Postnatal Fluoxetine-Evoked Anxiety Is Prevented by Concomitant 5-HT2A/C Receptor Blockade and Mimicked by Postnatal 5-HT2A/C Receptor Stimulation

doi:10.1016/j.biopsych.2013.11.005

Biological Psychiatry

Volume 76, Issue 11, 1 December 2014, Pages 858-868

https://doi.org/10.1016/j.biopsych.2013.11.005 Get rights and content

Background

Postnatal treatment with the selective serotonin reuptake inhibitor fluoxetine, evokes anxiety and depressive behavior in rodent models in adulthood. We examined the role of serotonin 2A (5-HT_2A), serotonin 2C (5-HT_2C) and serotonin 1A (5-HT_1A) receptors, implicated in the development of anxiety, in the behavioral consequences of postnatal fluoxetine (PNFlx).

Methods

Control and PNFlx rat pups received concomitant treatment with the 5-HT_2A/C receptor antagonist, ketanserin, the 5-HT_2A receptor antagonist, MDL100907, the 5-HT_2C receptor antagonist, SB242084, or the 5-HT_1A receptor antagonist, WAY-100635, and were tested for behavior in adulthood. The effect of postnatal treatment with the 5-HT_2A/C receptor agonist, DOI, on anxiety behavior was examined in adulthood.

Results

Postnatal 5-HT_2A/C receptor blockade prevented PNFlx-evoked anxiety, attenuated depressive behavior, and normalized specific gene expression changes in the prefrontal cortex. Postnatal, selective 5-HT_2A receptor antagonist treatment blocked PNFlx-evoked anxiety and depressive behavior, whereas 5-HT_2C receptor antagonist treatment prevented anxiety but not depressive behavior. Postnatal 5-HT_2A/C receptor stimulation was sufficient to evoke anxiety in adulthood. Serotonin 1A receptor blockade did not alter PNFlx-evoked anxiety but resulted in anxiety in control animals, an effect attenuated by concomitant 5-HT_2A/C receptor blockade.

Conclusions

Postnatal fluoxetine-evoked anxiety and depressive behavior, as well as specific gene expression changes in the prefrontal cortex, were prevented by 5-HT_2A/C receptor blockade. Adult anxiety was evoked by either 5-HT_2A/C receptor stimulation or 5-HT_1A receptor blockade of naive control pups. Our findings implicate serotonin 2 receptors in the development of perturbed emotionality following PNFlx and suggest that an altered balance of signaling through 5-HT_1A and 5-HT_2A/C receptors in early life influences anxiety behavior.

Section snippets

Animals

Male Sprague-Dawley rats bred in the Tata Institute of Fundamental Research animal facility and maintained on a 12-hour light-dark cycle with ad libitum access to food and water were used for all experiments. Experimental procedures followed the National Institute of Health Guide for the care and use of animals and the Committee for the Purpose of Control and Supervision of Experimental Animals and were approved by the Tata Institute of Fundamental Research Animal Ethics Committee

Postnatal 5-HT_2A/C Receptor Antagonist Treatment Prevents the Development of PNFlx-Evoked Adult Anxiety

We examined whether concomitant 5-HT_2A/C receptor antagonist treatment altered the development of adult anxiety following PNFlx on the OFT and EPM (Figure 1A–I). Postnatal fluoxetine treatment enhanced anxiety behavior on the OFT (Figure 1B–E) as indicated by decreased percent path length, percent time spent, and number of visits to the center of the arena. Postnatal fluoxetine-evoked anxiety on the OFT was completely prevented by concomitant ketanserin treatment (Figure 1B–E). Two-way ANOVA

Discussion

The major novel finding of our study indicates that PNFlx-evoked anxiety is prevented by postnatal 5-HT_2A/C receptor blockade and that postnatal 5-HT_2A/C receptor stimulation behaviorally mimics the anxiogenic effects of PNFlx. Our results with selective 5-HT_2A and 5-HT_2C receptor antagonists indicate that both PNFlx-evoked adult anxiety and depressive behavior are normalized by concomitant 5-HT_2A receptor blockade, whereas 5-HT_2C receptor blockade prevents the development of anxiety, but not

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: Authors AS and PC contributed equally to this work.

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Archival ReportPostnatal Fluoxetine-Evoked Anxiety Is Prevented by Concomitant 5-HT2A/C Receptor Blockade and Mimicked by Postnatal 5-HT2A/C Receptor Stimulation

Background

Methods

Results

Conclusions

Section snippets

Animals

Postnatal 5-HT2A/C Receptor Antagonist Treatment Prevents the Development of PNFlx-Evoked Adult Anxiety

Discussion

Psychiatr Clin North Am

Prog Neuropsychopharmacol Biol Psychiatry

Neurotoxicology

Eur Neuropsychopharmacol

J Affect Disord

Curr Opin Pharmacol

Neuropharmacology

Brain Res Dev Brain Res

Biol Psychiatry

Biol Psychiatry

Neuron

Neurosci Biobehav Rev

Trends Pharmacol Sci

Brain Res

Neurosci Lett

Behav Brain Res

Eur J Pharmacol

Pharmacol Biochem Behav

Trends Pharmacol Sci

Neuropsychopharmacology

Biol Psychiatry

Int J Dev Neurosci

Biol Psychiatry

Behav Brain Res

Behav Brain Res

Eur J Pharmacol

Neuropharmacology

Behav Brain Res

Behav Brain Res

Neuroscience

Int J Dev Neurosci

Brain Res Mol Brain Res

Neuroscience

The developmental origins of anxiety

Nat Rev Neurosci

The developmental role of serotonin: News from mouse molecular genetics

Nat Rev Neurosci

Pharmacotherapy for anxiety disorders in children and adolescents

Dialogues Clin Neurosci

Placental transfer of SSRI and SNRI antidepressants and effects on the neonate

Pharmacopsychiatry

Safety and side effect profile of fluoxetine

Expert Opin Drug Saf

Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors

Acta Paediatr

Archival Report
Postnatal Fluoxetine-Evoked Anxiety Is Prevented by Concomitant 5-HT_2A/C Receptor Blockade and Mimicked by Postnatal 5-HT_2A/C Receptor Stimulation

Postnatal 5-HT_2A/C Receptor Antagonist Treatment Prevents the Development of PNFlx-Evoked Adult Anxiety