, Volume 187, Issue 1, pp 13–21

A method for single-session cocaine self-administration in the mouse

Original Investigation



Drug self-administration is a powerful method to measure the reinforcing effects of a drug, as well as to investigate behavioral, biochemical, and physiological effects of a drug specific to contingent delivery. With the spectrum of genetically modified mice available, there is a need for well-designed drug self-administration studies tailored for rapid completion of studies in mice.


We set out to develop a methodology in mice for obtaining high levels of cocaine self-administration during the first exposure to the drug.

Materials and methods

C57Bl/6J mice were trained to lever press for liquid reinforcer on a fixed ratio 1, then a progressive ratio (PR) schedule of reinforcement before intravenous self-administration of cocaine on a PR schedule.


Within a single 16-h session, each mouse self-administered either saline or 0.1, 0.3, 0.6, or 1.2 mg kg−1 infusion−1 of cocaine during four distinct 4-h subsessions. Mice showed a strong preference for cocaine vs saline, as demonstrated by higher breakpoints and greater preference for the active lever. Likewise, there was a dose-dependent increase in breakpoints obtained and in drug intake. Finally, animals receiving noncontingent cocaine pressed significantly less than mice self-administering the same dose of cocaine, indicating that a significant amount of active lever pressing is driven by drug-seeking and not the psychomotor-activating effects of cocaine alone.


Mice will reach high breakpoints and cocaine intake during an initial exposure to cocaine. This method is well-suited to rapidly obtain progressive ratio cocaine self-administration in mice.


Cocaine Self-administration Mouse 



Fixed ratio




Progressive ratio


  1. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300PubMedCrossRefGoogle Scholar
  2. Ator NA, Griffiths RR (1987) Self-administration of barbiturates and benzodiazepines: a review. Pharmacol Biochem Behav 27:391–398PubMedCrossRefGoogle Scholar
  3. Beninger RJ, Hanson DR, Phillips AG (1981) The acquisition of responding with conditioned reinforcement: effects of cocaine, (+)-amphetamine and pipradrol. Br J Pharmacol 74:149–154PubMedGoogle Scholar
  4. Berlanga ML, Olsen CM, Chen V, Ikegami A, Herring BE, Duvauchelle CL, Alcantara AA (2003) Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine. Neuroscience 120:1149–1156PubMedCrossRefGoogle Scholar
  5. Blokhina EA, Kashkin VA, Zvartau EE, Danysz W, Bespalov AY (2005) Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice. Eur Neuropsychopharmacol 15:219–225PubMedCrossRefGoogle Scholar
  6. Brabant C, Quertemont E, Tirelli E (2005) Evidence that the relations between novelty-induced activity, locomotor stimulation and place preference induced by cocaine qualitatively depend upon the dose: a multiple regression analysis in inbred C57BL/6J mice. Behav Brain Res 158:201–210PubMedCrossRefGoogle Scholar
  7. Caine SB, Negus SS, Mello NK (1999) Method for training operant responding and evaluating cocaine self-administration behavior in mutant mice. Psychopharmacology (Berl) 147:22–24CrossRefGoogle Scholar
  8. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4:873–874PubMedCrossRefGoogle Scholar
  9. Ciccocioppo R, Martin-Fardon R, Weiss F (2004) Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nat Neurosci 7:495–496PubMedCrossRefGoogle Scholar
  10. Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (2003) Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine. J Neurosci 23:2488–2493PubMedGoogle Scholar
  11. Crabbe JC, Belknap JK, Buck KJ (1994) Genetic animal models of alcohol and drug abuse. Science 264:1715–1723PubMedCrossRefGoogle Scholar
  12. 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
  13. Dumont EC, Mark GP, Mader S, Williams JT (2005) Self-administration enhances excitatory synaptic transmission in the bed nucleus of the stria terminalis. Nat Neurosci 8:413–414PubMedGoogle Scholar
  14. Gosnell BA (2000) Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology (Berl) 149:286–292CrossRefGoogle Scholar
  15. Grahame NJ, Phillips TJ, Burkhart-Kasch S, Cunningham CL (1995) Intravenous cocaine self-administration in the C57BL/6J mouse. Pharmacol Biochem Behav 51:827–834PubMedCrossRefGoogle Scholar
  16. Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944PubMedCrossRefGoogle Scholar
  17. Iwamoto E, Martin W (1988) A critique of drug self-administration as a method for predicting abuse potential of drugs. NIDA Res Monogr 81:457–465PubMedGoogle Scholar
  18. Kuzmin A, Zvartau E, Gessa GL, Martellotta MC, Fratta W (1992) Calcium antagonists isradipine and nimodipine suppress cocaine and morphine intravenous self-administration in drug-naive mice. Pharmacol Biochem Behav 41:497–500PubMedCrossRefGoogle Scholar
  19. Kuzmin A, Semenova S, Ramsey NF, Zvartau EE, Van Ree JM (1996) Modulation of cocaine intravenous self-administration in drug-naive animals by dihydropyridine Ca2+ channel modulators. Eur J Pharmacol 295:19–25PubMedCrossRefGoogle Scholar
  20. Larson EB, Carroll ME (2005) Wheel running as a predictor of cocaine self-administration and reinstatement in female rats. Pharmacol Biochem Behav 82:590–600PubMedCrossRefGoogle Scholar
  21. Lesscher HM, Hoogveld E, Burbach JP, van Ree JM, Gerrits MA (2005) Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. Eur Neuropsychopharmacol 15:31–37PubMedCrossRefGoogle Scholar
  22. Mark GP, Hajnal A, Kinney AE, Keys AS (1999) Self-administration of cocaine increases the release of acetylcholine to a greater extent than response-independent cocaine in the nucleus accumbens of rats. Psychopharmacology (Berl) 143:47–53CrossRefGoogle Scholar
  23. Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology (Berl) 112:163–182CrossRefGoogle Scholar
  24. Mathon DS, Lesscher HM, Gerrits MA, Kamal A, Pintar JE, Schuller AG, Spruijt BM, Burbach JP, Smidt MP, van Ree JM, Ramakers GM (2005) Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice. Neuroscience 130:359–367PubMedCrossRefGoogle Scholar
  25. Mitchell JM, Cunningham CL, Mark GP (2005) Locomotor activity predicts acquisition of self-administration behavior but not cocaine intake. Behav Neurosci 119:464–472PubMedCrossRefGoogle Scholar
  26. Morgan D, Roberts DC (2004) Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration. Neurosci Biobehav Rev 27:803–812PubMedCrossRefGoogle Scholar
  27. Mutschler NH, Miczek KA (1998) Withdrawal from i.v. cocaine “binges” in rats: ultrasonic distress calls and startle. Psychopharmacology (Berl) 135:161–168CrossRefGoogle Scholar
  28. Nestler EJ (2001) Psychogenomics: opportunities for understanding addiction. J Neurosci 21:8324–8327PubMedGoogle Scholar
  29. Paladini CA, Mitchell JM, Williams JT, Mark GP (2004) Cocaine self-administration selectively decreases noradrenergic regulation of metabotropic glutamate receptor-mediated inhibition in dopamine neurons. J Neurosci 24:5209–5215PubMedCrossRefGoogle Scholar
  30. Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005) Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats. Psychopharmacology (Berl) 178:193–201CrossRefGoogle Scholar
  31. Piazza PV, Deminiere JM, Maccari S, Mormede P, Le Moal M, Simon H (1990) Individual reactivity to novelty predicts probability of amphetamine self-administration. Behav Pharmacol 1:339–345PubMedGoogle Scholar
  32. 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 USA 88:2088–2092PubMedCrossRefGoogle Scholar
  33. 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
  34. Ripley TL, Gadd CA, De Felipe C, Hunt SP, Stephens DN (2002) Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology 43:1258–1268PubMedCrossRefGoogle Scholar
  35. Robbins TW, Cador M, Taylor JR, Everitt BJ (1989) Limbic–striatal interactions in reward-related processes. Neurosci Biobehav Rev 13:155–162PubMedCrossRefGoogle Scholar
  36. 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
  37. Rocha BA (1999) Methodology for analyzing the parallel between cocaine psychomotor stimulant and reinforcing effects in mice. Psychopharmacology (Berl) 147:27–29CrossRefGoogle Scholar
  38. Rocha BA (2003) Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol 479:107–115PubMedCrossRefGoogle Scholar
  39. Rocha BA, Odom LA, Barron BA, Ator R, Wild SA, Forster MJ (1998) Differential responsiveness to cocaine in C57BL/6J and DBA/2J mice. Psychopharmacology (Berl) 138:82–88CrossRefGoogle Scholar
  40. SAMHSA (2005) Results from the 2004 National Survey on Drug Use and Health: National FindingsGoogle Scholar
  41. Schramm-Sapyta NL, Olsen CM, Winder DG (2005) Cocaine self-administration reduces excitatory responses in the mouse nucleus accumbens shell. Neuropsychopharmacology (Epub ahead of print)Google Scholar
  42. Schuster CR, Thompson T (1969) Self administration of and behavioral dependence on drugs. Annu Rev Pharmacol 9:483–502PubMedCrossRefGoogle Scholar
  43. Smith A, Piercey M, Roberts DC (1995) Effect of (−)-DS 121 and (+)-UH 232 on cocaine self-administration in rats. Psychopharmacology (Berl) 120:93–98CrossRefGoogle Scholar
  44. Soria G, Mendizabal V, Tourino C, Robledo P, Ledent C, Parmentier M, Maldonado R, Valverde O (2005) Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30(9):1670–1680PubMedCrossRefGoogle Scholar
  45. Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169–184CrossRefGoogle Scholar
  46. Szumlinski KK, Dehoff MH, Kang SH, Frys KA, Lominac KD, Klugmann M, Rohrer J, Griffin W, 3rd, Toda S, Champtiaux NP, Berry T, Tu JC, Shealy SE, During MJ, Middaugh LD, Worley PF, Kalivas PW (2004) Homer proteins regulate sensitivity to cocaine. Neuron 43:401–413PubMedCrossRefGoogle Scholar
  47. Thomsen M, Woldbye DP, Wortwein G, Fink-Jensen A, Wess J, Caine SB (2005) Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice. J Neurosci 25:8141–8149PubMedCrossRefGoogle Scholar
  48. Tornatzky W, Miczek KA (2000) Cocaine self-administration “binges”: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology (Berl) 148:289–298CrossRefGoogle Scholar
  49. Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587PubMedCrossRefGoogle Scholar
  50. Wilson JM, Nobrega JN, Corrigall WA, Coen KM, Shannak K, Kish SJ (1994) Amygdala dopamine levels are markedly elevated after self- but not passive-administration of cocaine. Brain Res 668:39–45PubMedCrossRefGoogle Scholar
  51. Wise RA (1984) Neural mechanisms of the reinforcing action of cocaine. NIDA Res Monogr 50:15–33PubMedGoogle Scholar
  52. Wise RA, Bozarth MA (1981) Brain substrates for reinforcement and drug self-administration. Prog Neuropsychopharmacol 5:467–474PubMedCrossRefGoogle Scholar
  53. Wolterink G, Phillips G, Cador M, Donselaar-Wolterink I, Robbins TW, Everitt BJ (1993) Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. Psychopharmacology (Berl) 110:355–364CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Department of Molecular Physiology and BiophysicsVanderbilt University Medical CenterNashvilleUSA
  2. 2.Center for Molecular NeuroscienceVanderbilt University Medical CenterNashvilleUSA
  3. 3.John F. Kennedy Center for Research on Human DevelopmentVanderbilt University Medical CenterNashvilleUSA

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