Accelerated development of cocaine-associated dopamine transients and cocaine use vulnerability following traumatic stress


Post-traumatic stress disorder and cocaine use disorder are highly co-morbid psychiatric conditions. The onset of post-traumatic stress disorder generally occurs prior to the development of cocaine use disorder, and thus it appears that the development of post-traumatic stress disorder drives cocaine use vulnerability. We recently characterized a rat model of post-traumatic stress disorder with segregation of rats as susceptible and resilient based on anxiety-like behavior in the elevated plus maze and context avoidance. We paired this model with in vivo fast scan cyclic voltammetry in freely moving rats to test for differences in dopamine signaling in the nucleus accumbens core at baseline, in response to a single dose of cocaine, and in response to cocaine-paired cues. Further, we examined differences in the acquisition of cocaine self-administration across groups. Results indicate that susceptibility to traumatic stress is associated with alterations in phasic dopamine signaling architecture that increase the rate at which dopamine signals entrain to cocaine-associated cues and increase the magnitude of persistent cue-evoked dopamine signals following training. These changes in phasic dopamine signaling correspond with increases in the rate at which susceptible rats develop excessive cocaine-taking behavior. Together, our studies demonstrate that susceptibility to traumatic stress is associated with a cocaine use-vulnerable phenotype and suggests that differences in phasic dopamine signaling architecture may contribute to the process by which this vulnerability occurs.

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  1. 1.

    Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048–60.

  2. 2.

    Back S, Dansky BS, Coffey SF, Saladin ME, Sonne S, Brady KT. Cocaine dependence with and without post-traumatic stress disorder: a comparison of substance use, trauma history and psychiatric comorbidity. Am J Addict. 2000;9:51–62.

  3. 3.

    Khoury L, Tang YL, Bradley B, Cubells JF, Ressler KJ. Substance use, childhood traumatic experience, and Posttraumatic Stress Disorder in an urban civilian population. Depress anxiety. 2010;27:1077–86.

  4. 4.

    Chilcoat HD, Breslau N. Posttraumatic stress disorder and drug disorders: testing causal pathways. Arch Gen Psychiatry. 1998;55:913–7.

  5. 5.

    Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26:6583–8.

  6. 6.

    Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW. Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems. Ann N Y Acad Sci. 1999;877:412–38.

  7. 7.

    Volkow ND, Morales M. The brain on drugs: from reward to addiction. Cell. 2015;162:712–25.

  8. 8.

    Saladin ME, Drobes DJ, Coffey SF, Dansky BS, Brady KT, Kilpatrick DG. PTSD symptom severity as a predictor of cue-elicited drug craving in victims of violent crime. Addict Behav. 2003;28:1611–29.

  9. 9.

    Regier PS, Monge ZA, Franklin TR, Wetherill RR, Teitelman A, Jagannathan K, et al. Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues. Addict Biol. 2017;22:1768–77.

  10. 10.

    LeBlanc KH, Ostlund SB, Maidment NT. Pavlovian-to-instrumental transfer in cocaine seeking rats. Behav Neurosci. 2012;126:681–9.

  11. 11.

    Ostlund SB, LeBlanc KH, Kosheleff AR, Wassum KM, Maidment NT. Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. Neuropsychopharmacology. 2014;39:2441–9.

  12. 12.

    Everitt BJ, Robbins TW. From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. Neurosci Biobehav Rev. 2013;37:1946–54.

  13. 13.

    Ito R, Robbins TW, Everitt BJ. Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci. 2004;7:389–97.

  14. 14.

    Fuchs RA, Evans KA, Parker MC, See RE. Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2004;176:459–65.

  15. 15.

    Di Ciano P, Robbins TW, Everitt BJ. Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer. Neuropsychopharmacology. 2008;33:1413–25.

  16. 16.

    Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM. Subsecond dopamine release promotes cocaine seeking. Nature. 2003;422:614–8.

  17. 17.

    Stuber GD, Wightman RM, Carelli RM. Extinction of cocaine self-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens. Neuron. 2005;46:661–9.

  18. 18.

    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.

  19. 19.

    Arena DT, Covington HE III, DeBold JF, Miczek KA. Persistent increase of I.V. cocaine self-administration in a subgroup of C57BL/6J male mice after social defeat stress. Psychopharmacology. 2019;236:2027–37.

  20. 20.

    Schwendt M, Shallcross J, Hadad NA, Namba MD, Hiller H, Wu L, et al. A novel rat model of comorbid PTSD and addiction reveals intersections between stress susceptibility and enhanced cocaine seeking with a role for mGlu5 receptors. Transl Psychiatry. 2018;8:209.

  21. 21.

    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.

  22. 22.

    Clark JJ, Sandberg SG, Wanat MJ, Gan JO, Horne EA, Hart AS, et al. Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals. Nat Methods. 2010;7:126–9.

  23. 23.

    Cohen H, Kozlovsky N, Alona C, Matar MA, Joseph Z. Animal model for PTSD: from clinical concept to translational research. Neuropharmacology. 2012;62:715–24.

  24. 24.

    Cohen H, Zohar J, Matar MA, Zeev K, Loewenthal U, Richter-Levin G. Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder. Neuropsychopharmacology. 2004;29:1962–70.

  25. 25.

    File SE, Lippa AS, Beer B, Lippa MT. Animal tests of anxiety. Curr Protoc Neurosci. 2004. Chapter 8: p. Unit 8.3.

  26. 26.

    Fendt M, Endres T. 2,3,5-Trimethyl-3-thiazoline (TMT), a component of fox odor—just repugnant or really fear-inducing? Neurosci Biobehav Rev. 2008;32:1259–66.

  27. 27.

    Feyissa DD, Aher YD, Engidawork E, Hoger H, Lubec G, Korz V. Individual differences in male rats in a behavioral test battery: a multivariate statistical approach. Front Behav Neurosci. 2017;11:26.

  28. 28.

    Curé M, Rolinat JP. Behavioral heterogeneity in Sprague-Dawley rats. Physiol Behav. 1992;51:771–4.

  29. 29.

    Aragona BJ, Day JJ, Roitman MF, Cleaveland NA, Wightman RM, Carelli RM. Regional specificity in the real-time development of phasic dopamine transmission patterns during acquisition of a cue-cocaine association in rats. Eur J Neurosci. 2009;30:1889–99.

  30. 30.

    Yorgason JT, España RA, Jones SR. Demon voltammetry and analysis software: analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures. J Neurosci Methods. 2011;202:158–64.

  31. 31.

    Robinson DL, Wightman RM. Nomifensine amplifies subsecond dopamine signals in the ventral striatum of freely-moving rats. J Neurochem. 2004;90:894–903.

  32. 32.

    Roberts JG, Toups JV, Eyualem E, McCarty GS, Sombers LA. In situ electrode calibration strategy for voltammetric measurements in vivo. Anal Chem. 2013;85:11568–75.

  33. 33.

    Howard CD, Daberkow DP, Ramsson ES, Keefe KA, Garris PA. Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling. Eur J Neurosci. 2013;38:2078–88.

  34. 34.

    Aragona BJ, Cleaveland NA, Stuber GD, Day JJ, Carelli RM, Wightman RM. Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events. J Neurosci. 2008;28:8821–31.

  35. 35.

    Stuber GD, Roitman MF, Phillips PEM, Carelli RM, Wightman RM. Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration. Neuropsychopharmacology. 2004;30:853–63.

  36. 36.

    Covey DP, Roitman MF, Garris PA. Illicit dopamine transients: reconciling actions of abused drugs. Trends Neurosci. 2014;37:200–10.

  37. 37.

    Willuhn I, Burgeno LM, Groblewski PA, Phillips PE. Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat Neurosci. 2014;17:704–9.

  38. 38.

    Shimamoto A, Holly EN, Boyson CO, DeBold JF, Miczek KA. Individual differences in anhedonic and accumbal dopamine responses to chronic social stress and their link to cocaine self-administration in female rats. Psychopharmacology. 2015;232:825–34.

  39. 39.

    Dreyer JK, Hounsgaard J. Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling. J Neurophysiol. 2013;109:171–82.

  40. 40.

    Federici M, Latagliata EC, Ledonne A, Rizzo FR, Feligioni M, Sulzer D, et al. Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate. J Biol Chem. 2014;289:264–74.

  41. 41.

    Saunders BT, Yager LM, Robinson TE. Cue-evoked cocaine “craving”: role of dopamine in the accumbens core. J Neurosci. 2013;33:13989–4000.

  42. 42.

    Sombers LA, Beyene M, Carelli RM, Wightman RM. Synaptic overflow of dopamine in the nucleus accumbens arises from neuronal activity in the ventral tegmental area. J Neurosci. 2009;29:1735–42.

  43. 43.

    Owesson-White CA, Roitman MF, Sombers LA, Belle AM, Keithley RB, Peele JL, et al. Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens. J Neurochem. 2012;121:252–62.

  44. 44.

    Goeders NE. The HPA axis and cocaine reinforcement. Psychoneuroendocrinology. 2002;27:13–33.

  45. 45.

    Mantsch J, Ho A, Schlussman S, Kreek M. Predictable individual differences in the initiation of cocaine self-administration by rats under extended-access conditions are dose-dependent. Psychopharmacology. 2001;157:31–9.

  46. 46.

    Vsevolozhskaya OA, Anthony JC. Transitioning from first drug use to dependence onset: Illustration of a multiparametric approach for comparative epidemiology. Neuropsychopharmacology. 2016;41:869–76.

  47. 47.

    Vsevolozhskaya OA, Anthony JC. Estimated probability of becoming a case of drug dependence in relation to duration of drug-taking experience: a functional analysis approach. Int J Methods Psychiatr Res. 2016;26:e1513.

  48. 48.

    Siegel RK. Changing patterns of cocaine use: longitudinal observations, consequences, and treatment. NIDA Res Monogr. 1984;50:92–110.

  49. 49.

    Canavier CC, Landry RS. An increase in AMPA and a decrease in SK conductance increase burst firing by different mechanisms in a model of a dopamine neuron in vivo. J Neurophysiol. 2006;96:2549–63.

  50. 50.

    Chergui K, Charlety PJ, Akaoka H, Saunier CF, Brunet JL, Buda M, et al. Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Eur J Neurosci. 1993;5:137–44.

  51. 51.

    Johnson SW, Seutin V, North RA. Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. Science. 1992;258:665–7.

  52. 52.

    Kuznetsov AS, Kopell NJ, Wilson CJ. Transient high-frequency firing in a coupled-oscillator model of the mesencephalic dopaminergic neuron. J Neurophysiol. 2006;95:932–47.

  53. 53.

    Stuber GD, Klanker M, de Ridder B, Bowers MS, Joosten RN, Feenstra MG, et al. Reward-predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons. Science. 2008;321:1690–2.

  54. 54.

    Zweifel LS, Fadok JP, Argilli E, Garelick MG, Jones GL, Dickerson TM, et al. Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci. 2011;14:620–6.

  55. 55.

    Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 2000;25:515–32.

  56. 56.

    Dong Y, Nestler EJ. The neural rejuvenation hypothesis of cocaine addiction. Trends Pharm Sci. 2014;35:374–83.

  57. 57.

    Stuber GD, Hopf FW, Tye KM, Chen BT, Bonci A. Neuroplastic alterations in the limbic system following cocaine or alcohol exposure. Curr Top Behav Neurosci. 2010;3:3–27.

  58. 58.

    Chen BT, Bowers MS, Martin M, Hopf FW, Guillory AM, Carelli RM, et al. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron. 2008;59:288–97.

  59. 59.

    Ungless MA, Whistler JL, Malenka RC, Bonci A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature. 2001;411:583–7.

  60. 60.

    Wanat MJ, Bonci A. Dose-dependent changes in the synaptic strength on dopamine neurons and locomotor activity after cocaine exposure. Synapse. 2008;62:790–5.

  61. 61.

    Roberts DC, Koob GF, Klonoff P, Fibiger HC. Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav. 1980;12:781–7.

  62. 62.

    Roberts AJ, Koob GF. The neurobiology of addiction: an overview. Alcohol Health Res World. 1997;21:101–6.

  63. 63.

    Ahmed SH, Koob GF. Transition from moderate to excessive drug intake: change in hedonic set point. Science. 1998;282:298–300.

  64. 64.

    Bentzley BS, Jhou TC, Aston-Jones G. Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat. Proc Natl Acad Sci USA. 2014;111:11822–7.

  65. 65.

    Miczek KA, Nikulina EM, Shimamoto A, Covington HE III. Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats. J Neurosci. 2011;31:9848–57.

  66. 66.

    Tidey JW, Miczek KA. Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology. 1997;130:203–12.

  67. 67.

    Garcia-Keller C, Martinez SA, Esparza MA, Bollati F, Kalivas PW, Cancela LM. Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens. Eur J Neurosci. 2013;37:982–95.

  68. 68.

    Sorg BA, Kalivas PW. Effects of cocaine and footshock stress on extracellular dopamine levels in the medial prefrontal cortex. Neuroscience. 1993;53:695–703.

  69. 69.

    Saal D, Dong Y, Bonci A, Malenka RC. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003;37:577–82.

  70. 70.

    Cao JL, Covington HE III, Friedman AK, Wilkinson MB, Walsh JJ, Cooper DC, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci. 2010;30:16453–8.

  71. 71.

    Friedman A. Neuroscience. Jump-starting natural resilience reverses stress susceptibility. Science. 2014;346:555.

  72. 72.

    Chandra R, Francis TC, Nam H, Riggs LM, Engeln M, Rudzinskas S, et al. Reduced Slc6a15 in nucleus accumbens D2-neurons underlies stress susceptibility. J Neurosci. 2017;37:6527–38.

  73. 73.

    Whitaker AM, Farooq MA, Edwards S, Gilpin NW. Post-traumatic stress avoidance is attenuated by corticosterone and associated with brain levels of steroid receptor co-activator-1 in rats. Stress. 2016;19:69–77.

  74. 74.

    Whitaker AM, Gilpin NW. Blunted hypothalamo-pituitary adrenal axis response to predator odor predicts high stress reactivity. Physiol Behav. 2015;147:16–22.

  75. 75.

    Danan D, Matar MA, Kaplan Z, Zohar J, Cohen H. Blunted basal corticosterone pulsatility predicts post-exposure susceptibility to PTSD phenotype in rats. Psychoneuroendocrinology. 2018;87:35–42.

  76. 76.

    Nam H, Chandra R, Francis TC, Dias C, Cheer JF, Lobo MK. Reduced nucleus accumbens enkephalins underlie vulnerability to social defeat stress. Neuropsychopharmacology. 2019;44:1876–85.

  77. 77.

    Wook Koo J, Labonte B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biol Psychiatry. 2016;80:469–78.

  78. 78.

    Muir J, Lorsch ZS, Ramakrishnan C, Deisseroth K, Nestler EJ, Calipari ES, et al. In vivo fiber photometry reveals signature of future stress susceptibility in nucleus accumbens. Neuropsychopharmacology. 2018;43:255–63.

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Correspondence to Rodrigo A. España.

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Brodnik, Z.D., Black, E.M. & España, R.A. Accelerated development of cocaine-associated dopamine transients and cocaine use vulnerability following traumatic stress. Neuropsychopharmacol. 45, 472–481 (2020).

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