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Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice

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Abstract

Rationale

Multiple lines of evidence suggest that the sex steroid hormone 17-β estradiol (E2) plays a protective role in schizophrenia. Systemic E2 enhances prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating known to be impaired in schizophrenia and related disorders. However, the relative contribution of different estrogen-receptor (ER) isoforms in these associations still awaits examination.

Objectives

The present study explored the effects of ER-α and ER-β stimulation or blockade on PPI and their functional relevance in an amphetamine-induced PPI deficiency model in male mice.

Methods

Prior to the assessment of PPI, C57BL/6N male mice were injected with the ER-α agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), the ER-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1N-pyrozole dihydrochloride (MPP), the ER-β agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN), or the ER-β antagonist 4-[2-phenyl-5,7-bis (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-3-yl] phenol (PHTPP), with or without concomitant amphetamine treatment.

Results

Acute pharmacological stimulation and blockade of ER-α, respectively, led to a dose-dependent increase and decrease in basal PPI. In contrast, acute treatment with preferential ER-β modulators spared PPI under basal conditions. Pretreatment with either ER-α or ER-β agonist was, however, effective in blocking amphetamine-induced PPI disruption.

Conclusions

Our study demonstrates that activation of either ER isoform is capable of modulating dopamine-dependent PPI levels. At the same time, our results suggest that endogenous ER-α signaling may be more relevant than ER-β in the regulation of sensorimotor gating under basal conditions.

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Acknowledgments

We would like to thank Selina Frei for assisting the behavioral experiments. This work was supported by grants from the Swiss National Science Foundation (310030_146217) and the European Union Seventh Framework Program (FP7/2007–2011; Grant Agreement No. 259679) awarded to U.M.

Disclosure

All authors declare that they have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603, Schwerzenbach, Switzerland

    Marie A. Labouesse, Wolfgang Langhans & Urs Meyer

  2. Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland

    Urs Meyer

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  1. Marie A. Labouesse
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  2. Wolfgang Langhans
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  3. Urs Meyer
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Correspondence to Marie A. Labouesse.

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Labouesse, M.A., Langhans, W. & Meyer, U. Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice. Psychopharmacology 232, 2981–2994 (2015). https://doi.org/10.1007/s00213-015-3935-9

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