Drug discrimination
Behavioral test comparing drugs
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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][5] 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][5] 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".[6]
The discriminative stimulus properties of drugs are believed to reflect their subjective effects.[1][5] 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][5] Drug discrimination tests are usually performed in rodents, but have also been conducted in non-human primates and humans.[5][7][8]
Drug discrimination assays have been employed to assess whether drugs have stimulant-, hallucinogen- or entactogen-like effects, among many other varieties of drug effects.[9][10][11] The exact neural basis leading to an animal's interoceptive response is unknown and is likely to vary depending on the drug class.[5]
Serotonergic psychedelics
Drug discrimination was first used with psychedelic drugs in 1971.[12][13] This was with rats, whereas the first use of drug discrimination with psychedelics in mice was published in 2003.[12][14]
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).[12][15] 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).[12][15] 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.[12][10][16][14][17] The dopamine D4 receptor is involved in the discriminative stimulus properties of LSD as well.[12][10][18]
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.[10][19][20][21] The 5-MeO-DMT stimulus is mediated primarily by the serotonin 5-HT1A receptor and partially by the serotonin 5-HT2A receptor.[12][21] The serotonin 5-HT2C receptor is importantly involved in the discriminative stimulus properties of DiPT in rodents but not in those of dimethyltryptamine (DMT).[16] 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.[12][21]
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.[12][22][23][24][25][16][26]
Lisuride partially to fully substitutes for LSD and other psychedelics in drug discrimination tests in rodents and monkeys.[12][16][9][27][28][29][30] Lisuride is generally thought to be non-hallucinogenic in humans and hence this has been regarded as a false positive for drug discrimination.[6][16] 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.[16][31] As such, this false positive can be overcome.[16][31]
Species differences, for instance between rats and mice, have been apparent in studies of drug discrimination with psychedelics.[12][14] For example, DOI was several times more potent in rats than in mice.[12][14] In addition, the discriminative stimulus properties of DOI in rats appear to be solely mediated by the serotonin 5-HT2A receptor, whereas the DOI stimulus in mice is also partially mediated by the serotonin 5-HT2A receptor.[12][14] 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.[12]
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.[12]