Brain Region-Specific Transcriptomic Markers of Serotonin-1A Receptor Agonist Action Mediating Sexual Rejection and Aggression in Female Marmoset Monkeys

Authors

  • Yves Aubert PhD,

    Corresponding author
    1. Bergen fMRI Group, Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
    2. Wisconsin National Primate Research Center, University of Wisconsin-Madison, WI, USA
    • Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, The Netherlands
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  • Kelly A. Allers PhD,

    1. Department of CNS Diseases, Boehringer Ingelheim, Biberach, Germany
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  • Bernd Sommer PhD,

    1. Department of CNS Diseases, Boehringer Ingelheim, Biberach, Germany
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  • E. Ronald de Kloet PhD,

    1. Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, The Netherlands
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  • David H. Abbott PhD,

    1. Wisconsin National Primate Research Center, University of Wisconsin-Madison, WI, USA
    2. Department of Obstetrics and Gynecology, University of Wisconsin-Madison, WI, USA
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  • Nicole A. Datson PhD

    1. Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, The Netherlands
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Corresponding Author: Yves Aubert, PhD, Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden 2333 CC, The Netherlands. Tel: +31715276301; Fax: +31715274715; E-mail: yvesaubert@gmail.com

Abstract

Introduction.

In a marmoset model of hypoactive female sexual function, we have shown that repeated administration of the serotonin (5-HT)-1A agonist R-(+)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) inhibits sexual receptivity in female marmoset monkeys and increases aggression toward the male pairmate.

Aim.

The aims of this study are to investigate gene expression changes induced by 8-OH-DPAT in laser-microdissected brain areas that regulate female sexual function and to identify genes, functional gene classes, and pathways associated with 8-OH-DPAT-mediated inhibition of female sexual receptivity.

Methods.

Gene expression was measured in the medial prefrontal cortex (mPFC), medial preoptic area (mPOA), cornu ammonis-1 (CA1) area of the hippocampus (CA1), and dorsal raphé nucleus (DRN) of four 8-OH-DPAT-treated (0.1 mg/kg; daily administration for 16 weeks) and four vehicle-treated female marmosets using a marmoset-specific microarray (European Marmoset Microarray [EUMAMA]) and validated by real-time quantitative polymerase chain reaction (RTqPCR). Enriched functional gene classes were determined. In a parallel candidate gene approach, the expression of serotonergic candidate genes, i.e., the 5-HT1A, 5-HT2A, and 5-HT7 receptors and the 5-HT transporter (5-HTT), was measured by RTqPCR.

Main Outcome Measures.

The main outcome is the differential expression of genes between 8-OH-DPAT- and vehicle-treated marmosets.

Results.

8-OH-DPAT affected the gene classes important to neural development (mPFC, mPOA, and DRN), neurotransmission (mPOA), energy production (mPFC and mPOA), learning and memory (CA1), and intracellular signal transduction (DRN). Oxytocin (OXT) in the mPOA and 5-HTT in the DRN were strongly increased by 8-OH-DPAT. 5-HT1A tended to increase in the mPFC, while 5-HT7 was decreased in the CA1.

Conclusions.

Brain region-specific alterations of gene expression regulating neural circuitries, energy demands, and learning processes are associated with 8-OH-DPAT-induced decrease in female sexual receptivity and increase in pairmate aggression. The role of OXT in the serotonergic regulation of female sexual behavior and partner interactions warrants attention in future studies.

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