Dual actions of 5‐MeO‐DIPT at the serotonin transporter and serotonin 5‐HT(1A) receptor in the mouse striatum and prefrontal cortex

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.