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-HT1A ) receptor in the striatum and prefrontal cortex (PFC). Methods We investigated the effects of 5-MeO-DIPT on extracellular 5-HT (5-HTex ) and dopamine (DAex ) 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-HT1A receptor antagonist WAY100635 and the 5-HT1A receptor agonist 8-OH-DPAT on 5-HTex . Results 5-MeO-DIPT decreased 5-HTex levels in the striatum, but not PFC. In SERT-KO mice, 5-MeO-DIPT did not affect 5-HTex levels in the striatum or PFC. In the presence of WAY100635, 5-MeO-DIPT substantially increased 5-HTex levels, suggesting that 5-MeO-DIPT acts on SERT and these effects are masked by its 5-HT1A actions in the absence of WAY100635. 8-OH-DPAT decreased 5-HTex levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8-OH-DPAT-induced decrease in 5-HTex levels. In SERT-KO mice, 8-OH-DPAT did not decrease 5-HTex levels in the striatum and PFC. 5-MeO-DIPT dose-dependently increased DAex levels in the PFC, but not striatum, in wildtype and SERT-KO mice. The increase in DAex levels that was induced by 5-MeO-DIPT was not antagonized by WAY100635. Conclusion 5-MeO-DIPT influences both 5-HTex and DAex levels in the striatum and PFC. 5-MeO-DIPT dually acts on SERT and 5-HT1A receptors so that elevations in 5-HTex levels produced by reuptake inhibition are limited by actions of the drug on 5-HT1A receptors.