, Volume 175, Issue 2, pp 154–162 | Cite as

The sigma11) receptor activation is a key step for the reactivation of cocaine conditioned place preference by drug priming

  • Pascal Romieu
  • Johann Meunier
  • Déborah Garcia
  • Nadia Zozime
  • Rémi Martin-Fardon
  • Wayne D. Bowen
  • Tangui Maurice
Original Investigation



Cocaine-seeking behavior can be investigated in rodents using the conditioned place preference (CPP) paradigm, in which the drug-paired environment serves as a conditioned stimulus. Such approach allowed to previously demonstrate the importance of the neuromodulatory sigma11) receptor in acquisition of cocaine-induced CPP. CPP can be extinguished and then reactivated, notably using a cocaine challenge (i.e., priming).

Objectives and methods

In order to examine the role of the σ1 receptor in reinstatement of Cocaine-seeking, Swiss mice acquired CPP with cocaine (30 mg/kg, ip) and then CPP was extinguished.


A challenge cocaine priming (15 mg/kg) reactivated CPP up to 140% of the post-conditioning response. Pre-administration of the σ1 receptor antagonist BD1047 (330 mg/kg, ip) or repeated treatment with an antisense probe targeting the σ1 receptor prevented CPP reactivation. The σ1 agonist igmesine (1–10 mg/kg, ip) or the steroid dehydroepiandrosterone (DHEA, 10–40 mg/kg, sc) reactivated CPP, in a BD1047-sensitive manner. Moreover, the in vivo [3H](+)-SKF-10,047 binding levels to the σ1 receptor were increased after cocaine conditioning in numerous brain structures and these increases subsisted after extinction. Finally, cross-reactivation of cocaine-induced CPP was observed after phencyclidine (PCP), morphine, nicotine and ethanol administration. However, BD1047 blocked reactivation of CPP induced by PCP, morphine and nicotine but not ethanol.


Since activation of the σ1 receptor is not sufficient to sustain CPP in naive animals [Neuropsychopharmacology 26 (2002) 444], it is concluded that σ1 receptor activation is a key event for relapse to drug seeking. Activation may occur via sensitization due to enhanced in vivo available of receptors.


Cocaine relapse Conditioned place preference Sigma11) receptor Sensitization Dehydroepiandrosterone Mouse 



We thank M. Michaud, and Drs J.-M. Kamenka and F.J. Roman for their gifts of drugs. This work was supported by CNRS.


  1. Alonso G, Phan VL, Guillemain I, Saunier M, Legrand A, Anoal M, Maurice T (2000) Immunocytochemical localization of the σ1 receptor in the adult rat central nervous system. Neuroscience 97:155–170CrossRefPubMedGoogle Scholar
  2. Baulieu EE (1981) Steroid hormones in the brain: several mechanisms? In: Fuxe K, Gustafson JA, Wettenberg L (eds) Steroid hormone regulation of the brain. Pergamon Press, Oxford, pp 3–14Google Scholar
  3. Bergeron R, de Montigny C, Debonnel G (1996) Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors. J Neurosci 16:1193–1202PubMedGoogle Scholar
  4. Buydens-Branchey L, Branchey M, Hudson J, Majewska MD (2002) Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addict. Psychoneuroendocrinology 27:83–97CrossRefPubMedGoogle Scholar
  5. Carlezon WA, Wise RA (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 16:3112–3122PubMedGoogle Scholar
  6. De Costa BR, Radesca L, Di Paolo L, Bowen WD (1992) Synthesis, characterization and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: structural requirements and binding affinity at the sigma receptor. J Med Chem 35:38–47PubMedGoogle Scholar
  7. Gonzalez-Alvear GM, Werling LL (1994) regulation of [3H]dopamine release from rat striatal slices by sigma ligands. J Pharmacol Exp Ther 271:212–219Google Scholar
  8. Hayashi T, Su TP (2001) Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci USA 98:491–496PubMedGoogle Scholar
  9. Hayashi T, Maurice T, Su TP (2000) Ca2+signaling via sigma1-receptors: novel regulatory mechanism affecting intracellular Ca2+ concentration. J Pharmacol Exp Ther 293:788–798PubMedGoogle Scholar
  10. Itzhak Y, Martin JL (2002) Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants. Neuropsychopharmacology 26:130–134PubMedGoogle Scholar
  11. Jaffe JH, Cascella NG, Kumor KH, Sherer MA (1989) Cocaine-induced cocaine craving. Psychopharmacology 97:59–64PubMedGoogle Scholar
  12. Leshner AI (1997) Addiction is a brain disease, and it matters. Science 278:45–47PubMedGoogle Scholar
  13. Lu L, Xu NJ, Ge X, Yue W, Su WJ, Pei G, Ma L (2002a) Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization. Psychopharmacology 159:125–132CrossRefPubMedGoogle Scholar
  14. Lu L, Zhang B, Liu Z, Zhang Z (2002b) Reactivation of cocaine conditioned place preference induced by stress is reversed by cholecystokinin-B receptors antagonist in rats. Brain Res 954:132–140CrossRefPubMedGoogle Scholar
  15. Matsumoto RR, Bowen WD, Tom MA, Vo VN, Truong DD, De Costa BR (1995) Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur J Pharmacol 280:301–310CrossRefPubMedGoogle Scholar
  16. Matsumoto RR, McCracken KA, Pouw B, Miller J, Bowen WD, Williams W, De Costa BR (2001) N-alkyl substituted analogs of the s receptor ligand BD1008 and traditional sigma receptor ligands affect cocaine-induced convulsions and lethality in mice. Eur J Pharmacol 411:261–273CrossRefPubMedGoogle Scholar
  17. Maurice T, Phan VL, Urani A, Kamei H, Noda Y, Nabeshima T (1999) Neuroactive neurosteroids as endogenous effector for the sigma11) receptor: pharmacological evidences and therapeutic opportunities. Jpn J Pharmacol 81:125–155Google Scholar
  18. Maurice T, Phan VL, Privat A (2001a) The anti-amnesic effect of sigma11) receptor agonists confirmed by in vivo antisense strategy in the mouse. Brain Res 898:113–121CrossRefPubMedGoogle Scholar
  19. Maurice T, Urani A, Phan VL, Romieu P (2001b) The interaction between neuroactive steroids and the sigma11) receptor function: behavioral consequences and therapeutic opportunities. Brain Res Rev 37:116–132PubMedGoogle Scholar
  20. Maurice T, Martin-Fardon R, Romieu P, Matsumoto RR (2002) Selective sigma11) receptor antagonists as a new promising strategy to prevent cocaine-induced behaviors and toxicity. Neurosci Biobehav Res 26:499–527CrossRefGoogle Scholar
  21. McCracken KA, Bowen WD, Matsumoto RR (1999) Novel s receptor ligands attenuate the locomotor stimulatory effects of cocaine. Eur J Pharmacol 365:35–38CrossRefPubMedGoogle Scholar
  22. Mellon SH, Griffin LD (2002) Neurosteroids: biochemistry and clinical relevance. Trends Endocrinol Metab 13:35–43CrossRefPubMedGoogle Scholar
  23. Mellon SH, Griffin LD, Compagnone NA (2001) Biosynthesis and action of neurosteroids. Brain Res Rev 37:3–12CrossRefPubMedGoogle Scholar
  24. Menkel M, Terry M, Pontecorvo M, Katz JL, Witkin JM (1991) Selective s ligands block stimulant effects of cocaine. Eur J Pharmacol 201:251–252CrossRefPubMedGoogle Scholar
  25. Monnet FP, Blier P, Debonnel G, de Montigny C (1992) Modulation by sigma ligands of N-methyl-d-aspartate-induced [3H]noradrenaline release in the rat hippocampus: G-protein dependency. Naunyn Schmiedebergs Arch Pharmacol 346:32–39PubMedGoogle Scholar
  26. Monnet FP, Mahé V, Robel P, Baulieu EE (1995) Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-d-aspartate in the rat hippocampus. Proc Natl Acad Sci USA 92:3774–3778PubMedGoogle Scholar
  27. Mueller D, Stewart J (2000) Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction. Behav Brain Res 115:39–47PubMedGoogle Scholar
  28. Noda Y, Nabeshima T (1998) Neuronal mechanisms of phencyclidine-induced place aversion and preference in the conditioned place preference task. Meth Find Exp Clin Pharmacol 20:607–611Google Scholar
  29. O’Brien CP, McLellan AT (1996) Myths about the treatment of addiction. Lancet 347:237240Google Scholar
  30. O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22PubMedGoogle Scholar
  31. Orentreich N, Brind JL, Rizer RL, Vogelman JH (1984) Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59:551–555PubMedGoogle Scholar
  32. Romieu P, Martin-Fardon R, Maurice T (2000) Involvement of the σ1 receptor in the cocaine-induced conditioned place preference. Neuroreport 11:2885–2888PubMedGoogle Scholar
  33. Romieu P, Phan VL, Martin-Fardon R, Maurice T (2002) The sigma1 receptor involvement in cocaine-induced conditioned place preference is consequent upon dopamine uptake blockade. Neuropsychopharmacology 26:444–455CrossRefPubMedGoogle Scholar
  34. Romieu P, Martin-Fardon R, Bowen WD, Maurice T (2003) Sigma1 (s1) receptor-related neuroactive steroids modulate cocaine-induced reward. J Neurosci 23:3572–3576PubMedGoogle Scholar
  35. Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20CrossRefPubMedGoogle Scholar
  36. Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and Cocaine seeking: a review. Pharmacol Rev 54:1–42PubMedGoogle Scholar
  37. Su TP, Hayashi T (2003) Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem 10:2075–2082Google Scholar
  38. Su TP, London ED, Jaffe JH (1988) Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 240:219–221PubMedGoogle Scholar
  39. Szumlinski KK, Price KL, Frys KA, Middaugh LD (2002) Unconditioned and conditioned factors contribute to the ‘reinstatement’ of cocaine place conditioning following extinction in C57BL/6 mice. Behav Brain Res 136:151–160CrossRefPubMedGoogle Scholar
  40. Ujike H, Tsuchida K, Akiyama K, Otsuki S (1992) Supersensitivity of sigma receptors after repeated administration of cocaine. Life Sci 51:PL31–PL6CrossRefPubMedGoogle Scholar
  41. Ujike H, Kuroda S, Otsuki S (1996) s receptor antagonists block the development of sensitization to cocaine. Eur J Pharmacol 296:123–128CrossRefPubMedGoogle Scholar
  42. Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O (2000) Control of Cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant responding and extracellular dopamine levels in amygdala and nucleus accumbens. Proc Natl Acad Sci USA 97:4321–4326PubMedGoogle Scholar
  43. Weiss F, Martin-Fardon R, Ciccocioppo R, Kerr TM, Smith DL, Ben-Shahar O (2001) Enduring resistance to extinction of Cocaine-seeking behavior induced by drug-related cues. Neuropsychopharmacology 25:361–372Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Pascal Romieu
    • 1
  • Johann Meunier
    • 1
  • Déborah Garcia
    • 1
  • Nadia Zozime
    • 1
  • Rémi Martin-Fardon
    • 2
  • Wayne D. Bowen
    • 3
  • Tangui Maurice
    • 1
  1. 1.CNRS FRE 2693University of Montpellier IIMontpellier cedex 5France
  2. 2.Department of NeuropharmacologyThe Scripps Research InstituteLa JollaUSA
  3. 3.Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal ChemistryNIDDK/NIHBethesdaUSA

Personalised recommendations