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-HT1A/5-HT7 receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). The aim of the present study was to examine the role of dopamine D1 and D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 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 D1/D2 receptor agonist apomorphine. Part 2 of this study compared these effects to the ability of various antagonists in reversing the action of 8-OH-DPAT and apomorphine on PPI. Female Sprague-Dawley rats were ovariectomized (OVX), and, where appropriate, they received silastic implants 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 prevented by E100 treatment. 8-OH-DPAT-induced PPI disruption was reversed by pretreatment with the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg) and the typical antipsychotic and dopamine D2 receptor antagonist haloperidol (0.25 mg/kg), but it was not reversed by pretreatment with the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0.1 mg/kg), the 5-HT2A/2C receptor antagonist ketanserin (2 mg/kg), or the 5-HT7 receptor antagonist SB-269970 (10 mg/kg). Apomorphine-induced disruptions 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 D2 receptors downstream of 5-HT1A receptors.
Footnotes
- Received September 30, 2009.
- Accepted December 29, 2009.
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-tetrahydro-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.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|