Drug discrimination

Not to be confused with Discrimination against drug addicts.

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]

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-HT_2A receptor antagonist volinanserin (M100907).^[11][14] Although serotonin 5-HT_2A receptor agonism is accepted as the mechanism mediating the hallucinogenic effects of psychedelics, other receptors, including the serotonin 5-HT_1A receptor, the serotonin 5-HT_2C receptor, and the serotonin 5-HT_5A 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-HT_1A 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-HT_1A receptor and partially by the serotonin 5-HT_2A receptor.^[11] The serotonin 5-HT_2C receptor is importantly involved in the discriminative stimulus properties of DiPT in rodents but not in those of dimethyltryptamine (DMT).^[15] A serotonin 5-HT_2C 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-HT_2A receptor, whereas its the DOI stimulus in mice is also partially mediated by the serotonin 5-HT_2A receptor.^[11][13] Similarly, the LSD stimulus appears to be solely mediated by the serotonin 5-HT_2A receptor in rats, whereas mice also have a significant 5-HT_1A 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-HT_2A receptor activation.^[11]

See also

• Head-twitch response