Skip to main content

Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs

  • Chapter
  • First Online:
The Behavioral Neuroscience of Drug Discrimination

Abstract

Drug-discrimination procedures empirically evaluate the control that internal drug states have over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs in vivo. As a result, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This chapter provides a basic overview of human drug-discrimination procedures and reviews the extant literature concerning the use of these procedures to elucidate the underlying neuropharmacological mechanisms of commonly abused illicit drugs (i.e., stimulants, opioids, and cannabis) in humans. This chapter is not intended to review every available study that used drug-discrimination procedures in humans. Instead, when possible, exemplary studies that used a stimulant, opioid, or Δ9-tetrahydrocannabinol (the primary psychoactive constituent of cannabis) to assess the discriminative-stimulus effects of drugs in humans are reviewed for illustrative purposes. We conclude by commenting on the current state and future of human drug-discrimination research.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

References

  1. Conger JJ (1951) The effects of alcohol on conflict behavior in the albino rat. Q J Stud Alcohol 12(1):1–29. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14828044

  2. Porter JH, Prus AJ (2009) Drug discrimination: 30 years of progress. Psychopharmacology (Berl) 203(2):189–191. doi:10.1007/s00213-009-1478-7

    Article  CAS  PubMed  Google Scholar 

  3. Preston KL (1991) Drug discrimination methods in human drug abuse liability evaluation. Br J Addict 86(12):1587–1594. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1786491

  4. Jellinek EM (1946) Role of the placebo in tests for drug discrimination. Fed Proc 5(1 Pt 2):184. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21064408

  5. Preston KL, Bigelow GE (1991) Subjective and discriminative effects of drugs. Behav Pharmacol 2(4 and 5):293–313. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11224073

  6. Schuster CR, Fischman MW, Johanson CE (1981) Internal stimulus control and subjective effects of drugs. NIDA Res Monogr 37:116–129. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6798454

  7. Schuster CR, Johanson CE (1988) Relationship between the discriminative stimulus properties and subjective effects of drugs. Psychopharmacol Ser 4:161–175. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3293041

  8. Kamien JB, Bickel WK, Hughes JR, Higgins ST, Smith BJ (1993) Drug discrimination by humans compared to nonhumans: current status and future directions. Psychopharmacology (Berl) 111(3):259–270. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7870962

  9. Kelly TH, Stoops WW, Perry AS, Prendergast MA, Rush CR (2003) Clinical neuropharmacology of drugs of abuse: a comparison of drug-discrimination and subject-report measures. Behav Cogn Neurosci Rev 2(4):227–260. doi:10.1177/1534582303262095

    Article  PubMed  Google Scholar 

  10. Rush CR, Critchfield TS, Troisi JR, Griffiths RR (1995) Discriminative stimulus effects of diazepam and buspirone in normal volunteers. J Exp Anal Behav 63(3):277–294. doi:10.1901/jeab.1995.63-277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Silverman K, Griffiths RR (1992) Low-dose caffeine discrimination and self-reported mood effects in normal volunteers. J Exp Anal Behav 57(1):91–107. doi:10.1901/jeab.1992.57-91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lile JA, Stoops WW, Glaser PE, Hays LR, Rush CR (2011) Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans. J Psychopharmacol 25(11):1469–1479. doi:10.1177/0269881110385597

    Article  CAS  PubMed  Google Scholar 

  13. Oliveto A, Mancino M, Sanders N, Cargile C, Benjamin Guise J, Bickel W, Brooks Gentry W (2013) Effects of prototypic calcium channel blockers in methadone-maintained humans responding under a naloxone discrimination procedure. Eur J Pharmacol 715(1–3):424–435. doi:10.1016/j.ejphar.2013.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Preston KL, Bigelow GE, Bickel WK, Liebson IA (1989) Drug discrimination in human postaddicts: agonist–antagonist opioids. J Pharmacol Exp Ther 250(1):184–196. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2473187

  15. Brauer LH, Goudie AJ, de Wit H (1997) Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data. Psychopharmacology (Berl) 130(1):2–13. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9089844

  16. Rush CR, Kelly TH, Hays LR, Wooten AF (2002) Discriminative-stimulus effects of modafinil in cocaine-trained humans. Drug Alcohol Depend 67(3):311–322. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12127202

  17. Sevak RJ, Stoops WW, Hays LR, Rush CR (2009) Discriminative stimulus and subject-rated effects of methamphetamine, d-amphetamine, methylphenidate, and triazolam in methamphetamine-trained humans. J Pharmacol Exp Ther 328(3):1007–1018. doi:10.1124/jpet.108.147124

    Article  CAS  PubMed  Google Scholar 

  18. Kelly TH, Emurian CS, Baseheart BJ, Martin CA (1997) Discriminative stimulus effects of alcohol in humans. Drug Alcohol Depend 48(3):199–207. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9449019

  19. McMahon LR (2015) The rise (and fall?) of drug discrimination research. Drug Alcohol Depend 151:284–288. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26207268

  20. Colpaert FC (1999) Drug discrimination in neurobiology. Pharmacol Biochem Behav 64(2):337–345. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10515310

  21. Holtzman SG, Locke KW (1988) Neural mechanisms of drug stimuli: experimental approaches. Psychopharmacol Ser 4:138–153. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3293038

  22. Huskinson SL, Naylor JE, Rowlett JK, Freeman KB (2014) Predicting abuse potential of stimulants and other dopaminergic drugs: overview and recommendations. Neuropharmacology 87:66–80. doi:10.1016/j.neuropharm.2014.03.009

    Article  CAS  PubMed  Google Scholar 

  23. Substance Abuse and Mental Health Services Administration (2014) Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings (NSDUH Series H-48, HHS Publication No. (SMA) 14-4863). Substance Abuse and Mental Health Services Administration, Rockville

    Google Scholar 

  24. Fleckenstein AE, Gibb JW, Hanson GR (2000) Differential effects of stimulants on monoaminergic transporters: pharmacological consequences and implications for neurotoxicity. Eur J Pharmacol 406(1):1–13. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11011026

  25. Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41(1):3–52. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2682679

  26. Rothman RB, Glowa JR (1995) A review of the effects of dopaminergic agents on humans, animals, and drug-seeking behavior, and its implications for medication development. Focus on GBR 12909. Mol Neurobiol 11(1–3):1–19. doi:10.1007/BF02740680

    Article  CAS  PubMed  Google Scholar 

  27. Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–677. doi:10.1146/annurev.pa.33.040193.003231

    Article  CAS  PubMed  Google Scholar 

  28. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39(1):32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3

    Article  CAS  PubMed  Google Scholar 

  29. Heal DJ, Gosden J, Smith SL (2014) Dopamine reuptake transporter (DAT) “inverse agonism” – a novel hypothesis to explain the enigmatic pharmacology of cocaine. Neuropharmacology 87:19–40. doi:10.1016/j.neuropharm.2014.06.012

    Article  CAS  PubMed  Google Scholar 

  30. Barrett RL, Appel JB (1989) Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine. Psychopharmacology (Berl) 99(1):13–16. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2528777

  31. Callahan PM, Appel JB, Cunningham KA (1991) Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine. Psychopharmacology (Berl) 103(1):50–55. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2006243

  32. Callahan PM, Bryan SK, Cunningham KA (1995) Discriminative stimulus effects of cocaine: antagonism by dopamine D1 receptor blockade in the amygdala. Pharmacol Biochem Behav 51(4):759–766. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7675856

  33. Callahan PM, Cunningham KA (1995) Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors. J Pharmacol Exp Ther 274(3):1414–1424. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7562516

  34. Colpaert FC, Niemegeers CJ, Janssen PA (1979) Discriminative stimulus properties of cocaine: neuropharmacological characteristics as derived from stimulus generalization experiments. Pharmacol Biochem Behav 10(4):535–546. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/37526

  35. Johanson CE, Barrett JE (1993) The discriminative stimulus effects of cocaine in pigeons. J Pharmacol Exp Ther 267(1):1–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8229735

  36. Spealman RD (1995) Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 275(1):53–62. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7562595

  37. Spealman RD, Bergman J, Madras BK, Melia KF (1991) Discriminative stimulus effects of cocaine in squirrel monkeys: involvement of dopamine receptor subtypes. J Pharmacol Exp Ther 258(3):945–953. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1679852

  38. Terry P, Witkin JM, Katz JL (1994) Pharmacological characterization of the novel discriminative stimulus effects of a low dose of cocaine. J Pharmacol Exp Ther 270(3):1041–1048. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7932151

  39. Chait LD, Uhlenhuth EH, Johanson CE (1986) The discriminative stimulus and subjective effects of d-amphetamine, phenmetrazine and fenfluramine in humans. Psychopharmacology (Berl) 89(3):301–306. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3088654

  40. Cauli O, Pinna A, Valentini V, Morelli M (2003) Subchronic caffeine exposure induces sensitization to caffeine and cross-sensitization to amphetamine ipsilateral turning behavior independent from dopamine release. Neuropsychopharmacology 28(10):1752–1759. doi:10.1038/sj.npp.1300240

    Article  CAS  PubMed  Google Scholar 

  41. Garrett BE, Griffiths RR (1997) The role of dopamine in the behavioral effects of caffeine in animals and humans. Pharmacol Biochem Behav 57(3):533–541. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9218278

  42. Chait LD, Johanson CE (1988) Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers. Psychopharmacology (Berl) 96(3):302–308. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3146764

  43. Chait LD, Uhlenhuth EH, Johanson CE (1984) An experimental paradigm for studying the discriminative stimulus properties of drugs in humans. Psychopharmacology (Berl) 82(3):272–274. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6425913

  44. Chait LD, Uhlenhuth EH, Johanson CE (1985) The discriminative stimulus and subjective effects of d-amphetamine in humans. Psychopharmacology (Berl) 86(3):307–312. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3929301

  45. Chait LD, Uhlenhuth EH, Johanson CE (1986) The discriminative stimulus and subjective effects of phenylpropanolamine, mazindol and d-amphetamine in humans. Pharmacol Biochem Behav 24(6):1665–1672. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3737634

  46. Heishman SJ, Henningfield JE (1991) Discriminative stimulus effects of d-amphetamine, methylphenidate, and diazepam in humans. Psychopharmacology (Berl) 103(4):436–442. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2062984

  47. Kollins SH, Rush CR (1999). Effects of training dose on the relationship between discriminative-stimulus and self-reported drug effects of d-amphetamine in humans. Pharmacol Biochem Behav 64(2):319–326. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10515308

  48. Lamb RJ, Henningfield JE (1994) Human d-amphetamine drug discrimination: methamphetamine and hydromorphone. J Exp Anal Behav 61(2):169–180. doi:10.1901/jeab.1994.61-169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rush CR, Kollins SH, Pazzaglia PJ (1998) Discriminative-stimulus and participant-rated effects of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans. Exp Clin Psychopharmacol 6(1):32–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9526144

  50. Rush CR, Stoops WW, Hays LR, Glaser PE, Hays LS (2003) Risperidone attenuates the discriminative-stimulus effects of d-amphetamine in humans. J Pharmacol Exp Ther 306(1):195–204. doi:10.1124/jpet.102.048439

    Article  CAS  PubMed  Google Scholar 

  51. Akaoka H, Roussel B, Lin JS, Chouvet G, Jouvet M (1991) Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity. Neurosci Lett 123(1):20–22. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1676498

  52. Ferraro L, Antonelli T, O’Connor WT, Tanganelli S, Rambert FA, Fuxe K (1997) Modafinil: an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry 42(12):1181–1183. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9426889

  53. Desai RI, Paronis CA, Martin J, Desai R, Bergman J (2010) Monoaminergic psychomotor stimulants: discriminative stimulus effects and dopamine efflux. J Pharmacol Exp Ther 333(3):834–843. doi:10.1124/jpet.110.165746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Baumann MH, Ayestas MA, Sharpe LG, Lewis DB, Rice KC, Rothman RB (2002) Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate. J Pharmacol Exp Ther 301(3):1190–1197. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12023554

  55. Howell LL, Kimmel HL (2008) Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 75(1):196–217. doi:10.1016/j.bcp.2007.08.003

    Article  CAS  PubMed  Google Scholar 

  56. Baker LE, Riddle EE, Saunders RB, Appel JB (1993) The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds. Behav Pharmacol 4(1):69–79. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11224173

  57. Broadbent J, Michael EK, Riddle EE, Apple JB (1991) Involvement of dopamine uptake in the discriminative stimulus effects of cocaine. Behav Pharmacol 2(3):187–197. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11224062

  58. Cunningham KA, Callahan PM (1991) Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat. Psychopharmacology (Berl) 104(2):177–180. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1831559

  59. Callahan PM, Cunningham KA (1993) Discriminative stimulus properties of cocaine in relation to dopamine D2 receptor function in rats. J Pharmacol Exp Ther 266(2):585–592. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8355192

  60. Stoops WW, Glaser PE, Rush CR (2009) Discriminative-stimulus effects of d-amphetamine following pretreatment with fluphenazine. Unpublished data

    Google Scholar 

  61. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302(1):381–389. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12065741

  62. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28(8):1400–1411. doi:10.1038/sj.npp.1300203

  63. Lile JA, Stoops WW, Vansickel AR, Glaser PE, Hays LR, Rush CR (2005) Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of D-amphetamine in humans. Neuropsychopharmacology 30(11):2103–2114. doi:10.1038/sj.npp.1300803

    Article  CAS  PubMed  Google Scholar 

  64. Exner M, Clark D (1992) Agonist and antagonist activity of low efficacy D2 dopamine receptor agonists in rats discriminating d-amphetamine from saline. Behav Pharmacol 3(6):609–619. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11224162

  65. Rush CR, Stoops WW, Wagner FP, Hays LR, Glaser PE (2004) Alprazolam attenuates the behavioral effects of d-amphetamine in humans. J Clin Psychopharmacol 24(4):410–420. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15232333

  66. Sevak RJ, Vansickel AR, Stoops WW, Glaser PE, Hays LR, Rush CR (2011) Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole. J Clin Psychopharmacol 31(4):470–480. doi:10.1097/JCP.0b013e318221b2db

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Vansickel AR, Stoops WW, Glaser PE, Rush CR (2009) Discriminative-stimulus effects of methamphetamine following pretreatment with d-amphetamine. Unpublished data

    Google Scholar 

  68. Vansickel AR, Stoops WW, Glaser PE, Rush CR (2009) Discriminative-stimulus effects of methamphetamine following pretreatment with bupropion. Unpublished data

    Google Scholar 

  69. Mechanic JA, Wasielewski JA, Carl KL, Holloway FA (2002) Attenuation of the amphetamine discriminative cue in rats with the atypical antipsychotic olanzapine. Pharmacol Biochem Behav 72(4):767–777. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12062565

  70. Tidey JW, Bergman J (1998) Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs. J Pharmacol Exp Ther 285(3):1163–1174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9618419

  71. Czoty PW, Ramanathan CR, Mutschler NH, Makriyannis A, Bergman J (2004) Drug discrimination in methamphetamine-trained monkeys: effects of monoamine transporter inhibitors. J Pharmacol Exp Ther 311(2):720–727. doi:10.1124/jpet.104.071035

    Article  CAS  PubMed  Google Scholar 

  72. Dewey SL, Chaurasia CS, Chen CE, Volkow ND, Clarkson FA, Porter SP, Straughter-Moore RM, Alexoff DL, Tedeschi D, Russo NB, Fowler JS, Brodie JD (1997) GABAergic attenuation of cocaine-induced dopamine release and locomotor activity. Synapse 25(4):393–398. doi:10.1002/(SICI)1098-2396(199704)25:4<393::AID-SYN11>3.0.CO;2-W

  73. Kalivas PW, Duffy P, Eberhardt H (1990) Modulation of A10 dopamine neurons by gamma-aminobutyric acid agonists. J Pharmacol Exp Ther 253(2):858–866. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2160011

  74. Kita H, Kitai ST (1988) Glutamate decarboxylase immunoreactive neurons in rat neostriatum: their morphological types and populations. Brain Res 447(2):346–352. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3390703

  75. Zetterstrom T, Fillenz M (1990) Local administration of flurazepam has different effects on dopamine release in striatum and nucleus accumbens: a microdialysis study. Neuropharmacology 29(2):129–134. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2109839

  76. Druhan JP, Fibiger HC, Phillips AG (1991) Influence of some drugs of abuse on the discriminative stimulus properties of amphetamine. Behav Pharmacol 2(4 and 5):391–403. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11224082

  77. Rush CR, Vansickel AR, Stoops WW (2011) Human drug discrimination: methodological considerations and application to elucidating the neuropharmacology of amphetamines. In: Glennon RA, Young R (eds) Drug discrimination: applications to medicinal chemistry and drug studies. Wiley, Hoboken

    Google Scholar 

  78. Klee H, Wright S, Carnwath T, Merrill J (2001) The role of substitute therapy in the treatment of problem amphetamine use. Drug Alcohol Rev 20:417–429

    Article  Google Scholar 

  79. Shearer J, Sherman J, Wodak A, van Beek I (2002) Substitution therapy for amphetamine users. Drug Alcohol Rev 21(2):179–185. doi:10.1080/09595230220139082

    Article  PubMed  Google Scholar 

  80. Shearer J, Wodak A, Mattick RP, Van Beek I, Lewis J, Hall W, Dolan K (2001) Pilot randomized controlled study of dexamphetamine substitution for amphetamine dependence. Addiction 96(9):1289–1296. doi:10.1080/09652140120070346

    Article  CAS  PubMed  Google Scholar 

  81. Tiihonen J, Kuoppasalmi K, Fohr J, Tuomola P, Kuikanmaki O, Vorma H, Sokero P, Haukka J, Meririnne E (2007) A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am J Psychiatry 164(1):160–162. doi:10.1176/ajp.2007.164.1.160

  82. de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl) 75(2):134–143. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6798603

  83. Stoops WW, Rush CR (2014) Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research. Expert Rev Clin Pharmacol 7(3):363–374. doi:10.1586/17512433.2014.909283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Janecka A, Fichna J, Janecki T (2004) Opioid receptors and their ligands. Curr Top Med Chem 4(1):1–17. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14754373

  85. Waldhoer M, Bartlett SE, Whistler JL (2004) Opioid receptors. Annu Rev Biochem 73:953–990. doi:10.1146/annurev.biochem.73.011303.073940

    Article  CAS  PubMed  Google Scholar 

  86. Borg L, Kreek MJ (1998) Pharmacology of opiates. In: Tarter RE, Ammerman RO, Peggy J (eds) Handbook of substance abuse. Springer, New York, pp 331–341

    Chapter  Google Scholar 

  87. Mello NK, Mendelson JH, Bree MP (1981) Naltrexone effects on morphine and food self-administration in morphine-dependent rhesus monkeys. J Pharmacol Exp Ther 218(2):550–557. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7195937

  88. Sullivan MA, Vosburg SK, Comer SD (2006) Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin. Psychopharmacology (Berl) 189(1):37–46. doi:10.1007/s00213-006-0509-x

    Article  CAS  PubMed  Google Scholar 

  89. Walsh SL, Sullivan JT, Preston KL, Garner JE, Bigelow GE (1996) Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans. J Pharmacol Exp Ther 279(2):524–538. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8930154

  90. Baldauf K, Braun K, Gruss M (2005) Opiate modulation of monoamines in the chick forebrain: possible role in emotional regulation? J Neurobiol 62(2):149–163. doi:10.1002/neu.20076

    Article  CAS  PubMed  Google Scholar 

  91. Chefer VI, Denoroy L, Zapata A, Shippenberg TS (2009) Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanisms. Eur J Neurosci 30(2):272–278. doi:10.1111/j.1460-9568.2009.06827.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vaughan CW, Ingram SL, Connor MA, Christie MJ (1997) How opioids inhibit GABA-mediated neurotransmission. Nature 390(6660):611–614. doi:10.1038/37610

    Article  CAS  PubMed  Google Scholar 

  93. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci 28(2):407–414. doi:10.1523/JNEUROSCI.4458-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI (2004) Agonist-specific regulation of the delta-opioid receptor. Life Sci 76(6):599–612. doi:10.1016/j.lfs.2004.07.020

    Article  CAS  PubMed  Google Scholar 

  95. Bickel WK, Bigelow GE, Preston KL, Liebson IA (1989) Opioid drug discrimination in humans: stability, specificity and relation to self-reported drug effect. J Pharmacol Exp Ther 251(3):1053–1063. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2481029

  96. Duke AN, Bigelow GE, Lanier RK, Strain EC (2011) Discriminative stimulus effects of tramadol in humans. J Pharmacol Exp Ther 338(1):255–262. doi:10.1124/jpet.111.181131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jones HE, Bigelow GE, Preston KL (1999) Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure. J Pharmacol Exp Ther 289(3):1350–1361. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10336526

  98. Preston KL, Bigelow GE (1994) Drug discrimination assessment of agonist–antagonist opioids in humans: a three-choice saline-hydromorphone-butorphanol procedure. J Pharmacol Exp Ther 271(1):48–60. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7525929

  99. Preston KL, Bigelow GE (1998) Opioid discrimination in humans: discriminative and subjective effects of progressively lower training dose. Behav Pharmacol 9(7):533–543. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9862079

  100. Preston KL, Bigelow GE (2000) Effects of agonist–antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination. J Pharmacol Exp Ther 295(1):114–124. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10991968

  101. Preston KL, Bigelow GE, Bickel W, Liebson IA (1987) Three-choice drug discrimination in opioid-dependent humans: hydromorphone, naloxone and saline. J Pharmacol Exp Ther 243(3):1002–1009. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2447262

  102. Preston KL, Bigelow GE, Liebson IA (1990) Discrimination of butorphanol and nalbuphine in opioid-dependent humans. Pharmacol Biochem Behav 37(3):511–522. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1708145

  103. Preston KL, Liebson IA, Bigelow GE (1992) Discrimination of agonist–antagonist opioids in humans trained on a two-choice saline-hydromorphone discrimination. J Pharmacol Exp Ther 261(1):62–71. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1373189

  104. Strickland JC, Rush CR, Stoops WW (2015) Mu opioid mediated discriminative-stimulus effects of tramadol: an individual subjects analysis. J Exp Anal Behav 103(2):361–374. doi:10.1002/jeab.137

    Article  PubMed  Google Scholar 

  105. Morgan D, Picker MJ (1998) The mu opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the mu opioid receptor. Psychopharmacology (Berl) 140(1):20–28. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9862398

  106. Picker MJ, Yarbrough J, Hughes CE, Smith MA, Morgan D, Dykstra LA (1993) Agonist and antagonist effects of mixed action opioids in the pigeon drug discrimination procedure: influence of training dose, intrinsic efficacy and interanimal differences. J Pharmacol Exp Ther 266(2):756–767. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8394915

  107. Beardsley PM, Aceto MD, Cook CD, Bowman ER, Newman JL, Harris LS (2004) Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys. Exp Clin Psychopharmacol 12(3):163–172. doi:10.1037/1064-1297.12.3.163

    Article  CAS  PubMed  Google Scholar 

  108. Morgan D, Cook CD, Picker MJ (1999) Sensitivity to the discriminative stimulus and antinociceptive effects of mu opioids: role of strain of rat, stimulus intensity, and intrinsic efficacy at the mu opioid receptor. J Pharmacol Exp Ther 289(2):965–975. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10215676

  109. Shannon HE, Holtzman SG (1977) Further evaluation of the discriminative effects of morphine in the rat. J Pharmacol Exp Ther 201(1):55–66. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15104

  110. Shannon HE, Holtzman SG (1977) Discriminative effects of morphine administered intracerebrally in the rat. Life Sci 21(4):585–594. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/904437

  111. Shannon HE, Holtzman SG (1979) Morphine training dose: a determinant of stimulus generalization to narcotic antagonists in the rat. Psychopharmacology (Berl) 61(3):239–244. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/156379

  112. Platt DM, Rowlett JK, Izenwasser S, Spealman RD (2004) Opioid partial agonist effects of 3-O-methylnaltrexone in rhesus monkeys. J Pharmacol Exp Ther 308(3):1030–1039. doi:10.1124/jpet.103.060962

    Article  CAS  PubMed  Google Scholar 

  113. Platt DM, Rowlett JK, Spealman RD (2001) Discriminative stimulus effects of intravenous heroin and its metabolites in rhesus monkeys: opioid and dopaminergic mechanisms. J Pharmacol Exp Ther 299(2):760–767. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11602692

  114. Oliveto AH, Rosen MI, Kosten TA, Hameedi FA, Woods SW, Kosten TR (1998) Hydromorphone-naloxone combinations in opioid-dependent humans under a naloxone novel-response discrimination procedure. Exp Clin Psychopharmacol 6(2):169–178. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9608349

  115. France CP, Jacobson AE, Woods JH (1984) Discriminative stimulus effects of reversible and irreversible opiate agonists: morphine, oxymorphazone and buprenorphine. J Pharmacol Exp Ther 230(3):652–657. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6206224

  116. Bowen CA, Fischer BD, Mello NK, Negus SS (2002) Antagonism of the antinociceptive and discriminative stimulus effects of heroin and morphine by 3-methoxynaltrexone and naltrexone in rhesus monkeys. J Pharmacol Exp Ther 302(1):264–273. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12065726

  117. Bailey CP, Connor M (2005) Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol 5(1):60–68. doi:10.1016/j.coph.2004.08.012

    Article  CAS  PubMed  Google Scholar 

  118. Ashton CH (2001) Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 178:101–106. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11157422

  119. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284):561–564. doi:10.1038/346561a0

    Article  CAS  PubMed  Google Scholar 

  120. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441):61–65. doi:10.1038/365061a0

    Article  CAS  PubMed  Google Scholar 

  121. Onaivi ES (2006) Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. Neuropsychobiology 54(4):231–246. doi:10.1159/000100778

    Article  CAS  PubMed  Google Scholar 

  122. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74(2):129–180. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9336020

  123. Pertwee RG (2006) The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 30(Suppl 1): S13–S18. doi:10.1038/sj.ijo.0803272

  124. Compton DR, Rice KC, De Costa BR, Razdan RK, Melvin LS, Johnson MR, Martin BR (1993) Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. J Pharmacol Exp Ther 265(1):218–226. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8474008

  125. Breivogel CS, Childers SR (1998) The functional neuroanatomy of brain cannabinoid receptors. Neurobiol Dis 5(6 Pt B):417–431. doi:10.1006/nbdi.1998.0229

  126. Järbe TU, Liu Q, Makriyannis A (2006) Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats. Psychopharmacology (Berl) 184(1):36–45. doi:10.1007/s00213-005-0225-y

    Article  CAS  PubMed  Google Scholar 

  127. McMahon LR (2006) Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol. Psychopharmacology (Berl) 188(3):306–314. doi:10.1007/s00213-006-0500-6

    Article  CAS  PubMed  Google Scholar 

  128. Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, Mark L, Pearson MS, Miller W, Shan S, Rabadi L, Rotshteyn Y, Chaffer SM, Turchin PI, Elsemore DA, Toth M, Koetzner L, Whiteside GT (2005) Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48(5):658–672. doi:10.1016/j.neuropharm.2004.12.008

  129. Compton DR, Aceto MD, Lowe J, Martin BR (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Ther 277(2):586–594. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8627535

  130. Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58(4):322–328. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11296091

  131. Järbe TU, Lamb RJ, Liu Q, Makriyannis A (2006) Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Delta9-THC or (R)-methanandamide (AM-356). Psychopharmacology (Berl) 188(3):315–323. doi:10.1007/s00213-006-0517-x

    Article  CAS  PubMed  Google Scholar 

  132. Zuurman L, Roy C, Schoemaker RC, Amatsaleh A, Guimaeres L, Pinquier JL, Cohen AF, van Gerven JM (2010) Inhibition of THC-induced effects on the central nervous system and heart rate by a novel CB1 receptor antagonist AVE1625. J Psychopharmacol 24(3):363–371. doi:10.1177/0269881108096509

  133. Szabo B, Schlicker E (2005) Effects of cannabinoids on neurotransmission. Handb Exp Pharmacol (168):327–365. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16596780

  134. Chait LD, Evans SM, Grant KA, Kamien JB, Johanson CE, Schuster CR (1988) Discriminative stimulus and subjective effects of smoked marijuana in humans. Psychopharmacology (Berl) 94(2) 206–212. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3127846

  135. Lile JA, Kelly TH, Hays LR (2010) Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating delta9-tetrahydrocannabinol. Clin Neuropharmacol 33(5):235–242. doi:10.1097/WNF.0b013e3181e77428

    Article  CAS  PubMed  Google Scholar 

  136. Lile JA, Kelly TH, Hays LR (2011) Separate and combined effects of the cannabinoid agonists nabilone and Delta(9)-THC in humans discriminating Delta(9)-THC. Drug Alcohol Depend 116(1–3):86–92. doi:10.1016/j.drugalcdep.2010.11.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lile JA, Kelly TH, Hays LR (2012) Separate and combined effects of the GABA reuptake inhibitor tiagabine and Delta9-THC in humans discriminating Delta9-THC. Drug Alcohol Depend 122(1–2):61–69. doi:10.1016/j.drugalcdep.2011.09.010

    Article  CAS  PubMed  Google Scholar 

  138. Lile JA, Kelly TH, Hays LR (2012) Separate and combined effects of the GABA(B) agonist baclofen and Delta9-THC in humans discriminating Delta9-THC. Drug Alcohol Depend 126(1–2):216–223. doi:10.1016/j.drugalcdep.2012.05.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lile JA, Kelly TH, Hays LR (2014) Separate and combined effects of the GABAA positive allosteric modulator diazepam and Delta(9)-THC in humans discriminating Delta(9)-THC. Drug Alcohol Depend 143:141–148. doi:10.1016/j.drugalcdep.2014.07.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lile JA, Kelly TH, Pinsky DJ, Hays LR (2009) Substitution profile of Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Delta9-tetrahydrocannabinol. Psychopharmacology (Berl) 203(2):241–250. doi:10.1007/s00213-008-1393-3

    Article  CAS  PubMed  Google Scholar 

  141. Lile JA, Wesley MJ, Kelly TH, Hays LR (2015) Separate and combined effects of gabapentin and Delta(9)-tetrahydrocananbinol in humans discriminating Delta(9)-tetrahydrocananbinol. Behav Pharmacol. doi:10.1097/FBP.0000000000000187

    Article  Google Scholar 

  142. De Vry J, Jentzsch KR (2003) Intrinsic activity estimation of cannabinoid CB1 receptor ligands in a drug discrimination paradigm. Behav Pharmacol 14(5–6):471–476. doi:10.1097/01.fbp.0000087739.21047.d8

    Article  CAS  PubMed  Google Scholar 

  143. Järbe TU, Li C, Vadivel SK, Makriyannis A (2010) Discriminative stimulus functions of methanandamide and delta(9)-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol. Psychopharmacology (Berl) 208(1):87–98. doi:10.1007/s00213-009-1708-z

    Article  CAS  PubMed  Google Scholar 

  144. Järbe TU, Tai S, LeMay BJ, Nikas SP, Shukla VG, Zvonok A, Makriyannis A (2012) AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice. Psychopharmacology (Berl) 220(2):417–426. doi:10.1007/s00213-011-2491-1

    Article  CAS  PubMed  Google Scholar 

  145. Browne RG, Weissman A (1981) Discriminative stimulus properties of delta 9-tetrahydrocannabinol: mechanistic studies. J Clin Pharmacol 21(8–9 Suppl):227S–234S. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6271828

  146. Järbe TU, Hiltunen AJ (1988) Limited stimulus generalization between delta 9-THC and diazepam in pigeons and gerbils. Psychopharmacology (Berl) 94(3):328–331. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2833760

  147. Solinas M, Goldberg SR (2005) Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats. Psychopharmacology (Berl) 179(4):804–812. doi:10.1007/s00213-004-2118-x

    Article  CAS  PubMed  Google Scholar 

  148. Solinas M, Zangen A, Thiriet N, Goldberg SR (2004) Beta-endorphin elevations in the ventral tegmental area regulate the discriminative effects of Delta-9-tetrahydrocannabinol. Eur J Neurosci 19(12):3183–3192. doi:10.1111/j.0953-816X.2004.03420.x

    Article  CAS  PubMed  Google Scholar 

  149. Wiley JL, Huffman JW, Balster RL, Martin BR (1995) Pharmacological specificity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rhesus monkeys. Drug Alcohol Depend 40(1):81–86. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8746928

  150. Bueno OF, Carlini EA, Finkelfarb E, Suzuki JS (1976) Delta 9-Tetrahydrocannabinol, ethanol, and amphetamine as discriminative stimuli-generalization tests with other drugs. Psychopharmacologia 46(3):235–243. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/951459

  151. Barrett RL, Wiley JL, Balster RL, Martin BR (1995) Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats. Psychopharmacology (Berl) 118(4), 419–424. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7568628

  152. Mokler DJ, Nelson BD, Harris LS, Rosecrans JA (1986) The role of benzodiazepine receptors in the discriminative stimulus properties of delta-9-tetrahydrocannabinol. Life Sci 38(17):1581–1589. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3010019

  153. Wiley JL, Martin BR (1999) Effects of SR141716A on diazepam substitution for delta9-tetrahydrocannabinol in rat drug discrimination. Pharmacol Biochem Behav 64(3):519–522. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10548265

  154. Järbe TU, Gifford RS, Makriyannis A (2010) Antagonism of (9)-THC induced behavioral effects by rimonabant: time course studies in rats. Eur J Pharmacol 648(1–3):133–138. doi:10.1016/j.ejphar.2010.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Järbe TU, LeMay BJ, Halikhedkar A, Wood J, Vadivel SK, Zvonok A, Makriyannis A (2014) Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats. Psychopharmacology (Berl) 231(3):489–500. doi:10.1007/s00213-013-3257-8

    Article  CAS  PubMed  Google Scholar 

  156. Wiley JL, Breivogel CS, Mahadevan A, Pertwee RG, Cascio MG, Bolognini D, Huffman JW, Walentiny DM, Vann RE, Razdan RK, Martin BR (2011) Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB(1) receptor antagonist. Eur J Pharmacol 651(1–3):96–105. doi:10.1016/j.ejphar.2010.10.085

  157. Mason BJ, Crean R, Goodell V, Light JM, Quello S, Shadan F, Buffkins K, Kyle M, Adusumalli M, Begovic A, Rao S (2012) A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology 37(7):1689–1698. doi:10.1038/npp.2012.14

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Craig R. Rush .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Bolin, B.L., Alcorn, J.L., Reynolds, A.R., Lile, J.A., Stoops, W.W., Rush, C.R. (2016). Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs. In: Porter, J.H., Prus, A.J. (eds) The Behavioral Neuroscience of Drug Discrimination. Current Topics in Behavioral Neurosciences, vol 39. Springer, Cham. https://doi.org/10.1007/7854_2016_10

Download citation

Publish with us

Policies and ethics