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 D₄ receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D₂/D₃ 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 D₂/D₃ receptor.