human cocaine addicts. Synapse. 1993;13:357–69.
Mash DC, Staley JK. D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims. Ann N Y Acad Sci. 1999;877:507–22.
Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC. Kappa2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. J Neurosci. 1997;17:8225–33.
Muschamp JW, Carlezon WA Jr. Roles of nucleus accumbens CREB and dynorphin in dysregulation of motivation. Cold Spring Harb Perspect Med. 2013;3:a012005.
Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44–55.
Wee S, Koob GF. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology. 2010;210:121–35.
Chavkin C, Koob GF. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology. 2016;41:373–4.
Nabulsi NB, Zheng MQ, Ropchan J, Labaree D, Ding YS, Blumberg L, et al. [11C]GR103545: novel one-pot radiosynthesis with high specific activity. Nucl Med Biol. 2011;38:215–21.
Naganawa M, Jacobsen LK, Zheng MQ, Lin SF, Banerjee A, Byon W, et al. Evaluation of the agonist PET radioligand [(1)(1)C]GR103545 to image kappa opioid receptor in humans: kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242. NeuroImage. 2014;99:69–79.
Schoultz BW, Hjornevik T, Willoch F, Marton J, Noda A, Murakami Y, et al. Evaluation of the kappa-opioid receptor-selective tracer [(11)C]GR103545 in awake rhesus macaques. Eur J Nucl Med Mol Imaging. 2010;37:1174–80.
Back SE, Brady KT, Jackson JL, Salstrom S, Zinzow H. Gender differences in stress reactivity among cocaine-dependent individuals. Psychopharmacology. 2005;180:169–76.
Compton MA. Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manag. 1994;9:462–73.
Talbot PS, Narendran R, Butelman ER, Huang Y, Ngo K, Slifstein M, et al. 11C-GR103545, a radiotracer for imaging kappa-opioid receptors in vivo with PET: synthesis and evaluation in baboons. J Nucl Med. 2005;46:484–94.
Peng XM, Knapp BI, Bidlack JM, Neumeyer JL. Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors. J Med Chem. 2007;50:2254–8.
Butelman ER, Rus S, Prisinzano TE, Kreek MJ. The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects. Psychopharmacology. 2010;210:253–62.
Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab. 2003;23:285–300.
Abi-Dargham A, Martinez D, Mawlawi O, Simpson N, Hwang DR, Slifstein M, et al. Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility. J Cereb Blood Flow Metab. 2000;20:225–43.
Girgis RR, Xu X, Gil RB, Hackett E, Ojeil N, Lieberman JA, et al. Antipsychotic binding to the dopamine-3 receptor in humans: a PET study with [(11)C]-(+)-PHNO. Schizophr Res. 2015;168:373–6.
Ichise M, Toyama H, Innis RB, Carson RE. Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab. 2002;22:1271–81.
Slifstein M, van de Giessen E, Van Snellenberg J, Thompson JL, Narendran R, Gil R, et al. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry. 2015;72:316–24.
Foltin RW, Fischman MW. Residual effects of repeated cocaine smoking in humans. Drug Alcohol Depend. 1997;47:117–24.
Haney M, Rubin E, Foltin RW. Aripiprazole maintenance increases smoked cocaine self-administration in humans. Psychopharmacology. 2011;216:379–87.
Martinez D, Slifstein M, Narendran R, Foltin RW, Broft A, Hwang DR, et al. Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine. Neuropsychopharmacology. 2009;34:1774–82.
Ward AS, Haney M, Fischman MW, Foltin RW. Binge cocaine self-administration by humans: smoked cocaine. Behav Pharmacol. 1997;8:736–44.
Kowalczyk WJ, Evans SM, Bisaga AM, Sullivan MA, Comer SD. Sex differences and hormonal influences on response to cold pressor pain in humans. J Pain. 2006;7:151–60.
Vadhan NP, Hart CL, Haney M, van Gorp WG, Foltin RW. Decision-making in long-term cocaine users: effects of a cash monetary contingency on Gambling task performance. Drug Alcohol Depend. 2009;102:95–101.
Foltin RW, Ward AS, Collins ED, Haney M, Hart CL, Fischman MW. The effects of venlafaxine on the subjective, reinforcing, and cardiovascular effects of cocaine in opioid-dependent and non-opioid-dependent humans. Exp Clin Psychopharmacol. 2003;11:123–30.
Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2010;30:46–50.
Groblewski PA, Zietz C, Willuhn I, Phillips PE, Chavkin C. Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats. Addict Biol. 2015;20:297–301.
Polter AM, Bishop RA, Briand LA, Graziane NM, Pierce RC, Kauer JA. Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. Biol Psychiatry. 2014;76:785–93.
Fagergren P, Smith HR, Daunais JB, Nader MA, Porrino LJ, Hurd YL. Temporal upregulation of prodynorphin mRNA in the primate striatum after cocaine self-administration. Eur J Neurosci. 2003;17:2212–8.
Frankel PS, Alburges ME, Bush L, Hanson GR, Kish SJ. Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users. Neuropharmacology. 2008;55:41–6.
Placzek MS, Schroeder FA, Che T, Wey HY, Neelamegam R, Wang C, et al. Discrepancies in kappa opioid agonist binding revealed through PET imaging. ACS Chem Neurosci. 2018;10:384–95.
Placzek MS, Van de Bittner GC, Wey HY, Lukas SE, Hooker JM. Immediate and persistent effects of salvinorin A on the kappa opioid receptor in rodents, monitored in vivo with PET. Neuropsychopharmacology. 2015;40:2865–72.
Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab. 2000;20:423–51.
Placzek MS, Zhao W, Wey HY, Morin TM, Hooker JM. PET neurochemical imaging modes. Semin Nucl Med. 2016;46:20–27.
Tejeda HA, Bonci A. Dynorphin/kappa-opioid receptor control of dopamine dynamics: Implications for negative affective states and psychiatric disorders. Brain Res. 2018;pii: S0006-8993:30488-8.
Tejeda HA, Natividad LA, Orfila JE, Torres OV, O’Dell LE. Dysregulation of kappa-opioid receptor systems by chronic nicotine modulate the nicotine withdrawal syndrome in an age-dependent manner. Psychopharmacology. 2012;224:289–301.
Walker BM, Zorrilla EP, Koob GF. Systemic kappa-opioid receptor antagonism by nor-binaltorphimine reduces dependence-induced excessive alcohol self-administration in rats. Addict Biol. 2011;16:116–9.
Whitfield TW Jr., Schlosburg JE, Wee S, Gould A, George O, Grant Y, et al. kappa Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake. J Neurosci. 2015;35:4296–305.
Acknowledgements
We thank Margaret Haney PhD for her input on binge cocaine dosing and Charles Chavkin PhD for his input on study design regarding previous rodent work.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
41386_2019_398_MOESM1_ESM.docx
Kappa Opioid Receptors, Dynorphin and Cocaine Addiction: A Positron Emission Tomography Study Additional supporting material
Rights and permissions
About this article
Cite this article
Martinez, D., Slifstein, M., Matuskey, D. et al. Kappa-opioid receptors, dynorphin, and cocaine addiction: a positron emission tomography study. Neuropsychopharmacol. 44, 1720–1727 (2019). https://doi.org/10.1038/s41386-019-0398-4
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-019-0398-4
This article is cited by
-
Endogenous mu-opioid modulation of social connection in humans: a systematic review and meta-analysis
Translational Psychiatry (2024)
-
Kappa opioid receptor availability predicts severity of anhedonia in schizophrenia
Neuropsychopharmacology (2024)
-
Co-targeting the kappa opioid receptor and dopamine transporter reduces motivation to self-administer cocaine and partially reverses dopamine system dysregulation
Scientific Reports (2024)
-
Acquisition of cocaine reinforcement using fixed-ratio and concurrent choice schedules in socially housed female and male monkeys
Psychopharmacology (2024)
-
PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration
Neuropsychopharmacology (2023)
