Dual actions of 5‐MeO‐DIPT at the serotonin transporter and serotonin 5‐HT1A receptor in the mouse striatum and prefrontal cortex

The hallucinogenic tryptamine analogue 5-MeO-DIPT decreases extracellular serotonin in the striatum but not in the prefrontal cortex of mice. In mice lacking the serotonin transporter, 5-MeO-DIPT does not affect serotonin levels, indicating its action depends on that transporter. When a 5-HT1A receptor antagonist is present, 5-MeO-DIPT substantially increases serotonin, suggesting the drug's serotonin reuptake inhibition is masked by its concurrent activation of 5-HT1A receptors. 5-MeO-DIPT also dose-dependently increases extracellular dopamine in the prefrontal cortex regardless of serotonin transporter presence, an effect not blocked by the 5-HT1A antagonist. Thus, 5-MeO-DIPT dually acts on the serotonin transporter and 5-HT1A receptors, limiting serotonin elevation while independently raising dopamine in the prefrontal cortex.

Study at a glance

Abstract

Abstract Aims 5‐Methoxy‐ N , N ‐diisopropyltryptamine (5‐MeO‐DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of 5‐MeO‐DIPT involve the serotonin transporter (SERT) and serotonin 5‐hydroxytryptamine‐1A (5‐HT 1A ) receptor in the striatum and prefrontal cortex (PFC). Methods We investigated the effects of 5‐MeO‐DIPT on extracellular 5‐HT (5‐HT ex ) and dopamine (DA ex ) levels in the striatum and PFC in wildtype and SERT knockout (KO) mice using in vivo microdialysis, and for comparison the effects of the 5‐HT 1A receptor antagonist WAY100635 and the 5‐HT 1A receptor agonist 8‐OH‐DPAT on 5‐HT ex . Results 5‐MeO‐DIPT decreased 5‐HT ex levels in the striatum, but not PFC. In SERT‐KO mice, 5‐MeO‐DIPT did not affect 5‐HT ex levels in the striatum or PFC. In the presence of WAY100635, 5‐MeO‐DIPT substantially increased 5‐HT ex levels, suggesting that 5‐MeO‐DIPT acts on SERT and these effects are masked by its 5‐HT 1A actions in the absence of WAY100635. 8‐OH‐DPAT decreased 5‐HT ex levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8‐OH‐DPAT‐induced decrease in 5‐HT ex levels. In SERT‐KO mice, 8‐OH‐DPAT did not decrease 5‐HT ex levels in the striatum and PFC. 5‐MeO‐DIPT dose‐dependently increased DA ex levels in the PFC, but not striatum, in wildtype and SERT‐KO mice. The increase in DA ex levels that was induced by 5‐MeO‐DIPT was not antagonized by WAY100635. Conclusion 5‐MeO‐DIPT influences both 5‐HT ex and DA ex levels in the striatum and PFC. 5‐MeO‐DIPT dually acts on SERT and 5‐HT 1A receptors so that elevations in 5‐HT ex levels produced by reuptake inhibition are limited by actions of the drug on 5‐HT 1A receptors.