Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors.
We previously reported that high-affinity sigma type 1 (sigma 1) ligands attenuate the learning impairment induced in mice by dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist. Neurosteroids, such as pregnenolone sulfate, progesterone and dehydroepiandrosterone sulfate (DHEAS), modulate NMDA-evoked responses in the central nervous system. Furthermore, some of them were reported to interact with sigma-receptors. This study was carried out to investigate whether DHEAS, a neurosteroid with memory-enhancing effects, attenuates the dizocilpine-induced learning impairment in mice, and, if so, by a mechanism involving sigma 1-receptors. Learning was evaluated using spontaneous alternation in the Y-maze for spatial working memory and step-down type of passive avoidance for long-term memory. At doses about 10-20 mg/kg s.c., DHEAS significantly attenuated dizocilpine (0.15 mg/kg i.p.)-induced impairment of learning on both tests. The enhancing effect of DHEAS (20 mg/kg s.c.) was antagonized by co-administration of the sigma-antagonist BMY-14802 (5 mg/kg i.p.) and suppressed by a subchronic treatment with haloperidol (4 mg/kg/day s.c. for 7 days). These results indicate that DHEAS attenuates dizocilpine-induced learning impairment via an interaction with sigma 1-receptors.
Maurice
T
T
INSERM U 336, Développement, Plasticité et Vieillessement du Système Nerveux, Ecole Nationale Supérieure de Chimie, Montpellier, France. maurice@cit.enscm.fr
Junien
J L
JL
Privat
A
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D006220:Haloperidol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007859:Learning Disabilities / Q000139:chemically induced / Q000517:prevention & control*; D008024:Ligands; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced; D051379:Mice; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017480:Receptors, sigma / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D011743:Pyrimidines; D017480:Receptors, sigma; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D019314:Dehydroepiandrosterone Sulfate; D016291:Dizocilpine Maleate; D006220:Haloperidol