Effects of σ₁ receptor agonist SA4503 and neuroactive steroids on performance in a radial arm maze task in rats

This study examined the effects of σ₁ receptor agonist SA4503 and neuroactive steroids dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate (PREGS) and progesterone (PROG) on spatial working and reference memory in a radial arm maze task in rats. The insertion of a 6-min delay between the 2nd and 3rd choices caused a specific decline in working memory, but had no effect on reference memory. This decline in working memory was improved by SA4503, but not by DHEAS, PREGS or PROG. A non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine significantly impaired both working and reference memory in the presence or absence of a delay. The dizocilpine-induced impairments in the presence of a 6-min delay were ameliorated by SA4503, DHEAS and PREGS, whereas PROG had no effect. The beneficial effects of SA4503, DHEAS and PREGS were antagonized by treatment with σ₁ receptor antagonist N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-ethylamine hydrochloride (NE-100). Furthermore, PROG attenuated the ameliorating effects of SA4503, DHEAS and PREGS on dizocilpine-induced memory deficits. These results suggest that σ₁ receptors play a significant role in short-term working memory. Furthermore, it is suggested that DHEAS and PREGS ameliorate dizocilpine-induced memory impairments by acting as σ₁ receptor agonists, while PROG antagonizes their effects by acting as a σ₁ receptor antagonist. Copyright (C) 2000 Elsevier Science Ltd.