, 218:293 | Cite as

Environmental-induced differences in corticosterone and glucocorticoid receptor blockade of amphetamine self-administration in rats

  • Dustin J. Stairs
  • Mark A. Prendergast
  • Michael T. Bardo
Original Investigation



Rats raised in isolation self-administer more amphetamine than rats raised in enrichment.


This study examined whether differential rearing alters basal and amphetamine-stimulated corticosterone and whether blocking glucocorticoid receptors alters amphetamine self-administration in differentially reared rats.


The rats were raised from 21 to 51 days of age in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Following the repeated collection of basal blood samples, the rats were administered amphetamine (0.5 or 2.0 mg/kg, i.p.) or saline, and blood samples were collected again. In another experiment, EC and IC rats were trained to i.v. self-administer amphetamine (0.003 or 0.03 mg/kg/infusion) and then were pretreated with the glucocorticoid receptor antagonist RU-486 (5, 10, or 20 mg/kg; i.p.) or vehicle prior to the session.


Basal-free corticosterone levels were ~4 times higher in IC rats than in either EC or SC rats with the first blood collection, but not with repeated collections. IC rats showed a more rapid amphetamine-induced increase in corticosterone levels than EC and SC rats. RU-486 pretreatment decreased amphetamine self-administration dose-dependently in both EC and IC rats; however, using an amphetamine unit dose of 0.03 mg/kg/infusion, the effect of RU-486 was blunted in IC rats (maximal decrease of ~40% in IC and ~90% in EC), suggesting an environment-induced difference in the role of glucocorticoid receptors in stimulant reinforcement.


The increase in stimulant self-administration produced by social isolation may involve enhanced reactivity of the hypothalamo–pituitary–adrenal stress axis.


Stress Environmental enrichment Social isolation Amphetamine Self-administration Rats 



This study is supported by NIH grants P50 DA 05312 and R01 DA 12964.


  1. Adams J, Bowman K, Burke B, Casson L, Caviness L, Coffey LE, Devore J, Durham J, Ellis C, Hewitt D, Hinsdale M, Johnson I, Myers S, Penne M, Zelon H (1999) National Household Survey on Drug Abuse Data Collection. Final ReportGoogle Scholar
  2. Ahima RS, Harlan RE (1990) Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system. Neuroscience 39:579–604PubMedCrossRefGoogle Scholar
  3. Anker JJ, Carroll ME (2010) Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacol (Berl) 208:211–222CrossRefGoogle Scholar
  4. Bardo MT, Bowling SL, Rowlett JK, Manderscheid P, Buxton ST, Dwoskin LP (1995) Environmental enrichment attenuates locomotor sensitization, but not in vitro dopamine release, induced by amphetamine. Pharmacol Biochem Behav 51:397–405PubMedCrossRefGoogle Scholar
  5. Bardo MT, Klebaur JE, Valone JM, Deaton C (2001) Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats. Psychopharmacol (Berl) 155:278–284CrossRefGoogle Scholar
  6. Belz EE, Kennell JS, Czambel RK, Rubin RT, Rhodes ME (2003) Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats. Pharmacol Biochem Behav 76:481–486PubMedCrossRefGoogle Scholar
  7. Bowling SL, Bardo MT (1994) Locomotor and rewarding effects of amphetamine in enriched, social, and isolate reared rats. Pharmacol Biochem Behav 48:459–464PubMedCrossRefGoogle Scholar
  8. Bowling SL, Rowlett JK, Bardo MT (1993) The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release. Neuropharmacology 32:885–893PubMedCrossRefGoogle Scholar
  9. Butte JC, Kakihana R, Noble EP (1976) Circadian rhythm of corticosterone levels in rat brain. J Endocrinol 68:235–239PubMedCrossRefGoogle Scholar
  10. Cador M, Dulluc J, Mormede P (1993) Modulation of the locomotor response to amphetamine by corticosterone. Neuroscience 56:981–988PubMedCrossRefGoogle Scholar
  11. Cheifetz P, Gaffud N, Dingman JF (1968) Effects of bilateral adrenalectomy and continuous light on the circadian rhythm of corticotropin in female rats. Endocrinology 82:1117–1124PubMedCrossRefGoogle Scholar
  12. Cho K, Little HJ (1999) Effects of corticosterone on excitatory amino acid responses in dopamine-sensitive neurons in the ventral tegmental area. Neuroscience 88:837–845PubMedCrossRefGoogle Scholar
  13. De Vries TJ, Schoffelmeer AN, Tjon GH, Nestby P, Mulder AH, Vanderschuren LJ (1996) Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine. Eur J Pharmacol 307:R3–R4PubMedCrossRefGoogle Scholar
  14. Deroche V, Piazza PV, Maccari S, Le Moal M, Simon H (1992) Repeated corticosterone administration sensitizes the locomotor response to amphetamine. Brain Res 584:309–313PubMedCrossRefGoogle Scholar
  15. Deroche V, Marinelli M, Le Moal M, Piazza PV (1997) Glucocorticoids and behavioral effects of psychostimulants. II: cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels. J Pharmacol Exp Ther 281:1401–1407PubMedGoogle Scholar
  16. Deroche-Gamonet V, Sillaber I, Aouizerate B, Izawa R, Jaber M, Ghozland S, Kellendonk C, Le Moal M, Spanagel R, Schutz G, Tronche F, Piazza PV (2003) The glucocorticoid receptor as a potential target to reduce cocaine abuse. J Neurosci 23:4785–4790PubMedGoogle Scholar
  17. Fitch TE, Roberts DC (1993) The effects of dose and access restrictions on the periodicity of cocaine self-administration in the rat. Drug Alcohol Depend 33:119–128PubMedCrossRefGoogle Scholar
  18. Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22:237–259PubMedCrossRefGoogle Scholar
  19. Goeders NE, Guerin GF (1994) Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Psychopharmacol (Berl) 114:63–70CrossRefGoogle Scholar
  20. Goeders NE, Guerin GF (1996) Role of corticosterone in intravenous cocaine self-administration in rats. Neuroendocrinology 64:337–348PubMedCrossRefGoogle Scholar
  21. Goeders NE, Peltier RL, Guerin GF (1998) Ketoconazole reduces low dose cocaine self-administration in rats. Drug Alcohol Depend 53:67–77PubMedCrossRefGoogle Scholar
  22. Green TA, Gehrke BJ, Bardo MT (2002) Environmental enrichment decreases intravenous amphetamine self-administration in rats: dose-response functions for fixed- and progressive-ratio schedules. Psychopharmacol (Berl) 162:373–378CrossRefGoogle Scholar
  23. Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, Hedou G, Feldon J, Moran MC, Nelson P (2000) Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience 100:749–768PubMedCrossRefGoogle Scholar
  24. Hiroshige T, Sakakura M (1971) Circadian rhythm of corticotropin-releasing activity in the hypothalamus of normal and adrenalectomized rats. Neuroendocrinology 7:25–36PubMedCrossRefGoogle Scholar
  25. Institute of Laboratory Animal Resources (U.S.) (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington, DC, p 125Google Scholar
  26. Klebaur JE, Bevins RA, Segar TM, Bardo MT (2001) Individual differences in behavioral responses to novelty and amphetamine self-administration in male and female rats. Behav Pharmacol 12:267–275PubMedCrossRefGoogle Scholar
  27. Koenig HN, Olive MF (2004) The glucocorticoid receptor antagonist mifepristone reduces ethanol intake in rats under limited access conditions. Psychoneuroendocrinology 29:999–1003PubMedCrossRefGoogle Scholar
  28. Meaney MJ, Aitken DH (1985) The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrations: temporal parameters. Brain Res 354:301–304PubMedGoogle Scholar
  29. Meaney MJ, Aitken DH, Bodnoff SR, Iny LJ, Sapolsky RM (1985a) The effects of postnatal handling on the development of the glucocorticoid receptor systems and stress recovery in the rat. Prog Neuropsychopharmacol Biol Psychiatry 9:731–734PubMedCrossRefGoogle Scholar
  30. Meaney MJ, Aitken DH, Bodnoff SR, Iny LJ, Tatarewicz JE, Sapolsky RM (1985b) Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions. Behav Neurosci 99:765–770PubMedCrossRefGoogle Scholar
  31. Meaney MJ, Sapolsky RM, McEwen BS (1985c) The development of the glucocorticoid receptor system in the rat limbic brain. I. Ontogeny and autoregulation. Brain Res 350:159–164PubMedGoogle Scholar
  32. Misslin R, Herzog F, Koch B, Ropartz P (1982) Effects of isolation, handling and novelty on the pituitary–adrenal response in the mouse. Psychoneuroendocrinology 7:217–221PubMedCrossRefGoogle Scholar
  33. Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, Petre CO (2005) Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 29:1214–1224PubMedCrossRefGoogle Scholar
  34. Olsson T, Mohammed AH, Donaldson LF, Henriksson BG, Seckl JR (1994) Glucocorticoid receptor and NGFI-A gene expression are induced in the hippocampus after environmental enrichment in adult rats. Brain Res Mol Brain Res 23:349–353PubMedCrossRefGoogle Scholar
  35. Ostrander MM, Ulrich-Lai YM, Choi DC, Richtand NM, Herman JP (2006) Hypoactivity of the hypothalamo–pituitary–adrenocortical axis during recovery from chronic variable stress. Endocrinology 147:2008–2017PubMedCrossRefGoogle Scholar
  36. Pauly JR, Robinson SF, Collins AC (1993) Chronic corticosterone administration enhances behavioral sensitization to amphetamine in mice. Brain Res 620:195–202PubMedCrossRefGoogle Scholar
  37. Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74PubMedCrossRefGoogle Scholar
  38. Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513PubMedCrossRefGoogle Scholar
  39. Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, Simon H (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci U S A 88:2088–2092PubMedCrossRefGoogle Scholar
  40. Piazza PV, Barrot M, Rouge-Pont F, Marinelli M, Maccari S, Abrous DN, Simon H, Le Moal M (1996) Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission. Proc Natl Acad Sci U S A 93:15445–15450PubMedCrossRefGoogle Scholar
  41. Roberts DC, Andrews MM (1997) Baclofen suppression of cocaine self-administration: demonstration using a discrete trials procedure. Psychopharmacol (Berl) 131:271–277CrossRefGoogle Scholar
  42. Roberts DC, Brebner K, Vincler M, Lynch WJ (2002) Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure. Drug Alcohol Depend 67:291–299PubMedCrossRefGoogle Scholar
  43. Sarnyai Z (1998) Neurobiology of stress and cocaine addiction. Studies on corticotropin-releasing factor in rats, monkeys, and humans. Ann N Y Acad Sci 851:371–387PubMedCrossRefGoogle Scholar
  44. Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev 53:209–243PubMedGoogle Scholar
  45. Smith JK, Neill JC, Costall B (1997) Post-weaning housing conditions influence the behavioural effects of cocaine and d-amphetamine. Psychopharmacol (Berl) 131:23–33CrossRefGoogle Scholar
  46. Solinas M, Chauvet C, Thiriet N, El Rawas R, Jaber M (2008) Reversal of cocaine addiction by environmental enrichment. Proc Natl Acad Sci U S A 105:17145–17150PubMedCrossRefGoogle Scholar
  47. Spangler R, Zhou Y, Schlussman SD, Ho A, Kreek MJ (1997) Behavioral stereotypies induced by “binge” cocaine administration are independent of drug-induced increases in corticosterone levels. Behav Brain Res 86:201–204PubMedCrossRefGoogle Scholar
  48. Stairs DJ, Klein ED, Bardo MT (2006) Effects of environmental enrichment on extinction and reinstatement of amphetamine self-administration and sucrose-maintained responding. Behav Pharmacol 17:597–604PubMedCrossRefGoogle Scholar
  49. Svec F (1988) Differences in the interaction of RU 486 and ketoconazole with the second binding site of the glucocorticoid receptor. Endocrinology 123:1902–1906PubMedCrossRefGoogle Scholar
  50. Thiel KJ, Sanabria F, Pentkowski NS, Neisewander JL (2009) Anti-craving effects of environmental enrichment. Int J Neuropsychopharmacol 12:1151–1156PubMedCrossRefGoogle Scholar
  51. Zakharova E, Miller J, Unterwald E, Wade D, Izenwasser S (2009) Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats. Neuroscience 163(3):890–897PubMedCrossRefGoogle Scholar
  52. Zou B, Golarai G, Connor JA, Tang AC (2001) Neonatal exposure to a novel environment enhances the effects of corticosterone on neuronal excitability and plasticity in adult hippocampus. Brain Res Dev Brain Res 130:1–7PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Dustin J. Stairs
    • 1
  • Mark A. Prendergast
    • 2
  • Michael T. Bardo
    • 2
  1. 1.Department of PsychologyCreighton UniversityOmahaUSA
  2. 2.Department of PsychologyUniversity of KentuckyLexingtonUSA

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