Estrogen Treatment Blocks 8-Hydroxy-2-dipropylaminotetralin- and Apomorphine-Induced Disruptions of Prepulse Inhibition: Involvement of Dopamine D 1 or D 2 or Serotonin 5-HT 1A , 5-HT 2A , or 5-HT 7 Receptors Andrea Gogos, Perrin Kwek, Carolina Chavez, and Maarten van den Buuse Behavioural Neuroscience Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria, Australia (A.G., P.K., C.C., M.v.d.B.); Centre for Neuroscience, University of Melbourne, Victoria, Australia (A.G.); and Department of Pharmacology, University of Melbourne, Victoria, Australia (C.C., M.v.d.B.) Received September 30, 2009; accepted December 29, 2009 ABSTRACT Prepulse inhibition (PPI) is a measure of sensorimotor gating and an endophenotype of schizophrenia. We have shown previously in rats that estrogen treatment prevents disruption of PPI by the 5-HT 1A /5-HT 7 receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). The aim of the present study was to examine the role of dopamine D 1 and D 2 and serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors in these effects. Part 1 of this study investigated the ability of estrogen treatment to reverse PPI disruption induced by 8-OH-DPAT or the dopamine D 1 /D 2 receptor agonist apomor- phine. Part 2 of this study compared these effects to the ability of various antagonists in reversing the action of 8-OH-DPAT and apo- morphine on PPI. Female Sprague-Dawley rats were ovariecto- mized (OVX), and, where appropriate, they received silastic im- plants containing either a low (E20) or high dose (E100) of estrogen. Two weeks later, PPI was assessed using automated startle boxes. The disruption of PPI by either treatment with 8-OH- DPAT (0.5 mg/kg) or apomorphine (0.3 mg/kg) was similarly pre- vented by E100 treatment. 8-OH-DPAT-induced PPI disruption was reversed by pretreatment with the 5-HT 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcy- clohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg) and the typical antipsychotic and dopamine D 2 receptor antagonist haloperidol (0.25 mg/kg), but it was not reversed by pretreatment with the dopamine D 1 receptor antagonist R-(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz- epine hydrochloride (SCH 23390; 0.1 mg/kg), the 5-HT 2A/2C re- ceptor antagonist ketanserin (2 mg/kg), or the 5-HT 7 receptor antagonist SB-269970 (10 mg/kg). Apomorphine-induced disrup- tions of PPI were reversed by haloperidol and SCH 23390 only. Estrogen may prevent disruptions of PPI induced by both 8-OH- DPAT and apomorphine by an action on dopamine D 2 receptors downstream of 5-HT 1A receptors. Epidemiological, clinical, and animal studies have led to the hypothesis that the “female” sex steroid hormone estro- gen plays a protective role in schizophrenia (Seeman and Lang, 1990; Ha ¨ fner et al., 1993). Men and women with schizophrenia differ in terms of age at onset, symptom sever- ity, and functional outcome (Ha ¨ fner et al., 1993). In women, schizophrenia symptoms worsen during the low estrogen stage of the menstrual cycle (Riecher-Ro ¨ssler et al., 1994). However, the mechanism of action of a protective effect of estrogen is unclear. Prepulse inhibition (PPI) is a measure of sensorimotor gating that functions as a filter of irrelevant information, preventing information overload and allowing for coherent thought. Patients with schizophrenia have deficient PPI, and treatment with atypical antipsychotic medication may re- verse this deficit (Braff et al., 2001). The PPI disruption in schizophrenia has been identified as one of the most consis- tently observed endophenotypes of the illness (Braff et al., 2007). It is interesting to note that, as with schizophrenia, This study was funded by the National Health and Medical Research Council of Australia [Grant ID 509234], a Peter Doherty Fellowship [ID 435690] (to A.G.), and a senior research fellowship [ID 435500] (to M.v.d.B.); the J. and P. Clemenger Trust; and the Operational Infrastructure Support from the Victorian State Government. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.162123. ABBREVIATIONS: PPI, prepulse inhibition; D, dopamine; 5-HT, 5-hydroxytryptamine (serotonin); 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin; WAY 100,635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; SB-269970, (R)-3-[2-[2-(4- methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride; SCH 23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahy- dro-1H-3-benzazepine hydrochloride; OVX, ovariectomized; E20, 5-mm silastic implant containing 20% estradiol; E100, 5-mm silastic implant containing 100% estradiol; ANOVA, analysis of variance; BW, body weight. 0022-3565/10/3331-218–227$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 333, No. 1 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 162123/3567177 JPET 333:218–227, 2010 Printed in U.S.A. 218