Re-evaluation of the discriminative stimulus effects of lysergic acid diethylamide with male and female Sprague-Dawley rats
Keli A. Herr, Lisa E Baker
Behavioural Pharmacology December 1, 2020 DOI: 10.1097/fbp.0000000000000589 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical drug discrimination study Peer reviewed |
|---|---|
| Sample size | 16 |
| Population | Adult Sprague-Dawley rats (8 female, 8 male) |
| Interventions | LSD serotonergic hallucinogens psychostimulants mixed psychedelic-stimulants synthetic cathinones serotonin and dopamine antagonists |
| Dose | 0.08 mg/kg LSD |
| Topics | LSD |
| Citations | 9 |
| Key points | LSD's discriminative stimulus effects are mediated primarily by serotonergic activity in both male and female rats, with modest sex differences in substitution by MDMA, MDA, and synthetic cathinones, and in sensitivity to dopamine antagonist rate suppression and serotonin antagonist blockade. |
Abstract
Recent discoveries from clinical trials with psychedelic-assisted therapy have led to a resurgence of interest in the psychopharmacology of lysergic acid diethylamide (LSD). Preclinical drug discrimination is an invaluable tool to investigate the neurochemical mechanisms underlying subjective drug effects. The current study extends previous drug discrimination research by including both sexes. Adult female (n = 8) and male (n = 8) Sprague-Dawley rats were trained to discriminate 0.08 mg/kg LSD from saline under a fixed ratio 20 schedule of food reinforcement. Substitution tests were conducted with several substances, including other serotonergic hallucinogens, psychostimulants, mixed psychedelic-stimulants and synthetic cathinones. Stimulus antagonist tests were conducted with selected serotonin and dopamine antagonists. LSD-substitution with serotonergic hallucinogens was comparable between sexes. Modest but intriguing differences were observed between male and female rats in the extent of partial substitution by 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine enantiomers and the synthetic cathinones, 3,4-methylenedioxypyrovalerone and 4-methylmethcathinone. Dopamine antagonists failed to block the LSD cue in both sexes and exerted stronger rate suppressant effects in male rats. The 5-hydroxytryptamine antagonist, (R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol (MDL 100 907) blocked LSD discrimination in both sexes, although complete blockade was evident at lower doses in male rats. These results support previous findings regarding the prominent role of serotonergic activities underlying LSDs discriminative stimulus effects in male rats and generalize these findings to female rats. In consideration of the rising popularity in psychedelic-assisted psychotherapy, further research may be warranted to evaluate possible sex differences in the behavioral and subjective effects of LSD.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 6
- Psychedelic-like effects induced by 2,5-dimethoxy-4-iodoamphetamine, lysergic acid diethylamide, and psilocybin in male and female C57BL/6J mice. Psychopharmacology May 17, 2025
- Females in Psychedelic Research: A Perspective for Advancing Research and Practice. ACS Pharmacology & Translational Science July 11, 2025
- Lysergic Acid Diethylamide Alters the Effects of Brain Stimulation in Rodents. Psychedelic Medicine March 1, 2023
- Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice. Neuropsychopharmacology February 2, 2026
- LSD: Mechanisms and relevance to the treatment of depression Neuroscience & Biobehavioral Reviews October 10, 2025
and 1 more in the library
Cites 27
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- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects Journal of Psychopharmacology November 11, 2014
- Psychedelics as Medicines: An Emerging New Paradigm Clinical Pharmacology & Therapeutics November 4, 2016
- The paradoxical psychological effects of lysergic acid diethylamide (LSD) Psychological Medicine February 5, 2016
and 22 more in the library