Contrasting effects of DOI and lisuride on impulsive decision-making in delay discounting task

Rationale The 5-HT 2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT 2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT 2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). Objectives The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. Methods Impulsive decision-making was evaluated in male Sprague–Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32 s) across one session. Results DOI (0.5 and 1.0 mg/kg) increased impulsive decision-making, and the effects of DOI (1.0 mg/kg) were blocked by the 5-HT 2A receptor antagonist ketanserin (1.0 mg/kg) rather than the 5-HT 2C receptor antagonist SB-242084 (1.0 mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5 mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3 mg/kg) were not antagonized by ketanserin (1.0 mg/kg), selective 5-HT 1A antagonist WAY-100635 (1.0 mg/kg), or selective dopamine D 4 receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D 2 /D 3 receptor antagonist tiapride (40 mg/kg). Conclusions DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptors. DOI-induced increase of impulsivity is mediated by the 5-HT 2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D 2 /D 3 receptor.