, Volume 219, Issue 1, pp 213-224
Date: 29 Jul 2011

The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia

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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.


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.


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.


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.


Estrogen is functionally protective against 5-HT1A-, dopamine D2-, and NMDA receptor-induced PPI disruptions, while testosterone treatment enhances NMDA receptor-mediated PPI disruptions.