The Discriminative Stimulus Properties of Hallucinogenic and Dissociative Anesthetic Drugs

  • Tomohisa Mori
  • Tsutomu Suzuki
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 39)


The subjective effects of drugs are related to the kinds of feelings they produce, such as euphoria or dysphoria. One of the methods that can be used to study these effects is the drug discrimination procedure. Many researchers have been trying to elucidate the mechanisms that underlie the discriminative stimulus properties of abused drugs (e.g., alcohol, psychostimulants, and opioids). Over the past two decades, patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), ketamine, and cannabinoid, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. In particular, the abuse of designer drugs, which aim to mimic the subjective effects of psychostimulants (e.g., MDMA or amphetamines), has been problematic. However, the mechanisms of the discriminative stimulus effects of hallucinogenic and dissociative anesthetic drugs are not yet fully clear. This chapter focuses on recent findings regarding hallucinogenic and dissociative anesthetic drug-induced discriminative stimulus properties in animals.


Discriminative stimulus properties Hallucinogens Psychedelics Serotonin Sigma-1 receptor 



This work was supported in part by grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices from the Ministry of Health, Labour and Welfare, Japan (MHLW) to TS and/or TM, and by JSPS KAKENHI Grant Number 15 K07977.


  1. 1.
    MacLean KA, Johnson MW, Reissig CJ, Prisinzano TE, Griffiths RR (2013) Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Psychopharmacology (Berl) 226:381–392CrossRefGoogle Scholar
  2. 2.
    Sami M, Piggott K, Coysh C, Fialho A (2015) Psychosis, psychedelic substance misuse and head injury: a case report and 23 year follow-up. Brain Inj 29:1383–1386CrossRefPubMedGoogle Scholar
  3. 3.
    Su TP, Hayashi T, Vaupel DB (2009) When the endogenous hallucinogenic trance amine N,N-dimethyltryptamine meets the sigma-1 receptor. Sci Signal 2:pe12Google Scholar
  4. 4.
    Cozzi NV, Gopalakrishnan A, Anderson LL, Feih JT, Shulgin AT, Daley PF, Ruoho AE (2009) Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter. J Neural Transm (Vienna) 116:1591–1599CrossRefGoogle Scholar
  5. 5.
    Pabba M, Wong AY, Ahlskog N, Hristova E, Biscaro D, Nassrallah W, Ngsee JK, Snyder M, Beique JC, Bergeron R (2014) NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus. J Neurosci 34:11325–11338CrossRefPubMedGoogle Scholar
  6. 6.
    De La Garza R II, Fabrizio KR, Gupta A (2007) Relevance of rodent models of intravenous MDMA self-administration to human MDMA consumption patterns. Psychopharmacology (Berl) 189:425–434CrossRefGoogle Scholar
  7. 7.
    Mori T, Uzawa N, Kazawa H, Watanabe H, Mochizuki A, Shibasaki M, Yoshizawa K, Higashiyama K, Suzuki T (2014) Differential substitution for the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and methylphenidate in rats. J Pharmacol Exp Ther 350(2):403–11CrossRefPubMedGoogle Scholar
  8. 8.
    Fiorella D, Rabin RA, Winter JC (1995) Role of 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. II: reassessment of LSD false positives. Psychopharmacology (Berl) 121:357–363CrossRefGoogle Scholar
  9. 9.
    Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE (2002) Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine 1A receptor-mediated behavioral effects overlap its other properties in rats. Psychopharmacology (Berl) 164:93–107Google Scholar
  10. 10.
    Nielsen EB (1985) Discriminative stimulus properties of lysergic acid diethylamide in the monkey. J Pharmacol Exp Ther 234:244–249PubMedGoogle Scholar
  11. 11.
    Cole JC, Sumnall HR (2003) The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA). Neurosci Biobehav Rev 27:199–217CrossRefPubMedGoogle Scholar
  12. 12.
    Mori T, Ito S, Kuwaki T, Yanagisawa M, Sakurai T, Sawaguchi T (2010) Monoaminergic neuronal changes in orexin-deficient mice. Neuropharmacology 58:826–832CrossRefPubMedGoogle Scholar
  13. 13.
    Fantegrossi WE, Reissig CJ, Katz EB, Yarosh HL, Rice KC, Winter JC (2008) Hallucinogen-like effects of N, N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents. Pharmacol Biochem Behav 88(3):358–65CrossRefPubMedGoogle Scholar
  14. 14.
    Glennon RA, Young R (2000) MDMA stimulus generalization to the 5-HT(1A) serotonin agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Pharmacol Biochem Behav 66:483–488CrossRefPubMedGoogle Scholar
  15. 15.
    Winter JC (2009) Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines. Psychopharmacology (Berl) 203:251–263CrossRefGoogle Scholar
  16. 16.
    van Wel JH, Kuypers KP, Theunissen EL, Bosker WM, Bakker K, Ramaekers JG (2012) Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors. PLoS One 7, e40187CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Orejarena MJ, Lanfumey L, Maldonado R, Robledo P (2011) Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. Int J Neuropsychopharmacol 14:927–940CrossRefPubMedGoogle Scholar
  18. 18.
    Cami J, Farré M, Mas M, Roset PN, Poudevida S, Mas A, San L, de la Torre R (2000) Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): psychomotor performance and subjective effects. J Clin Psychopharmacol 20:455–466CrossRefPubMedGoogle Scholar
  19. 19.
    Tancer M, Johanson CE (2003) Reinforcing, subjective, and physiological effects of MDMA in humans: a comparison with d-amphetamine and mCPP. Drug Alcohol Depend 72:33–44CrossRefPubMedGoogle Scholar
  20. 20.
    Kirkpatrick MG, Gunderson EW, Perez AY, Haney M, Foltin RW, Hart CL (2012) A direct comparison of the behavioral and physiological effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl) 219:109–122CrossRefGoogle Scholar
  21. 21.
    Bondareva T, Wesołowska A, Dukat M, Lee M, Young R, Glennon RA (2005) S(+)- and R(−)N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: effect of cocaine. Pharmacol Biochem Behav 82:531–538CrossRefPubMedGoogle Scholar
  22. 22.
    Goodwin AK, Pynnonen DM, Baker LE (2003) Serotonergic-dopaminergic mediation of MDMA’s discriminative stimulus effects in a three-choice discrimination. Pharmacol Biochem Behav 74:987–995CrossRefPubMedGoogle Scholar
  23. 23.
    Harper DN, Langen AL, Schenk S (2014) A 3-lever discrimination procedure reveals differences in the subjective effects of low and high doses of MDMA. Pharmacol Biochem Behav 116:9–15CrossRefPubMedGoogle Scholar
  24. 24.
    Parrott AC (2005) Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy. J Psychopharmacol 19:71–83CrossRefPubMedGoogle Scholar
  25. 25.
    Mohamed WM, Ben Hamida S, Cassel JC, de Vasconcelos AP, de Jones BC (2011) MDMA: interactions with other psychoactive drugs. Pharmacol Biochem Behav 99(4):759–74CrossRefPubMedGoogle Scholar
  26. 26.
    Liechti ME, Vollenweider FX (2000) Acute psychological and physiological effects of MDMA (“Ecstasy”) after haloperidol pretreatment in healthy humans. Eur Neuropsychopharmacol 10:289–295CrossRefPubMedGoogle Scholar
  27. 27.
    Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX (2000) Psychological and physiological effects of MDMA (“Ecstasy”) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology 23:396–404CrossRefPubMedGoogle Scholar
  28. 28.
    Willetts J, Balster RL (1989) Pentobarbital-like discriminative stimulus effects of N-methyl-d-aspartate antagonists. J Pharmacol Exp Ther 249:438–443PubMedGoogle Scholar
  29. 29.
    Mori T, Nomura M, Yoshizawa K, Nagase H, Sawaguchi T, Narita M et al (2006) Generalization of NMDA-receptor agonists U-50,488H, but not TRK-820 in rats. J Pharmacol Sci 100:157–161CrossRefPubMedGoogle Scholar
  30. 30.
    Mori T, Baba J, Ichimaru Y, Suzuki T (2000) Effects of rolipram, a selective inhibitor of phosphodiesterase 4, on hyperlocomotion induced by several abused drugs in mice. Jpn J Pharmacol 83:113–118CrossRefPubMedGoogle Scholar
  31. 31.
    Rimoy GH, Wright DM, Bhaskar NK, Rubin PC (1994) The cardiovascular and central nervous system effects in the human of U-62066E. A selective opioid receptor agonist. Eur J Clinic Pharmacol 46:203–207Google Scholar
  32. 32.
    Walsh SL, Strain EC, Abreu ME, Bigelow GE (2001) Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology (Berl) 157:151–162CrossRefGoogle Scholar
  33. 33.
    Baker LE, Panos JJ, Killinger BA, Peet MM, Bell LM, Haliw LA et al (2009) Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats. Psychopharmacology (Berl) 203:203–211CrossRefGoogle Scholar
  34. 34.
    Yoshizawa K, Narita M, Saeki M, Narita M, Isotani K, Horiuchi H et al (2011) Activation of extracellular signal-regulated kinase is critical for the discriminative stimulus effects induced by U-50,488H. Synapse 65:1052–1061CrossRefPubMedGoogle Scholar
  35. 35.
    Mori T, Yoshizawa K, Nomura M, Isotani K, Torigoe K, Tsukiyama Y et al (2012) Sigma-1 receptor function is critical for both the discriminative stimulus and aversive effects of the kappa-opioid receptor agonist U-50488H. Addict Biol 17:717–724CrossRefPubMedGoogle Scholar
  36. 36.
    Narita M, Yoshizawa K, Aoki K, Takagi M, Miyatake M, Suzuki T (2001) A putative sigma1 receptor antagonist NE-100 attenuates the discriminative stimulus effects of ketamine in rats. Addict Biol 6:373–376CrossRefPubMedGoogle Scholar
  37. 37.
    Narita N, Hashimoto K, Tomitaka S, Minabe Y (1996) Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol 20(307):117–119CrossRefGoogle Scholar
  38. 38.
    Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596–610CrossRefPubMedGoogle Scholar
  39. 39.
    Fujimoto M, Hayashi T, Urfer R, Mita S, Su TP (2012) Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotropic factor. Synapse 66:630–639CrossRefPubMedGoogle Scholar
  40. 40.
    Hayashi T, Su TP (2001) Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci U S A 98:491–496CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Buch S, Yao H, Guo M, Mori T, Su TP, Wang J (2011) Cocaine and HIV-1 interplay: molecular mechanisms of action and addiction. J Neuroimmune Pharmacol 6:503–515CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hayashi T, Tsai SY, Mori T, Fujimoto M, Su TP (2011) Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders. Expert Opin Ther Targets 15:557–577CrossRefPubMedGoogle Scholar
  43. 43.
    Kourrich S, Hayashi T, Chuang JY, Tsai SY, Su TP, Bonci A (2013) Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152:236–247CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kyosseva SV, Owens SM, Elbein AD, Karson CN (2001) Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain. Neuropsychopharmacology 24:267–277CrossRefPubMedGoogle Scholar
  45. 45.
    Cormaci G, Mori T, Hayashi T, Su TP (2007) Protein kinase A activation down-regulates, whereas extracellular signal-regulated kinase activation up-regulates sigma-1 receptors in B-104 cells: implication for neuroplasticity. J Pharmacol Exp Ther 320:202–210CrossRefPubMedGoogle Scholar
  46. 46.
    Kourrich S, Su TP, Fujimoto M, Bonci A (2012) The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci 35:762–771CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bronson ME, Lin YP, Burchett K, Picker MJ, Dykstra LA (1993) Serotonin involvement in the discriminative stimulus effects of kappa opioids in pigeons. Psychopharmacology (Berl) 111:69–77CrossRefGoogle Scholar
  48. 48.
    Di Benedetto M, Bastias Candia Sdel C, D’Addario C, Porticella EE, Cavina C, Candeletti S et al (2011) Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade. Naunyn Schmiedebergs Arch Pharmacol 383:169–178Google Scholar
  49. 49.
    Dumont GJ, van Hasselt JG, de Kam M, van Gerven JM, Touw DJ, Buitelaar JK et al (2011) Acute psychomotor, memory and subjective effects of MDMA and THC co-administration over time in healthy volunteers. J Psychopharmacol 25:478–489CrossRefPubMedGoogle Scholar
  50. 50.
    Barrett RL, Wiley JL, Balster RL, Martin BR (1995) Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats. Psychopharmacology (Berl) 118:419–424CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of ToxicologyHoshi University School of Pharmacy and Pharmaceutical SciencesHoshiJapan

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