Re-evaluation of the discriminative stimulus effects of lysergic acid diethylamide with male and female Sprague-Dawley rats

In rats trained to distinguish LSD from saline, the drug's effects were largely similar between males and females, though some differences emerged with other substances. Both sexes showed comparable substitution by serotonergic hallucinogens. Partial substitution by MDMA, MDA enantiomers, and synthetic cathinones differed modestly between sexes. Dopamine antagonists did not block the LSD cue and suppressed behavior more in males. The serotonin antagonist MDL 100,907 blocked LSD discrimination in both sexes, but complete blockade occurred at lower doses in males. These findings confirm the central role of serotonin in LSD's effects and extend this to females, suggesting further research on sex differences in psychedelic effects is warranted.

Study at a glance

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.