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Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats

Abstract

A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when “price” was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.

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Fig. 1: DA uptake in the DMS predicts effortful responding for cocaine.
Fig. 2: Animals with faster rates of uptake in the DMS differ in the pattern of cocaine self-administration under the progressive ratio schedule.
Fig. 3: DA uptake in the DMS predicts cocaine-primed reinstatement.
Fig. 4: Reduced rate of DA uptake in the DMS attenuates cocaine potency at the DAT.

References

  1. 1.

    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.

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Roberts DC, Bennett SA, Vickers GJ. The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology. 1989;98:408–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Jackson LR, Robinson TE, Becker JB. Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology. 2006;31:129–38.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Davis BA, Clinton SM, Akil H, Becker JB. The effects of novelty-seeking phenotypes and sex differences on acquisition of cocaine self-administration in selectively bred High-Responder and Low-Responder rats. Pharm Biochem Behav. 2008;90:331–8.

    CAS  Article  Google Scholar 

  5. 5.

    Roth ME, Carroll ME. Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharm Biochem Behav. 2004;78:199–207.

    CAS  Article  Google Scholar 

  6. 6.

    Lynch WJ, Carroll ME. Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology. 2000;148:196–200.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Walker QD, Rooney MB, Wightman RM, Kuhn CM. Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience. 2000;95:1061–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Walker QD, Ray R, Kuhn CM. Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology. 2006;31:1193–202.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Calipari ES, Juarez B, Morel C, Walker DM, Cahill ME, Ribeiro E, et al. Dopaminergic dynamics underlying sex-specific cocaine reward. Nat Commun. 2017;8:13877.

  10. 10.

    Yajie D, Lin K, Baoming L, Lan M. Enhanced cocaine self-administration in adult rats with adolescent isolation experience. Pharm Biochem Behav. 2005;82:673–7.

    Article  CAS  Google Scholar 

  11. 11.

    Fosnocht AQ, Lucerne KE, Ellis AS, Olimpo NA, Briand LA. Adolescent social isolation increases cocaine seeking in male and female mice. Behav Brain Res. 2019;359:589–96.

  12. 12.

    Baarendse PJ, Limpens JH, Vanderschuren LJ. Disrupted social development enhances the motivation for cocaine in rats. Psychopharmacology. 2014;231:1695–704.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Yorgason JT, Calipari ES, Ferris MJ, Karkhanis AN, Fordahl SC, Weiner JL, et al. Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. Neuropharmacology. 2016;101:471–9.

  14. 14.

    Allen RM, Everett CV, Nelson AM, Gulley JM, Zahniser NR. Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague-Dawley rats. Pharm Biochem Behav. 2007;86:37–44.

    CAS  Article  Google Scholar 

  15. 15.

    Mandt BH, Schenk S, Zahniser NR, Allen RM. Individual differences in cocaine-induced locomotor activity in male Sprague-Dawley rats and their acquisition of and motivation to self-administer cocaine. Psychopharmacology. 2008;201:195–202.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Nelson AM, Larson GA, Zahniser NR. Low or high cocaine responding rats differ in striatal extracellular dopamine levels and dopamine transporter number. J Pharm Exp Ther. 2009;331:985–97.

    CAS  Article  Google Scholar 

  17. 17.

    Gong W, Neill DB, Justice JB Jr. Locomotor response to novelty does not predict cocaine place preference conditioning in rats. Pharm Biochem Behav. 1996;53:185–90.

    CAS  Article  Google Scholar 

  18. 18.

    Kosten TA, Miserendino MJ. Dissociation of novelty- and cocaine-conditioned locomotor activity from cocaine place conditioning. Pharm Biochem Behav. 1998;60:785–91.

    CAS  Article  Google Scholar 

  19. 19.

    Ferris MJ, Calipari ES, Melchior JR, Roberts DC, España RA, Jones SR. Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals. Eur J Neurosci. 2013;38:2628–36.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Piazza PV, Deroche-Gamonent V, Rouge-Pont F, Le Moal M. Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci. 2000;20:4226–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ. High impulsivity predicts the switch to compulsive cocaine-taking. Science. 2008;320:1352–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V. High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology. 2011;36:569–79.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Hooks MS, Colvin AC, Juncos JL, Justice JB Jr. Individual differences in basal and cocaine-stimulated extracellular dopamine in the nucleus accumbens using quantitative microdialysis. Brain Res. 1992;587:306–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Chefer VI, Zakharova I, Shippenberg TS. Enhanced responsiveness to novelty and cocaine is associated with decreased basal dopamine uptake and release in the nucleus accumbens: quantitative microdialysis in rats under transient conditions. J Neurosci. 2003;23:3076–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Verheij MM, de Mulder EL, De Leonibus E, van Loo KM, Cools AR. Rats that differentially respond to cocaine differ in their dopaminergic storage capacity of the nucleus accumbens. J Neurochem. 2008;105:2122–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Merritt KE, Bachtell RK. Initial d2 dopamine receptor sensitivity predicts cocaine sensitivity and reward in rats. PLoS One. 2013;8:e78258.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Anker JJ, Perry JL, Gliddon LA, Carroll ME. Impulsivity predicts the escalation of cocaine self-administration in rats. Pharm Biochem Behav. 2009;93:343–8.

    CAS  Article  Google Scholar 

  28. 28.

    Perry JL, Larson EB, German JP, Madden GJ, Carroll ME. Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats. Psychopharmacology. 2005;178:193–201.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Laane K, et al. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science. 2007;315:1267–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Caine SB, Negus SS, Mello NK, Patel S, Bristow L, Kulagowski J, et al. Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists. J Neurosci. 2002;22:2977–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Holroyd KB, Adrover MF, Fuino RL, Bock R, Kaplan AR, Gremel CM, et al. Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues. Neuropsychopharmacology. 2015;40:1495–509.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    de Jong JW, Roelofs TJ, Mol FM, Hillen AE, Meijboom KE, Luijendijk MC, et al. Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation. Neuropsychopharmacology. 2015;40:2085–95.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Bello EP, Mateo Y, Gelman DM, Noain D, Shin JH, Low MJ, et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci. 2011;14:1033–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Tacelosky DM, Alexander DN, Morse M, Hajnal A, Berg A, Levenson R, et al. Low expression of D2R and Wntless correlates with high motivation for heroin. Behav Neurosci. 2015;129:744–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Nader MA, Czoty PW, Gould RW, Riddick NV. Review. Positron emission tomography imaging studies of dopamine receptors in primate models of addiction. Philos Trans R Soc Lond B Biol Sci. 2008;363:3223–32.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Becker JB. Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharm Biochem Behav. 1999;64:803–12.

    CAS  Article  Google Scholar 

  37. 37.

    Becker JB, Rudick CN. Rapid effects of estrogen or progesterone on the amphetamine-induced increase in striatal dopamine are enhanced by estrogen priming: a microdialysis study. Pharm Biochem Behav. 1999;64:53–7.

    CAS  Article  Google Scholar 

  38. 38.

    Larson EB, Carroll ME. Estrogen receptor beta, but not alpha, mediates estrogen’s effect on cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized female rats. Neuropsychopharmacology. 2007;32:1334–45.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Anker JJ, Larson EB, Gliddon LA, Carroll ME. Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats. Exp Clin Psychopharmacol. 2007;15:472–80.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Ferris MJ, España RA, Locke JL, Konstantopoulos JK, Rose JH, Chen R, et al. Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci USA. 2014;111:E2751–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Alonso IP, Pino JA, Kortagere S, Torres GE, España RA. Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction. Neuropsychopharmacology. 2021;46:699–708.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Brodnik ZD, España RA. Dopamine uptake dynamics are preserved under isoflurane anesthesia. Neurosci Lett. 2015;606:129–34.

  43. 43.

    Shaw JK, Ferris MJ, Locke JL, Brodnik ZD, Jones SR, España RA. Hypocretin/orexin knock-out mice display disrupted behavioral and dopamine responses to cocaine. Addict Biol. 2017;22:1695–705.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    España RA, Oleson EB, Locke JL, Brookshire BR, Roberts DC, Jones SR. The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. Eur J Neurosci. 2010;31:336–48.

    PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Wightman RM, Zimmerman JB. Control of dopamine extracellular concentration in rat striatum by impulse flow and uptake. Brain Res Brain Res Rev. 1990;15:135–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    White NM, McDonald RJ. Acquisition of a spatial conditioned place preference is impaired by amygdala lesions and improved by fornix lesions. Behav Brain Res. 1993;55:269–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Wayman WN, Woodward JJ. Chemogenetic excitation of accumbens-projecting infralimbic cortical neurons blocks toluene-induced conditioned place preference. J Neurosci. 2018;38:1462–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Zakharova E, Leoni G, Kichko I, Izenwasser S. Differential effects of methamphetamine and cocaine on conditioned place preference and locomotor activity in adult and adolescent male rats. Behav Brain Res. 2009;198:45–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Prince CD, Rau AR, Yorgason JT, España RA. Hypocretin/Orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1. ACS Chem Neurosci. 2015;6:138–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    España RA, Melchior JR, Roberts DC, Jones SR. Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology. 2011;214:415–26.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  51. 51.

    Brodnik ZD, Black EM, Clark MJ, Kornsey KN, Snyder NW, España RA. Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine. Neuropharmacology. 2017;125:295–307.

  52. 52.

    Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW. Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci. 2010;30:7984–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Oleson EB, Roberts DC. Cocaine self-administration in rats: threshold procedures. Methods Mol Biol. 2012;829:303–19.

  54. 54.

    Bentzley BS, Fender KM, Aston-Jones G. The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures. Psychopharmacology. 2013;226:113–25.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Hursh SR, Silberberg A. Economic demand and essential value. Psychol Rev. 2008;115:186–98.

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Oleson EB, Richardson JM, Roberts DC. A novel IV cocaine self-administration procedure in rats: differential effects of dopamine, serotonin, and GABA drug pre-treatments on cocaine consumption and maximal price paid. Psychopharmacology. 2011;214:567–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Richardson NR, Roberts DC. Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods. 1996;66:1–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Levy KA, Brodnik ZD, Shaw JK, Perrey DA, Zhang Y, España RA. Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling. Psychopharmacology. 2017;234:2761–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Brodnik ZD, Ferris MJ, Jones SR, España RA. Reinforcing doses of intravenous cocaine produce only modest dopamine uptake inhibition. ACS Chem Neurosci. 2017;8:281–89.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Calipari ES, Siciliano CA, Zimmer BA, Jones SR. Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking. Neuropsychopharmacology. 2015;40:728–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Jones SR, Garris PA, Wightman RM. Different effects of cocaine and nomifensine on dopamine uptake in the caudate-putamen and nucleus accumbens. J Pharm Exp Ther. 1995;274:396–403.

    CAS  Google Scholar 

  62. 62.

    Verheij MM, Cools AR. Reserpine differentially affects cocaine-induced behavior in low and high responders to novelty. Pharm Biochem Behav. 2011;98:43–53.

    CAS  Article  Google Scholar 

  63. 63.

    Verheij MM, Cools AR. Differential contribution of storage pools to the extracellular amount of accumbal dopamine in high and low responders to novelty: effects of reserpine. J Neurochem. 2007;100:810–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Yamamoto DJ, Nelson AM, Mandt BH, Larson GA, Rorabaugh JM, Ng CM, et al. Rats classified as low or high cocaine locomotor responders: a unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors. Neurosci Biobehav Rev. 2013;37:1738–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Roberts DC, Loh EA, Vickers G. Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment. Psychopharmacology. 1989;97:535–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, et al. Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology. 2005;182:245–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Rivest R, Falardeau P, Di Paolo T. Brain dopamine transporter: gender differences and effect of chronic haloperidol. Brain Res. 1995;692:269–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Lavalaye J, Booij J, Reneman L, Habraken JB, van Royen EA. Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers. Eur J Nucl Med. 2000;27:867–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Belin D, Balado E, Piazza PV, Deroche-Gamonet V. Pattern of intake and drug craving predict the development of cocaine addiction-like behavior in rats. Biol Psychiatry. 2009;65:863–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Skjoldager P, Winger G, Woods JH. Analysis of fixed-ratio behavior maintained by drug reinforcers. J Exp Anal Behav. 1991;56:331–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Glick SD, Raucci J, Wang S, Keller RW Jr., Carlson JN. Neurochemical predisposition to self-administer cocaine in rats: individual differences in dopamine and its metabolites. Brain Res. 1994;653:148–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Brodnik ZD, Bernstein DL, Prince CD, España RA. Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep. Behav Brain Res. 2015;291:377–84.

  73. 73.

    Bernstein DL, Badve PS, Barson JR, Bass CE, España RA. Hypocretin receptor 1 knockdown in the ventral tegmental area attenuates mesolimbic dopamine signaling and reduces motivation for cocaine. Addict Biol. 2018;23:1032–45.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Ambroggi F, Ghazizadeh A, Nicola SM, Fields HL. Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition. J Neurosci. 2011;31:6820–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Willuhn I, Burgeno LM, Everitt BJ, Phillips PE. Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use. Proc Natl Acad Sci USA. 2012;109:20703–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Zhu J, Bardo MT, Bruntz RC, Stairs DJ, Dwoskin LP. Individual differences in response to novelty predict prefrontal cortex dopamine transporter function and cell surface expression. Eur J Neurosci. 2007;26:717–28.

    PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, Simon H. Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci USA. 1991;88:2088–92.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Coover GD, Goldman L, Levine S. Plasma corticosterone increases produced by extinction of operant behavior in rats. Physiol Behav. 1971;6:261–3.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Cason AM, Kohtz A, Aston-Jones G. Role of corticotropin releasing factor 1 signaling in cocaine seeking during early extinction in female and male rats. PLoS One. 2016;11:e0158577.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Moldow RL, Fischman AJ. Cocaine induced secretion of ACTH, beta-endorphin, and corticosterone. Peptides. 1987;8:819–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    Salahpour A, Ramsey AJ, Medvedev IO, Kile B, Sotnikova TD, Holmstrand E, et al. Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter. Proc Natl Acad Sci USA. 2008;105:4405–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Hadar R, Edemann-Callesen H, Reinel C, Wieske F, Voget M, Popova E, et al. Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders. Sci Rep. 2016;6:39145.

  83. 83.

    Cagniard B, Sotnikova TD, Gainetdinov RR, Zhuang X. The dopamine transporter expression level differentially affects responses to cocaine and amphetamine. J Neurogenet. 2014;28:112–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Zhu J, Green T, Bardo MT, Dwoskin LP. Environmental enrichment enhances sensitization to GBR 12935-induced activity and decreases dopamine transporter function in the medial prefrontal cortex. Behav Brain Res. 2004;148:107–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Darna M, Beckmann JS, Gipson CD, Bardo MT, Dwoskin LP. Effect of environmental enrichment on dopamine and serotonin transporters and glutamate neurotransmission in medial prefrontal and orbitofrontal cortex. Brain Res. 2015;1599:115–25.

  86. 86.

    Neugebauer NM, Cunningham ST, Zhu J, Bryant RI, Middleton LS, Dwoskin LP. Effects of environmental enrichment on behavior and dopamine transporter function in medial prefrontal cortex in adult rats prenatally treated with cocaine. Brain Res Dev Brain Res. 2004;153:213–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Wagner AK, Chen X, Kline AE, Li Y, Zafonte RD, Dixon CE. Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury. Exp Neurol. 2005;195:475–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Stairs DJ, Bardo MT. Neurobehavioral effects of environmental enrichment and drug abuse vulnerability. Pharm Biochem Behav. 2009;92:377–82.

    CAS  Article  Google Scholar 

  89. 89.

    Ranaldi R, Kest K, Zellner M, Hachimine-Semprebom P. Environmental enrichment, administered after establishment of cocaine self-administration, reduces lever pressing in extinction and during a cocaine context renewal test. Behav Pharm. 2011;22:347–53.

    CAS  Article  Google Scholar 

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Acknowledgements

We would like to thank Kristen Kornsey and Douglas Fox for their expert technical assistance, and the Drug Supply Program at NIDA for providing cocaine HCl. We would also like to thank Dr. Erik Oleson from the University of Colorado for providing the R-script used in behavioral economics analysis.

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JKS and RAE conceptualized the experiments. JKS, IPA, and SIL were responsible for conducting the experiments. OVM and SA designed and selected the viral construct and MOS and MDB packaged it. BMO was responsible for histology and confirming placement of viral infusions. JKS was primarily responsible for data analysis. Writing and editing were primarily conducted by JKS and RAE. All authors approved the final version of the manuscript.

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Correspondence to Rodrigo A. España.

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Shaw, J.K., Pamela Alonso, I., Lewandowski, S.I. et al. Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01009-2

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