, Volume 197, Issue 2, pp 203–216 | Cite as

NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking

  • Herbert E. CovingtonIII
  • Thomas F. Tropea
  • Anjali M. Rajadhyaksha
  • Barry E. Kosofsky
  • Klaus A. MiczekEmail author
Original Investigation



Cocaine strengthens behaviors associated with its administration. The stress response by individuals that are defeated in a brief aggressive confrontation can also promote enduring behavioral consequences similar to those of stimulants.


The study intends to find whether intermittent episodes of defeat promote cocaine’s reinforcing effects by triggering N-methyl-d-aspartic acid (NMDA)-receptor-mediated plasticity in the ventral tegmental area (VTA).

Materials and methods

Long–Evans rats were investigated after four social defeats in three experiments. Two experiments examined systemic or intra-VTA antagonism of NMDA receptors during stress on the later expression of behavioral sensitization and cocaine self-administration during fixed and progressive ratio (PR) schedules of reinforcement (0.3 mg/kg/infusion), including a novel 24-h variable-dose continuous access binge (0.2, 0.4, and 0.8 mg/kg/infusion, delivered in an irregular sequence). Third, the expression of receptor proteins NR1 (NMDA) and GluR1 [alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)] were examined in VTA and nucleus accumbens.


Intermittent defeats augment locomotor responses to cocaine and increase cocaine taking. Rates of responding during binges are increased after defeat stress. These effects are prevented when NMDA or AMPA receptor antagonists are administered before defeats. VTA infusions of the NMDA antagonist AP-5 (5 nmol/side) before stress prevents locomotor sensitization to cocaine and intensified responding for cocaine during a PR schedule or binge. Episodic defeats increase GluR1 AMPA subunit protein expression in the VTA.


Social stress stimulates NMDA receptors in the VTA, and this neural action of defeat may be essential for prompting a later increase in cocaine intake during binges.


Cocaine Self-administration Ventral tegmental area Glutamate NMDA–AMPA Progressive ratio schedule Binge 



This research was supported by USPHS research grants DA02632 (KAM), KO1DA14057 (AMR), and KO2DA00354 (BEK).


  1. Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ (1989) Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J Neurochem 52:1655–1658PubMedCrossRefGoogle Scholar
  2. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300PubMedCrossRefGoogle Scholar
  3. Ahmed SH, Koob GF (1999) Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146:303–312PubMedCrossRefGoogle Scholar
  4. Broadbent J, Weitemier AZ (1999) Dizocilpine (MK-801) prevents the development of sensitization to ethanol in DBA/2J mice. Alcohol Alcohol 34:283–288PubMedGoogle Scholar
  5. Covington HE III, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology 158:388–398PubMedCrossRefGoogle Scholar
  6. Covington HE III, Miczek KA (2005) Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation. Psychopharmacology 183:331–340PubMedCrossRefGoogle Scholar
  7. Covington HE III, Kikusui T, Goodhue J, Nikulina EM, Hammer RP Jr, Miczek KA (2005) Brief social defeat stress: long lasting effects on cocaine taking during a binge and zif268 mRNA expression in the amygdala and prefrontal cortex. Neuropsychopharmacology 30:310–321PubMedCrossRefGoogle Scholar
  8. Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320PubMedGoogle Scholar
  9. Fitzgerald LW, Ortiz J, Hamedani AG, Nestler EJ (1996) Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: Common adaptions among cross-sensitizing agents. J Neurosci 16:274–282PubMedGoogle Scholar
  10. Fowler SC, Covington HE III, Miczek KA (2007) Stereotyped and complex motor routines expressed during cocaine self-administration: results from a 24-h binge of unlimited cocaine access in rats. Psychopharmacology 192:465–478PubMedCrossRefGoogle Scholar
  11. Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730–5743PubMedCrossRefGoogle Scholar
  12. Gerber GJ, Wise RA (1989) Pharmacological regulation of intravenous cocaine and heroin self-administration in rats: a variable dose paradigm. Pharmacol Biochem Behav 32:527–531PubMedCrossRefGoogle Scholar
  13. Goeders NE (2002) The HPA axis and cocaine reinforcement. Psychoneuroendocrinology 27:13–33PubMedCrossRefGoogle Scholar
  14. Hernandez L, Hoebel BG (1988) Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis. Life Sci 42:1705–1712PubMedCrossRefGoogle Scholar
  15. Hurd YL, Kehr J, Ungerstedt U (1988) In vivo microdialysis as a technique to monitor drug transport: correlation of extracellular cocaine levels and dopamine overflow in the rat brain. J Neurochem 51:1314–1316PubMedCrossRefGoogle Scholar
  16. Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598PubMedCrossRefGoogle Scholar
  17. Kalivas PW (2005) How do we determine which drug-induced neuroplastic changes are important. Nat Neurosci 8:1440–1441PubMedCrossRefGoogle Scholar
  18. Kalivas PW, Alesdatter JE (1993) Involvement of N-methyl-d-aspartate receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine. J Pharmacol Exp Ther 267:486–495PubMedGoogle Scholar
  19. Kalivas PW, Duffy P (1995) Selective activation of dopamine transmission in the shell of the nucleus accumbens by stress. Brain Res 675:325–328PubMedCrossRefGoogle Scholar
  20. Kalivas PW, Sorg BA, Hooks MS (1993) The pharmacology and neural circuitry of sensitization to psychostimulants. Behav Pharmacol 4:315–334PubMedCrossRefGoogle Scholar
  21. Karler R, Calder LD, Chaudhry IA, Turkanis SA (1989) Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Life Sci 45:599–606PubMedCrossRefGoogle Scholar
  22. Kreek MJ, Koob GF (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23–47PubMedCrossRefGoogle Scholar
  23. Li Y, Hu XT, Berney TG, Vartanian AJ, Stine CD, Wolf ME et al (1999) Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations. Synapse 34:169–180PubMedCrossRefGoogle Scholar
  24. Marinelli M, Piazza PV (2002) Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci 16:387–394PubMedCrossRefGoogle Scholar
  25. Marinelli M, Le Moal M, Piazza PV (1996) Acute pharmacological blockade of corticosterone secretion reverses food restriction-induced sensitization of the locomotor response to cocaine. Brain Res 724:251–255PubMedCrossRefGoogle Scholar
  26. Markou A, Hauger RL, Koob GF (1992) Desmethylimipramine attenuates cocaine withdrawal in rats. Psychopharmacology 109:305–314PubMedCrossRefGoogle Scholar
  27. McEwen BS (2004) Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 1032:1–7PubMedCrossRefGoogle Scholar
  28. Mendrek A, Blaha CD, Phillips AG (1998) Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule. Psychopharmacology 135:416–422PubMedCrossRefGoogle Scholar
  29. Miczek KA (1979) A new test for aggression in rats without aversive stimulation: Differential effects of d-amphetamine and cocaine. Psychopharmacology 60:253–259PubMedCrossRefGoogle Scholar
  30. Miczek KA, Mutschler NH (1996) Activational effects of social stress on IV cocaine self-administration in rats. Psychopharmacology 128:256–264PubMedCrossRefGoogle Scholar
  31. Miczek KA, Covington HE, Nikulina EA, Hammer RP (2004) Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci Biobehav Rev 27:787–802PubMedCrossRefGoogle Scholar
  32. Mutschler NH, Miczek KA (1998) Withdrawal from a self-administered or non-contingent cocaine binge: differences in ultrasonic distress vocalizations in rats. Psychopharmacology 136:402–408PubMedCrossRefGoogle Scholar
  33. Mutschler NH, Miczek KA, Hammer RP Jr (2000) Reduction of zif268 messenger RNA expression during prolonged withdrawal following “binge” cocaine self-administration in rats. Neuroscience 100:531–538PubMedCrossRefGoogle Scholar
  34. Mutschler NH, Covington HE III, Miczek KA (2001) Repeated self-administered cocaine “binges” in rats: effects on cocaine intake and withdrawal. Psychopharmacology 154:292–300PubMedCrossRefGoogle Scholar
  35. Myin-Germeys I, Delespaul P, van Os J (2005) Behavioural sensitization to daily life stress in psychosis. Psychol Med 35:733–741PubMedCrossRefGoogle Scholar
  36. National Research Council (1996) Guide for the care and use of laboratory animals. National Academy, Washington, DCGoogle Scholar
  37. Nestler EJ (2004) Molecular mechanisms of drug addiction. Neuropharmacology 47(Suppl 1):24–32PubMedCrossRefGoogle Scholar
  38. Nikulina EM, Marchand JE, Kream RM, Miczek KA (1998) Behavioral sensitization to cocaine after a brief social stress is accompanied by changes in fos expression in the murine brainstem. Brain Res 810:200–210PubMedCrossRefGoogle Scholar
  39. Nikulina EM, Covington HE III, Ganschow L, Hammer RP Jr, Miczek KA (2004) Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala. Neuroscience 123:857–865PubMedCrossRefGoogle Scholar
  40. Nikulina EM, Miczek KA, Hammer RP Jr (2005) Prolonged effects of repeated social defeat stress on mRNA expression and function of mu-opioid receptors in the ventral tegmental area of rats. Neuropsychopharmacology 30:1096–1103PubMedCrossRefGoogle Scholar
  41. O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion. J Psychopharmacol 12:15–22PubMedCrossRefGoogle Scholar
  42. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
  43. Piazza PV, Deminiere JM, le Moal M, Simon H (1990) Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 514:22–26PubMedCrossRefGoogle Scholar
  44. Pierre PJ, Vezina P (1998) D1 dopamine receptor blockade prevents the facilitation of amphetamine self-administration induced by prior exposure to the drug. Psychopharmacology 138:159–166PubMedCrossRefGoogle Scholar
  45. Prasad BM, Ulibarri C, Sorg BA (1998) Stress-induced cross-sensitization to cocaine: effect of adrenalectomy and corticosterone after short- and long-term withdrawal. Psychopharmacology 136:24–33PubMedCrossRefGoogle Scholar
  46. Rajadhyaksha A, Husson I, Satpute SS, Kuppenbender KD, Ren JQ, Guerriero RM et al (2004) L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment. J Neurosci 24:7464–7476PubMedCrossRefGoogle Scholar
  47. Remie R, Coppes RP, Meurs H, Roffel AF, Zaagsma J (1990) Characterization of presynaptic vascular muscarinic receptors inhibiting endogenous noradrenaline overflow in the portal vein of the freely moving rat. Br J Pharmacol 99:223–226PubMedGoogle Scholar
  48. Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11PubMedCrossRefGoogle Scholar
  49. Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582PubMedCrossRefGoogle Scholar
  50. Sapolsky RM (2005) The influence of social hierarchy on primate health. Science 308:648–652PubMedCrossRefGoogle Scholar
  51. Schenk S, Partridge B (2000) Sensitization to cocaine’s reinforcing effects produced by various cocaine pretreatment regimens in rats. Pharmacol Biochem Behav 66:765–770PubMedCrossRefGoogle Scholar
  52. Shim I, Kim HT, Kim YH, Chun BG, Hahm DH, Lee EH et al (2002) Role of nitric oxide synthase inhibitors and NMDA receptor antagonist in nicotine-induced behavioral sensitization in the rat. Eur J Pharmacol 443:119–124PubMedCrossRefGoogle Scholar
  53. Sinha R (2001) How does stress increase risk of drug abuse and relapse. Psychopharmacology 158:343–359PubMedCrossRefGoogle Scholar
  54. Suto N, Tanabe LM, Austin JD, Creekmore E, Vezina P (2003) Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner. Neuropsychopharmacology 4:629–639CrossRefGoogle Scholar
  55. Takahata R, Moghaddam B (1998) Glutamatergic regulation of basal and stimulus-activated dopamine release in the prefrontal cortex. J Neurochem 71:1443–1449PubMedCrossRefGoogle Scholar
  56. Tidey JW, Miczek KA (1996) Social defeat stress selectively alters mesocorticolimbic dopamine release: An in vivo microdialysis study. Brain Res 721:140–149PubMedCrossRefGoogle Scholar
  57. Tidey JW, Miczek KA (1997) Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology 130:203–212PubMedCrossRefGoogle Scholar
  58. Tornatzky W, Miczek KA (1993) Long-term impairment of autonomic circadian rhythms after brief intermittent social stress. Physiol Behav 53:983–993PubMedCrossRefGoogle Scholar
  59. Tornatzky W, Miczek KA (2000) Cocaine self-administration “binges” transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology 148:289–298PubMedCrossRefGoogle Scholar
  60. Vanderschuren LJMJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120PubMedCrossRefGoogle Scholar
  61. Vezina P, Queen AL (2000) Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area. Psychopharmacology 151:184–191PubMedCrossRefGoogle Scholar
  62. Vezina P, Pierre PJ, Lorrain DS (1999) The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug. Psychopharmacology 147:125–134PubMedCrossRefGoogle Scholar
  63. Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB (2005) Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci 25:5389–5396PubMedCrossRefGoogle Scholar
  64. Weiss F, Markou A, Lorang MT, Koob GF (1992) Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration. Brain Res 593:314–318PubMedCrossRefGoogle Scholar
  65. Westerink BH, Enrico P, Feimann J, de Vries JB (1998) The pharmacology of mesocortical dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and prefrontal cortex of the rat brain. J Pharmacol Exp Ther 285:143–154PubMedGoogle Scholar
  66. Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720PubMedCrossRefGoogle Scholar
  67. Wolf ME, Jeziorski M (1993) Coadministration of MK-801 with amphetamine, cocaine or morphine prevents rather than transiently masks the development of behavioral sensitization. Brain Res 613:291–294PubMedCrossRefGoogle Scholar
  68. Wolf ME, White FJ, Hu XT (1994) MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine. Neuroscience 14:1735–1745PubMedGoogle Scholar
  69. Yap JJ, Miczek KA (2007) Social defeat stress, sensitization, and intravenous cocaine self-administration in mice. Psychopharmacology 192:261–273PubMedCrossRefGoogle Scholar
  70. Yap JJ, Covington HE III, Gale MC, Datta R, Miczek KA (2005) Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors. Psychopharmacology 179:230–239PubMedCrossRefGoogle Scholar
  71. Yui K, Ishiguro T, Goto K, Ikemoto S, Kamata Y (1999) Spontaneous recurrence of methampetamine psychosis: increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic change. Eur Arch Psychiatry Clin Neurosci 249:103–111PubMedCrossRefGoogle Scholar
  72. Zernig G, Wakonigg G, Madlung E, Haring C, Saria A (2004) Do vertical shifts in dose-response rate-relationships in operant conditioning procedures indicate “sensitization” to “drug wanting”. Psychopharmacology 171:349–351PubMedCrossRefGoogle Scholar
  73. Zhang XF, Hu XT, White FJ, Wolf ME (1997) Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors. J Pharmacol Exp Ther 281:699–706PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Herbert E. CovingtonIII
    • 1
    • 7
  • Thomas F. Tropea
    • 1
    • 5
  • Anjali M. Rajadhyaksha
    • 5
    • 6
  • Barry E. Kosofsky
    • 5
    • 6
  • Klaus A. Miczek
    • 1
    • 2
    • 3
    • 4
    • 8
    Email author
  1. 1.Department of PsychologyTufts UniversityMedford and BostonUSA
  2. 2.Department of PsychiatryTufts UniversityMedford and BostonUSA
  3. 3.Department of PharmacologyTufts UniversityMedford and BostonUSA
  4. 4.Department of NeuroscienceTufts UniversityMedford and BostonUSA
  5. 5.Division of Pediatric Neurology, Department of PediatricsWeill Medical College of Cornell UniversityNew YorkUSA
  6. 6.Department of Neurology and NeuroscienceWeill Medical College of Cornell UniversityNew YorkUSA
  7. 7.Department of Psychiatry and Center for Basic NeuroscienceUniversity of Texas Southwestern Medical CenterDallasUSA
  8. 8.Tufts UniversityMedfordUSA

Personalised recommendations