Drug discrimination

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Drug discrimination (DD) is a technique in behavioral neuroscience used to evaluate the discriminative stimulus properties or interoceptive cues of psychoactive drugs. [1] [2] [3] [4] In drug discrimination, a subject is trained on a training drug, and then it is tested with novel drugs to see if the novel drugs are experienced as similar to the training drug. [2] In essence, the drug discrimination paradigm has the subject "tell" the experimenter "I think you gave me the training drug" or "I don't think you gave me anything". [5]

Contents

The discriminative stimulus properties of drugs are believed to reflect their subjective effects. [1] When partial or full stimulus generalization of a test drug to a training drug occurs, the test drug can be assumed to have effects that are subjectively similar to those of the training drug. [2] Drug discrimination tests are usually performed in animals, but have also been conducted in humans. [6] [7]

Drug discrimination assays have been employed to assess whether drugs have stimulant-, hallucinogen- or entactogen-like effects, among many other varieties of drug effects. [8] [9] [10]

Serotonergic psychedelics

Drug discrimination was first used with psychedelic drugs in 1971. [11] [12] This was with rats, whereas the first use of drug discrimination with psychedelics in mice was published in 2003. [11] [13]

The area of the brain where the discriminative stimulus properties of LSD and presumably other serotonergic psychedelics in rats is mediated has been identified as the anterior cingulate cortex (ACC). [11] [14] Local infusions of LSD into the ACC dose-dependently and up to fully substituted for systemically administered LSD and this substitution could be completely blocked by the highly selective serotonin 5-HT2A receptor antagonist volinanserin (M100907). [11] [14] Although serotonin 5-HT2A receptor agonism is accepted as the mechanism mediating the hallucinogenic effects of psychedelics, other receptors, including the serotonin 5-HT1A receptor, the serotonin 5-HT2C receptor, and the serotonin 5-HT5A receptor, also variably contribute to their discriminative stimulus properties and may be involved in their subjective effects. [11] [9] [15] [13] [16] The dopamine D4 receptor is involved in the discriminative stimulus properties of LSD as well. [11] [9] [17]

The serotonin 5-HT1A receptor is involved in the discriminative stimulus properties of 5-MeO-DMT and LSD in rodents but not in those of psilocybin or DOM. [9] [18] [19] The 5-MeO-DMT stimulus is mediated primarily by the serotonin 5-HT1A receptor and partially by the serotonin 5-HT2A receptor. [11] The serotonin 5-HT2C receptor is importantly involved in the discriminative stimulus properties of DiPT in rodents but not in those of dimethyltryptamine (DMT). [15] A serotonin 5-HT2C receptor antagonist had only modest effects on the discriminative stimulus properties of psilocybin, suggesting against an important involvement of this receptor in psilocybin's subjective effects. [11]

Certain psychedelics and related drugs, like LSD, 25B-NBOMe, and Ariadne, fully substitute for the entactogen MDMA in rodents, whereas others, like DOM, DMT, and 25I-NBOMe, at most partially substitute for MDMA. [11] [20] [21] [22] [23] [15] [24]

Lisuride partially to fully substitutes for LSD and other psychedelics in drug discrimination tests in rodents and monkeys. [11] [15] [8] [25] [26] [27] [28] Lisuride is generally thought to be non-hallucinogenic in humans and hence this has been regarded as a false positive for drug discrimination. [5] [15] However, when a modified drug discrimination paradigm is employed in which animals are trained to discriminate two training drugs (lisuride and LSD) and vehicle, lisuride no longer substitutes for LSD. [15] [29] As such, this false positive can be overcome. [15] [29]

Species differences, for instance between rats and mice, have been apparent in studies of drug discrimination with psychedelics. [11] [13] For example, DOI was several times more potent in rats than in mice. [11] [13] In addition, the discriminative stimulus properties of DOI in rats appear to be solely mediated by the serotonin 5-HT2A receptor, whereas its the DOI stimulus in mice is also partially mediated by the serotonin 5-HT2A receptor. [11] [13] Similarly, the LSD stimulus appears to be solely mediated by the serotonin 5-HT2A receptor in rats, whereas mice also have a significant 5-HT1A receptor-mediated component. [11]

In monkeys, the discriminative stimulus effects of DOM, dipropyltryptamine (DPT), and 2C-T-7 are all predominantly if not exclusively mediated by serotonin 5-HT2A receptor activation. [11]

See also

References

  1. 1 2 Porter JH, Prus AJ, Overton DA (2018). "Drug Discrimination: Historical Origins, Important Concepts, and Principles". The Behavioral Neuroscience of Drug Discrimination. Current Topics in Behavioral Neurosciences. Vol. 39. pp. 3–26. doi:10.1007/7854_2018_40. ISBN   978-3-319-98559-6. PMID   29637526.
  2. 1 2 3 Young, Richard (2009). "Drug Discrimination". Methods of Behavior Analysis in Neuroscience. Boca Raton (FL): CRC Press/Taylor & Francis. ISBN   978-1-4200-5234-3. PMID   21204332 . Retrieved 1 November 2024.
  3. ↑ Colpaert FC (October 1999). "Drug discrimination in neurobiology". Pharmacol Biochem Behav. 64 (2): 337–345. doi:10.1016/s0091-3057(99)00047-7. PMID   10515310.
  4. ↑ Stolerman, I.P. (1993). "Drug discrimination". Techniques in the Behavioral and Neural Sciences. Vol. 10. Elsevier. pp. 217–243. doi:10.1016/b978-0-444-81444-9.50014-6. ISBN   978-0-444-81444-9. ISSN   0921-0709.
  5. 1 2 Nichols DE (February 2004). "Hallucinogens". Pharmacol Ther. 101 (2): 131–181. doi:10.1016/j.pharmthera.2003.11.002. PMID   14761703.
  6. ↑ Bolin BL, Alcorn JL, Reynolds AR, Lile JA, Rush CR (August 2016). "Human drug discrimination: A primer and methodological review". Exp Clin Psychopharmacol. 24 (4): 214–228. doi:10.1037/pha0000077. PMC   4965187 . PMID   27454673.
  7. ↑ Bolin BL, Alcorn JL, Reynolds AR, Lile JA, Stoops WW, Rush CR (2018). "Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs". The Behavioral Neuroscience of Drug Discrimination. Current Topics in Behavioral Neurosciences. Vol. 39. pp. 261–295. doi:10.1007/7854_2016_10. ISBN   978-3-319-98559-6. PMC   5461212 . PMID   27272070.
  8. 1 2 Baker LE (2018). "Hallucinogens in Drug Discrimination". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 201–219. doi:10.1007/7854_2017_476. ISBN   978-3-662-55878-2. PMID   28484970.
  9. 1 2 3 4 Winter JC (April 2009). "Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines". Psychopharmacology (Berl). 203 (2): 251–263. doi:10.1007/s00213-008-1356-8. PMID   18979087.
  10. ↑ Mori T, Suzuki T (2018). "The Discriminative Stimulus Properties of Hallucinogenic and Dissociative Anesthetic Drugs". The Behavioral Neuroscience of Drug Discrimination. Current Topics in Behavioral Neurosciences. Vol. 39. pp. 141–152. doi: 10.1007/7854_2016_29 . ISBN   978-3-319-98559-6. PMID   27586539.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Nichols, David E. (2016). "Psychedelics" (PDF). Pharmacological Reviews. 68 (2): 264–355. doi:10.1124/pr.115.011478. ISSN   0031-6997. PMC   4813425 . PMID   26841800. A selective 5-HT2C antagonist SB-24084 had only modest effects, arguing against a contribution by 5-HT2C receptors.
  12. ↑ Kozlenkov A, González-Maeso J (2013). "Animal Models and Hallucinogenic Drugs". The Neuroscience of Hallucinations. New York, NY: Springer New York. pp. 253–277. doi:10.1007/978-1-4614-4121-2_14. ISBN   978-1-4614-4120-5.
  13. 1 2 3 4 5 Smith RL, Barrett RJ, Sanders-Bush E (February 2003). "Discriminative stimulus properties of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)DOI] in C57BL/6J mice". Psychopharmacology (Berl). 166 (1): 61–68. doi:10.1007/s00213-002-1252-6. PMID   12474110.
  14. 1 2 Gresch PJ, Barrett RJ, Sanders-Bush E, Smith RL (February 2007). "5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide". J Pharmacol Exp Ther. 320 (2): 662–669. doi:10.1124/jpet.106.112946. PMID   17077317.
  15. 1 2 3 4 5 6 7 Canal CE (2018). "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 252: 227–260. doi:10.1007/164_2018_107. ISBN   978-3-030-10560-0. PMC   6136989 . PMID   29532180. Similar to the head-twitch model, compounds targeting receptors other than 5-HT2A modulate the discriminative stimulus effects of serotonergic psychedelics, and false positives, false negatives, and misunderstood results have emerged (Benneyworth et al. 2005; Reissig et al. 2005; Winter 2009). For example, lisuride substitutes for a number of serotonergic psychedelics in the two-lever drug discrimination paradigm; however, this can be overcome by training animals to discriminate two training drugs and vehicle. Thus, when animals are trained to discriminate lisuride, LSD, and vehicle, lisuride does not substitute for LSD (Appel et al. 2004).
  16. ↑ Popik P, Krawczyk M, Kuziak A, Bugno R, Hogendorf A, Staroń J, Nikiforuk A (November 2019). "Serotonin type 5A receptor antagonists inhibit D-lysergic acid diethylamide discriminatory cue in rats". J Psychopharmacol. 33 (11): 1447–1455. doi:10.1177/0269881119867603. PMID   31452444.
  17. ↑ Marona-Lewicka D, Chemel BR, Nichols DE (April 2009). "Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI". Psychopharmacology (Berl). 203 (2): 265–277. doi:10.1007/s00213-008-1238-0. PMID   18604600.
  18. ↑ Winter JC, Rice KC, Amorosi DJ, Rabin RA (October 2007). "Psilocybin-induced stimulus control in the rat". Pharmacol Biochem Behav. 87 (4): 472–480. doi:10.1016/j.pbb.2007.06.003. PMC   2000343 . PMID   17688928.
  19. ↑ Winter JC, Filipink RA, Timineri D, Helsley SE, Rabin RA (January 2000). "The paradox of 5-methoxy-N,N-dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors". Pharmacol Biochem Behav. 65 (1): 75–82. doi:10.1016/s0091-3057(99)00178-1. PMID   10638639.
  20. ↑ Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, Lankri D, Duggan P, Nazarova AL, Cao AB, Calkins MM, Khirsariya P, Hwu C, Katritch V, Chandra SS, McCorvy JD, Sames D (January 2023). "Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs". ACS Chemical Neuroscience. 14 (1): 119–135. doi:10.1021/acschemneuro.2c00597. PMC   10147382 . PMID   36521179. In rat drug discrimination assays, Ariadne substituted responding in LSD trained animals in one study, in another showed full substitution for MDMA stimulus.14,15 [...] 15). Glennon RA MDMA-like Stimulus Effects of α-Ethyltryptamine and the α-Ethyl Homolog of Dom. Pharmacology Biochemistry and Behavior 1993, 46 (2), 459–462. [PubMed: 7903460]
  21. ↑ Glennon RA (October 1993). "MDMA-like stimulus effects of alpha-ethyltryptamine and the alpha-ethyl homolog of DOM". Pharmacol Biochem Behav. 46 (2): 459–462. doi:10.1016/0091-3057(93)90379-8. PMID   7903460.
  22. ↑ Herian M, Świt P (January 2023). "25X-NBOMe compounds - chemistry, pharmacology and toxicology. A comprehensive review". Crit Rev Toxicol. 53 (1): 15–33. doi:10.1080/10408444.2023.2194907. PMID   37115704. For a better understanding of the actions of different NBOMes resulting from their molecular structure and receptor binding affinity, drug discrimination studies were performed. Animals trained with 4-methyl-2,5-dimethoxyamphetamine (DOM) and 3,4-methylenedioxymethamphetamine (MDMA) were used in the drug discrimination paradigm. 25B- and 25CNBOMe completely (80%) substituted DOM, while 25INBOMe produced 74% drug-appropriate responding (Gatch et al. 2017). On the other hand, only 25B-NBOMe fully substituted for MDMA, suggesting that this compound could be used as both a hallucinogen and an entactogen.
  23. ↑ Zawilska JB, Kacela M, Adamowicz P (2020). "NBOMes-Highly Potent and Toxic Alternatives of LSD". Front Neurosci. 14: 78. doi: 10.3389/fnins.2020.00078 . PMC   7054380 . PMID   32174803. Gatch et al. (2017) tested 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe for discriminative stimulus effects similar to a prototypical psychedelic/hallucinogen DOM and to an empathogen, 3,4-methylenedioxymethamphetamine (MDMA). In DOM-trained rats 25B-NBOMe and 25C-NBOMe, but not 25I-NBOMe, fully substituted for this drug. 25B-NBOMe also fully substituted for MDMA. In both tests, the dose-effect curves for 25B-NBOMe had an inverted U-shape. It is suggested that 25B-NBOMe and 25C-NBOMe are most likely used as recreational psychedelics, although 25B-NBOMe may also be used as an empathogenic compound (Gatch et al., 2017). However, the latter assumption should be taken with caution, as some compounds (e.g., fenfluramine) that substitute for MDMA in rats do not produce MDMA-like empathogenic effects in humans (Schechter, 1988).
  24. ↑ Gatch MB, Dolan SB, Forster MJ (August 2017). "Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents". Behav Pharmacol. 28 (5): 375–385. doi:10.1097/FBP.0000000000000309. PMC   5498282 . PMID   28537942.
  25. ↑ Kehler J, Lindskov MS (May 2025). "Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?". Journal of Psychopharmacology: 2698811251330741. doi:10.1177/02698811251330741. PMID   40322975.
  26. ↑ Murnane KS (2018). The renaissance in psychedelic research: What do preclinical models have to offer. Progress in Brain Research. Vol. 242. pp. 25–67. doi:10.1016/bs.pbr.2018.08.003. ISBN   978-0-12-814255-4. PMID   30471682. It should be noted when it comes to lisuride that its status as a non-psychedelic 5-HT2A receptor agonist is controversial as there appears to be some generalization in the subjective effects of lisuride and LSD in laboratory animals (Appel et al., 1999; Callahan and Appel, 1990; Fiorella et al., 1995) and high toxic doses of lisuride may induce reactions in humans that include visual and auditory hallucinations, reduced awareness, delusions, and paranoid ideation (Critchley et al., 1986; Lees and Bannister, 1981; Parkes et al., 1981). Nevertheless, such effects are not representative of typical experiences with lisuride administration, or psychedelic administration, and it would be hard to argue for substantial overlap in the effects of lisuride and psychedelics at typical doses. As such, we remain hopeful that lisuride and related compounds can be used to elucidate the critical signaling pathways of psychedelics and establish novel non-psychedelic 5-HT2A receptor agonists.{{cite book}}: |journal= ignored (help)
  27. ↑ Appel JB, West WB, Buggy J (January 2004). "LSD, 5-HT (serotonin), and the evolution of a behavioral assay". Neurosci Biobehav Rev. 27 (8): 693–701. doi:10.1016/j.neubiorev.2003.11.012. PMID   15019419.
  28. ↑ Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE (October 2002). "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats". Psychopharmacology (Berl). 164 (1): 93–107. doi:10.1007/s00213-002-1141-z. PMID   12373423.
  29. 1 2 Callahan PM, Appel JB (1990). "Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice, drug discrimination procedure". Psychopharmacology (Berl). 100 (1): 13–18. doi:10.1007/BF02245782. PMID   2296621.

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