Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Protocol
  • Published:

Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats

Abstract

Drug-discrimination (DD) techniques can be used to study abuse-related effects by establishing the interoceptive effects of a training drug (e.g., cocaine) as a cue for performing a specific operant response (e.g., lever pressing reinforced by food). During training with this protocol, pressing one lever is reinforced when the training drug is injected before the start of the session, and responding on a second lever is reinforced when vehicle is injected before the session. Lever choice during test sessions can then be used as an indication of whether a novel drug has effects similar to the training drug, or whether a potential therapeutic alters the effects of the training drug. Although training can be lengthy (up to several months), the pharmacological specificity of DD procedures make them a perfect complement to other techniques used to study drug-abuse phenomena, such as intravenous self-administration and conditioned place-preference procedures.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of the DD training and testing procedures.

Similar content being viewed by others

References

  1. Colpaert, F.C. Drug discrimination in neurobiology. Pharmacol. Biochem. Behav. 64, 337–345 (1999).

    Article  CAS  Google Scholar 

  2. Balster, R.L. & Prescott, W.R. Delta 9-tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neurosci. Biobehav. Rev. 16, 55–62 (1992).

    Article  CAS  Google Scholar 

  3. Callahan, P.M., de la Garza, R. & Cunningham, K.A. Mediation of the discriminative stimulus properties of cocaine by mesocorticolimbic dopamine systems. Pharmacol. Biochem. Behav. 57, 601–607 (1997).

    Article  CAS  Google Scholar 

  4. Dykstra, L.A., Preston, K.L. & Bigelow, G.E. Discriminative stimulus and subjective effects of opioids with mu and kappa activity: data from laboratory animals and human subjects. Psychopharmacology (Berl) 130, 14–27 (1997).

    Article  CAS  Google Scholar 

  5. Herling, S. & Woods, J.H. Discriminative stimulus effects of narcotics: evidence for multiple receptor-mediated actions. Life Sci. 28, 1571–1584 (1981).

    Article  CAS  Google Scholar 

  6. Holtzman, S.G. Caffeine as a model drug of abuse. Trends Pharmacol. Sci. 11, 355–356 (1990).

    Article  CAS  Google Scholar 

  7. Shoaib, M. Is dopamine important in nicotine dependence? J. Physiol. Paris 92, 229–233 (1998).

    Article  CAS  Google Scholar 

  8. Spealman, R.D. Use of cocaine-discrimination techniques for preclinical evaluation of candidate therapeutics for cocaine dependence. NIDA Res. Monogr. 119, 175–179 (1992).

    CAS  PubMed  Google Scholar 

  9. Stolerman, I.P., Kumar, R. & Reavill, C. Discriminative stimulus effects of cholinergic agonists and the actions of their antagonists. Psychopharmacol. Ser. 4, 32–43 (1988).

    CAS  PubMed  Google Scholar 

  10. Wiley, J.L. Cannabis: discrimination of “internal bliss”? Pharmacol. Biochem. Behav. 64, 257–260 (1999).

    Article  CAS  Google Scholar 

  11. Hill, H.E., Haertzen, C.A., Wolbach, A.B. & Miner, E.J. The addiction research center inventory: standardization of scales which evaluate subjective effects of morphine, amphetamine, pentobarbital, alcohol, LSD-25, pyrahexyl and chlorpromazine. Psychopharmacologia 65, 167–183 (1963).

    Article  Google Scholar 

  12. Schuster, C.R. & Johanson, C.E. Relationship between the discriminative stimulus properties and subjective effects of drugs. Psychopharmacol. Ser. 4, 161–175 (1988).

    CAS  PubMed  Google Scholar 

  13. Kamien, J.B., Bickel, W.K., Hughes, J.R., Higgins, S.T. & Smith, B.J. Drug discrimination by humans compared to nonhumans: current status and future directions. Psychopharmacology (Berl.) 111, 259–270 (1993).

    Article  CAS  Google Scholar 

  14. Colpaert, F.C. Drug discrimination: no evidence for tolerance to opiates. Pharmacol. Rev. 47, 605–629 (1995).

    CAS  PubMed  Google Scholar 

  15. Stolerman, I.P. & Jarvis, M.J. The scientific case that nicotine is addictive. Psychopharmacology (Berl.) 117, 2–10–discussion 14–20 (1995).

    Google Scholar 

  16. Stolerman, I.P. Components of drug dependence: reinforcement, discrimination and adaptation. Biochem. Soc. Symp. 59, 1–12 (1993).

    CAS  PubMed  Google Scholar 

  17. Koob, G.F. & Weiss, F. Pharmacology of drug self-administration. Alcohol 7, 193–197 (1990).

    Article  CAS  Google Scholar 

  18. Bardo, M.T. & : Bevins, R.A. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl.) 153, 31–43 (2000).

    Article  CAS  Google Scholar 

  19. Colpaert, F.C., Niemegeers, C.J., Lal, H. & Janssen, P.A. Investigations on drug produced and subjectively experienced discriminative stimuli. 2. Loperamide, an antidiarrheal devoid of narcotic cue producing actions. Life Sci. 16, 717–727 (1975).

    Article  CAS  Google Scholar 

  20. Gobbi, G. et al. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc. Natl. Acad. Sci. USA 102, 18620–18625 (2005).

    Article  CAS  Google Scholar 

  21. Di Chiara, G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav. Brain Res. 137, 75–114 (2002).

    Article  CAS  Google Scholar 

  22. Koob, G.F. Neurobiology of addiction. Toward the development of new therapies. Ann. NY Acad. Sci. 909, 170–185 (2000).

    Article  CAS  Google Scholar 

  23. Wise, R.A. Drug-activation of brain reward pathways. Drug Alcohol Depend. 51, 13–22 (1998).

    Article  CAS  Google Scholar 

  24. Barrett, R.L. & Appel, J.B. Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine. Psychopharmacology (Berl.) 99, 13–16 (1989).

    Article  CAS  Google Scholar 

  25. Munzar, P. & Goldberg, S.R. Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats. Psychopharmacology (Berl.) 148, 209–216 (2000).

    Article  CAS  Google Scholar 

  26. Munzar, P., Tanda, G., Justinova, Z. & Goldberg, S.R. Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology 29, 705–717 (2004).

    Article  CAS  Google Scholar 

  27. Justinova, Z. et al. Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats. J. Pharmacol. Exp. Ther. 307, 977–986 (2003).

    Article  CAS  Google Scholar 

  28. Solinas, M., Zangen, A., Thiriet, N. & Goldberg, S.R. Beta-endorphin elevations in the ventral tegmental area regulate the discriminative effects of delta-9-tetrahydrocannabinol. Eur. J. Neurosci. 19, 3183–3192 (2004).

    Article  CAS  Google Scholar 

  29. Solinas, M. & Goldberg, S.R. Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats. Psychopharmacology (Berl.) 179, 804–812 (2005).

    Article  CAS  Google Scholar 

  30. Solinas, M., Panlilio, L.V., Antoniou, K., Pappas, L.A. & Goldberg, S.R. The cannabinoid CB1 antagonist N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR-141716A) differentially alters the reinforcing effects of heroin under continuous reinforcement, fixed ratio, and progressive ratio schedules of drug self-administration in rats. J. Pharmacol. Exp. Ther. 306, 93–102 (2003).

    Article  CAS  Google Scholar 

  31. Corwin, R.L., Woolverton, W.L. & Schuster, C.R. Effects of cholecystokinin, d-amphetamine and fenfluramine in rats trained to discriminate 3 from 22 hr of food deprivation. J. Pharmacol. Exp. Ther. 253, 720–728 (1990).

    CAS  PubMed  Google Scholar 

  32. Benoit, S.C. & Davidson, T.L. Interoceptive sensory signals produced by 24-hr food deprivation, pharmacological glucoprivation, and lipoprivation. Behav. Neurosci. 110, 168–180 (1996).

    Article  CAS  Google Scholar 

  33. Weissman, A. The discriminability of apsirin in arthritic and nonarthritic rats. Pharmacol. Biochem. Behav. 5, 583–586 (1976).

    Article  CAS  Google Scholar 

  34. Colpaert, F.C., Niemegeers, C.J. & Janssen, P.A. Fentanyl and apomorphine: asymmetrical generalization of discriminative stimulus properties. Neuropharmacology 15, 541–545 (1976).

    Article  CAS  Google Scholar 

  35. Colpaert, F.C. Intrinsic activity and discriminative effects of drugs. Psychopharmacol. Ser. 4, 154–160 (1988).

    CAS  PubMed  Google Scholar 

  36. Colpaert, F.C. Discovering risperidone: the LSD model of psychopathology. Nat. Rev. Drug Discov. 2, 315–320 (2003).

    Article  CAS  Google Scholar 

  37. Yokel, R.A. & Pickens, R. Self-administration of optical isomers of amphetamine and methylamphetamine by rats. J. Pharmacol. Exp. Ther. 187, 27–33 (1973).

    CAS  PubMed  Google Scholar 

  38. Wise, R.A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology (Berl.) 120, 10–20 (1995).

    Article  CAS  Google Scholar 

  39. Wise, R.A., Leone, P., Rivest, R. & Leeb, K. Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration. Synapse 21, 140–148 (1995).

    Article  CAS  Google Scholar 

  40. Gerber, G.J. & Wise, R.A. Pharmacological regulation of intravenous cocaine and heroin self-administration in rats: a variable dose paradigm. Pharmacol. Biochem. Behav. 32, 527–531 (1989).

    Article  CAS  Google Scholar 

  41. Colpaert, F.C. Increased naloxone reversibility in fentanyl dose-dose discrimination. Eur. J. Pharmacol. 84, 229–231 (1982).

    Article  CAS  Google Scholar 

  42. Colpaert, F.C. & Janssen, P.A. OR discrimination: a new drug discrimination method. Eur. J. Pharmacol. 78, 141–144 (1982).

    Article  CAS  Google Scholar 

  43. Stolerman, I.P., Mariathasan, E.A., White, J.A. & Olufsen, K.S. Drug mixtures and ethanol as compound internal stimuli. Pharmacol. Biochem. Behav. 64, 221–228 (1999).

    Article  CAS  Google Scholar 

  44. Ahmed, S.H. & Koob, G.F. Transition from moderate to excessive drug intake: change in hedonic set point. Science 282, 298–300 (1998).

    Article  CAS  Google Scholar 

  45. Deroche-Gamonet, V., Belin, D. & Piazza, P.V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004).

    Article  CAS  Google Scholar 

  46. Vanderschuren, L.J. & Everitt, B.J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).

    Article  CAS  Google Scholar 

  47. Holtzman, S.G. Discriminative stimulus effects of morphine withdrawal in the dependent rat: suppression by opiate and nonopiate drugs. J. Pharmacol. Exp. Ther. 233, 80–86 (1985).

    CAS  PubMed  Google Scholar 

  48. Holtzman, S.G. Discrimination of a single dose of morphine followed by naltrexone: substitution of other agonists for morphine and other antagonists for naltrexone in a rat model of acute dependence. J. Pharmacol. Exp. Ther. 304, 1033–1041 (2003).

    Article  CAS  Google Scholar 

  49. Yasar, S., Schindler, C.W., Thorndike, E.B. & Goldberg, S.R. Evaluation of deprenyl for cocaine-like discriminative stimulus effects in rats. Eur. J. Pharmacol. 259, 243–250 (1994).

    Article  CAS  Google Scholar 

  50. Mastropaolo, J.P., Moskowitz, K.H., Dacanay, R.J. & Riley, A.L. Conditioned taste aversions as a behavioral baseline for drug discrimination learning: an assessment with phencyclidine. Pharmacol. Biochem. Behav. 32, 1–8 (1989).

    Article  CAS  Google Scholar 

  51. White, J.M. & Holtzman, S.G. Three-choice drug discrimination: phencyclidine-like stimulus effects of opioids. Psychopharmacology (Berl.) 80, 1–9 (1983).

    Article  CAS  Google Scholar 

  52. Swedberg, M.D. & Jarbe, T.U. Drug discrimination procedures: differential characteristics of the drug A vs drug B and the drug A vs drug B vs no drug cases. Psychopharmacology (Berl.) 90, 341–346 (1986).

    Article  CAS  Google Scholar 

  53. Overton, D.A. A historical perspective on drug discrimination. NIDA Res. Monogr. 5–24 (1991).

  54. Colpaert, F.C. The discriminative response: an elementary particle of behavior Commentary on Stolerman “Measures of stimulus generalization in drug discrimination experiments”. Behav. Pharmacol. 2, 283–286 (1991).

    Article  Google Scholar 

  55. Stolerman, I. Measures of stimulus generalization in drug discrimination experiments. Behav. Pharmacol. 2, 265–282 (1991).

    Article  Google Scholar 

  56. Stolerman, I.P. & Mariathasan, E.A. Nicotine trace discrimination in rats with midazolam as a mediating stimulus. Behav. Pharmacol. 14, 55–66 (2003).

    Article  CAS  Google Scholar 

  57. Stolerman, I.P., Childs, E., Hahn, B. & Morley, A. Drug trace discrimination with nicotine and morphine in rats. Behav. Pharmacol. 13, 49–58 (2002).

    Article  CAS  Google Scholar 

  58. Colpaert, F.C., Niemegeers, C.J. & Janssen, P.A. Differential haloperidol effect on two indices of fentanyl-saline discrimination. Psychopharmacology (Berl.) 53, 169–173 (1977).

    Article  CAS  Google Scholar 

  59. Yasar, S. & Bergman, J. Amphetamine-like effect of l-deprenyl (selegiline) in drug discrimination studies. Clin. Pharmacol. Ther. 56, 768–773 (1994).

    Article  CAS  Google Scholar 

  60. Mattson, M.P., Duan, W. & Guo, Z. Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. J. Neurochem. 84, 417–431 (2003).

    Article  CAS  Google Scholar 

  61. Ghozland, S. et al. Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J. Neurosci. 22, 1146–1154 (2002).

    Article  CAS  Google Scholar 

  62. Jarbe, T.U., Lamb, R.J., Makriyannis, A., Lin, S. & Goutopoulos, A. Delta9-THC training dose as a determinant for (R)-methanandamide generalization in rats. Psychopharmacology (Berl.) 140, 519–522 (1998).

    Article  CAS  Google Scholar 

  63. Jarbe, T.U., Lamb, R.J., Lin, S. & Makriyannis, A. Delta9-THC training dose as a determinant for (R)-methanandamide generalization in rats: a systematic replication. Behav. Pharmacol. 11, 81–86 (2000).

    Article  CAS  Google Scholar 

  64. Colombo, G. et al. T-maze and food reinforcement: an inexpensive drug discrimination procedure. J. Neurosci. Methods 67, 83–87 (1996).

    Article  CAS  Google Scholar 

  65. Extance, K. & Goudie, A.J. Inter-animal olfactory cues in operant drug discrimination procedures in rats. Psychopharmacology (Berl) 73, 363–371 (1981).

    Article  CAS  Google Scholar 

  66. Powell, K.R., Koppelman, L.F. & Holtzman, S.G. Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats. Behav. Pharmacol. 10, 707–716 (1999).

    Article  CAS  Google Scholar 

  67. Solinas, M. et al. Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats. Psychopharmacology (Berl.) 179, 576–586 (2005).

    Article  CAS  Google Scholar 

  68. Mumford, G.K. & Holtzman, S.G. Qualitative differences in the discriminative stimulus effects of low and high doses of caffeine in the rat. J. Pharmacol. Exp. Ther. 258, 857–865 (1991).

    CAS  PubMed  Google Scholar 

  69. Holtzman, S.G. Discriminative stimulus properties of caffeine in the rat: noradrenergic mediation. J. Pharmacol. Exp. Ther. 239, 706–714 (1986).

    CAS  PubMed  Google Scholar 

  70. Munzar, P., Justinova, Z., Kutkat, S.W., Ferre, S. & Goldberg, S.R. Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats. Psychopharmacology (Berl.) 161, 348–355 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, and Department of Health and Human Services, by the Centre National de la Recherche Scientifique, the University of Maryland School of Medicine, and by Johns Hopkins University School of Medicine. We thank J. Eaton for preparation of Figure 1.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Marcello Solinas or Steven R Goldberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Solinas, M., Panlilio, L., Justinova, Z. et al. Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1, 1194–1206 (2006). https://doi.org/10.1038/nprot.2006.167

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2006.167

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing