Abstract
Rationale
The sex steroid hormone, estrogen, may play a protective role in schizophrenia. We previously found that estrogen treatment inhibited serotonin-1A (5-HT1A) and dopamine D2 receptor-mediated disruptions of prepulse inhibition (PPI), a measure of sensorimotor gating which is deficient in schizophrenia.
Objectives
The present study aimed to further explore the role of sex steroid hormones in schizophrenia. Part 1 of this study examined whether estrogen could inhibit PPI disruption induced by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801. Part 2 investigated whether the functionally protective effect of estrogen occurs in another animal model of schizophrenia, amphetamine-induced locomotor hyperactivity. Part 3 compared our previous PPI findings in estrogen-treated rats, to treatment with testosterone.
Methods
Female Sprague–Dawley rats were ovariectomized (OVX) or sham-operated. Some OVX rats received silastic implants filled with either a low (E20) or high dose (E100) of estradiol, or a low (T5) or high dose (T20) of testosterone, for at least 2 weeks before behavioral testing.
Results
The disruption of PPI caused by MK-801 (0.1 mg/kg) was significantly reduced by treatment with estradiol (E20 and E100). However, estradiol treatment did not alter amphetamine-induced (0.25 and 0.5 mg/kg) locomotor hyperactivity, in terms of distance traveled, ambulation, or vertical counts. In contrast to estrogen, testosterone treatment did not affect disruption of PPI after administration of 8-OH-DPAT (0.5 mg/kg) or apomorphine (0.3 mg/kg). Testosterone treatment significantly enhanced the MK-801-induced (0.1 mg/kg) PPI disruption.
Conclusions
Estrogen is functionally protective against 5-HT1A-, dopamine D2-, and NMDA receptor-induced PPI disruptions, while testosterone treatment enhances NMDA receptor-mediated PPI disruptions.
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Acknowledgments
Funding for this study was provided by the National Health and Medical Research Council of Australia in the form of a Project Grant (ID 509234), a Peter Doherty Fellowship (ID 435690 to AG), and a senior research fellowship (ID 435500 to MvdB); the J. & P. Clemenger Trust; and the Operational Infrastructure Support (OIS) from the Victorian State Government. All experiments in this study were in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (1990) set out by the National Health and Medical Research Council of Australia. There are no conflicts of interest to report.
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Gogos, A., Kwek, P. & van den Buuse, M. The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia. Psychopharmacology 219, 213–224 (2012). https://doi.org/10.1007/s00213-011-2389-y
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DOI: https://doi.org/10.1007/s00213-011-2389-y