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

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.