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

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Abstract

Rationale

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.

Objectives

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.

Results

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.

Conclusions

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.

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Abbreviations

FR:

Fixed ratio

NC:

Noncontingent

PR:

Progressive ratio

References

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

    Article  PubMed  CAS  Google Scholar 

  • Ator NA, Griffiths RR (1987) Self-administration of barbiturates and benzodiazepines: a review. Pharmacol Biochem Behav 27:391–398

    Article  PubMed  CAS  Google Scholar 

  • Beninger RJ, Hanson DR, Phillips AG (1981) The acquisition of responding with conditioned reinforcement: effects of cocaine, (+)-amphetamine and pipradrol. Br J Pharmacol 74:149–154

    PubMed  CAS  Google Scholar 

  • 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 120:1149–1156

    Article  PubMed  CAS  Google Scholar 

  • 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 15:219–225

    Article  PubMed  CAS  Google Scholar 

  • 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 158:201–210

    Article  PubMed  CAS  Google Scholar 

  • Caine SB, Negus SS, Mello NK (1999) Method for training operant responding and evaluating cocaine self-administration behavior in mutant mice. Psychopharmacology (Berl) 147:22–24

    Article  CAS  Google Scholar 

  • 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 4:873–874

    Article  PubMed  CAS  Google Scholar 

  • Ciccocioppo R, Martin-Fardon R, Weiss F (2004) Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nat Neurosci 7:495–496

    Article  PubMed  CAS  Google Scholar 

  • Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (2003) Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine. J Neurosci 23:2488–2493

    PubMed  CAS  Google Scholar 

  • Crabbe JC, Belknap JK, Buck KJ (1994) Genetic animal models of alcohol and drug abuse. Science 264:1715–1723

    Article  PubMed  CAS  Google Scholar 

  • 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 23:4785–4790

    PubMed  CAS  Google Scholar 

  • 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 8:413–414

    PubMed  CAS  Google Scholar 

  • Gosnell BA (2000) Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology (Berl) 149:286–292

    Article  CAS  Google Scholar 

  • Grahame NJ, Phillips TJ, Burkhart-Kasch S, Cunningham CL (1995) Intravenous cocaine self-administration in the C57BL/6J mouse. Pharmacol Biochem Behav 51:827–834

    Article  PubMed  CAS  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto E, Martin W (1988) A critique of drug self-administration as a method for predicting abuse potential of drugs. NIDA Res Monogr 81:457–465

    PubMed  CAS  Google Scholar 

  • 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 41:497–500

    Article  PubMed  CAS  Google Scholar 

  • 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 295:19–25

    Article  PubMed  CAS  Google Scholar 

  • Larson EB, Carroll ME (2005) Wheel running as a predictor of cocaine self-administration and reinstatement in female rats. Pharmacol Biochem Behav 82:590–600

    Article  PubMed  CAS  Google Scholar 

  • 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 15:31–37

    Article  PubMed  CAS  Google Scholar 

  • 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) 143:47–53

    Article  CAS  Google Scholar 

  • Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology (Berl) 112:163–182

    Article  CAS  Google Scholar 

  • 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 130:359–367

    Article  PubMed  CAS  Google Scholar 

  • Mitchell JM, Cunningham CL, Mark GP (2005) Locomotor activity predicts acquisition of self-administration behavior but not cocaine intake. Behav Neurosci 119:464–472

    Article  PubMed  CAS  Google Scholar 

  • Morgan D, Roberts DC (2004) Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration. Neurosci Biobehav Rev 27:803–812

    Article  PubMed  CAS  Google Scholar 

  • Mutschler NH, Miczek KA (1998) Withdrawal from i.v. cocaine “binges” in rats: ultrasonic distress calls and startle. Psychopharmacology (Berl) 135:161–168

    Article  CAS  Google Scholar 

  • Nestler EJ (2001) Psychogenomics: opportunities for understanding addiction. J Neurosci 21:8324–8327

    PubMed  CAS  Google Scholar 

  • 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 24:5209–5215

    Article  PubMed  CAS  Google Scholar 

  • 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) 178:193–201

    Article  CAS  Google Scholar 

  • 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 1:339–345

    PubMed  Google Scholar 

  • 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 88:2088–2092

    Article  PubMed  CAS  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  PubMed  CAS  Google Scholar 

  • 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 43:1258–1268

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW, Cador M, Taylor JR, Everitt BJ (1989) Limbic–striatal interactions in reward-related processes. Neurosci Biobehav Rev 13:155–162

    Article  PubMed  CAS  Google Scholar 

  • 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 67:291–299

    Article  PubMed  CAS  Google Scholar 

  • Rocha BA (1999) Methodology for analyzing the parallel between cocaine psychomotor stimulant and reinforcing effects in mice. Psychopharmacology (Berl) 147:27–29

    Article  CAS  Google Scholar 

  • Rocha BA (2003) Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol 479:107–115

    Article  PubMed  CAS  Google Scholar 

  • 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) 138:82–88

    Article  CAS  Google Scholar 

  • SAMHSA (2005) Results from the 2004 National Survey on Drug Use and Health: National Findings

  • 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)

  • Schuster CR, Thompson T (1969) Self administration of and behavioral dependence on drugs. Annu Rev Pharmacol 9:483–502

    Article  PubMed  CAS  Google Scholar 

  • Smith A, Piercey M, Roberts DC (1995) Effect of (−)-DS 121 and (+)-UH 232 on cocaine self-administration in rats. Psychopharmacology (Berl) 120:93–98

    Article  CAS  Google Scholar 

  • 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):1670–1680

    Article  PubMed  CAS  Google Scholar 

  • Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169–184

    Article  CAS  Google Scholar 

  • 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 43:401–413

    Article  PubMed  CAS  Google Scholar 

  • 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 25:8141–8149

    Article  PubMed  CAS  Google Scholar 

  • Tornatzky W, Miczek KA (2000) Cocaine self-administration “binges”: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology (Berl) 148:289–298

    Article  CAS  Google Scholar 

  • Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587

    Article  PubMed  CAS  Google Scholar 

  • 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 668:39–45

    Article  PubMed  CAS  Google Scholar 

  • Wise RA (1984) Neural mechanisms of the reinforcing action of cocaine. NIDA Res Monogr 50:15–33

    PubMed  CAS  Google Scholar 

  • Wise RA, Bozarth MA (1981) Brain substrates for reinforcement and drug self-administration. Prog Neuropsychopharmacol 5:467–474

    Article  PubMed  CAS  Google Scholar 

  • 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) 110:355–364

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a NARSAD young investigator award and NIDA grant DA19112 (DGW), and NIMH grant 5-T32MH65215 (CMO). The authors would like to acknowledge the assistance of the Vanderbilt Mouse Metabolic Phenotyping Center and Murine Neurobehavioral Core.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, 37232-0615, USA

    Christopher M. Olsen & Danny G. Winder

  2. Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN, 37232-0615, USA

    Christopher M. Olsen & Danny G. Winder

  3. John F. Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN, 37232-0615, USA

    Danny G. Winder

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  1. Christopher M. Olsen
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Correspondence to Christopher M. Olsen.

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Olsen, C.M., Winder, D.G. A method for single-session cocaine self-administration in the mouse. Psychopharmacology 187, 13–21 (2006). https://doi.org/10.1007/s00213-006-0388-1

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