Dataset Information

Dual actions of 5-MeO-DIPT at the serotonin transporter and serotonin 5-HT_1A receptor in the mouse striatum and prefrontal cortex.

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.

SUBMITTER: Hagino Y

PROVIDER: S-EPMC8182963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1(+/-)) or homozygously (Gtf2ird1(-/-)) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1(-/-) mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1(-/-) mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1(-/-) mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT(1A) receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT(1A) receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT(1A) receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT(1A)-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1(-/-) mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-010-9044-5) contains supplementary material, which is available to authorized users.

Dataset Information

Dual actions of 5-MeO-DIPT at the serotonin transporter and serotonin 5-HT_1A receptor in the mouse striatum and prefrontal cortex.

Aims

Methods

Results

Conclusion

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Dataset Information

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

Aims

Methods

Results

Conclusion

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dual actions of 5-MeO-DIPT at the serotonin transporter and serotonin 5-HT_1A receptor in the mouse striatum and prefrontal cortex.