Abstract
The neurosteroid pregnenolone sulfate (PS) has been recently shown to positively modulate NMDA receptors and to have memory enhancing properties in mice. In the present study, we examined the ability of PS to increase retention performance and to reduce deficits induced by a competitive NMDA receptor antagonist, the 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), in a step-through passive avoidance task in rats. Pretraining administration of PS (0.84–1680 pmol, ICV) had minimal effects on retention performance assessed 24 h after training, while CPP significantly decreased retention performance at the doses of 1.2 and 1.6 nmol (ICV). However, when administered in combination with CPP (1.2 nmol), PS (0.84–840 pmol, ICV) dose-dependently blocked the deficit in passive avoidance response induced by the NMDA antagonist. At the dose of 840 nmol, PS also significantly reduced the motor impairment induced by CPP (1.2 nmol). The blockade of CPP-induced behavioral deficits by PS may result from its positive modulatory action at NMDA receptors.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Baulieu E-E, Robel P (1990) Neurosteroids: a new brain function? J Steroid Biochem Mol Biol 37:395–403
Bitran D, Hilvers RJ, Kellogg CK (1991) Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res 561:157–161
Bowlby MR (1993) Pregnenolone sulfate potentiation ofN-methyl-d-aspartate receptor channels in hippocampal neurons. Mol Pharmacol 43:813–819
Carette B, Poulain P (1984) Excitatory effect of dehydroepiandrosterone, its sulphate ester and pregnenolone sulphate, applied by iontophoresis and pressure, on single neurons in the septopreoptic area of the guinea pig. Neurosci Lett 45:205–210
Corpéchot C, Synguelakis M, Talha S, Axelson M, Sjövall J, Vihko R, Baulieu E-E, Robel P (1983) Pregnenolone and its sulfate ester in the rat brain. Brain Res 270:119–125
Crawley JN, Glowa JR, Majewska MD, Paul SM (1986) Anxiolytic activity of an endogenous adrenal steroid. Brain Res 398:382–385
Danysz W, Wroblewski JT (1989) Amnestic properties of glutamate receptor antagonists. Neurosci Res Commun 5:9–18
DeNoble VJ, Jones KW, Schaeffer CL, Bauerle LM (1990) 3-((±)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and phencyclidine produce a deficit of passive avoidance retention in rats. Eur J Pharmacol 175:197–202
Flood JF, Baker ML, Davis JL (1990) Modulation of memory processing by glutamic acid receptor agonists and antagonists. Brain Res 521:197–202
Flood JF, Morley JE, Roberts E (1992) Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci USA 89:1567–1571
Hu ZY, Bourreau E, Jung-Testas I, Robel P, Baulieu E-E (1987) Neurosteroids: Oligodendrocyte mitochondria convert cholesterol to pregnenolone. Proc Natl Acad Sci USA 84:8215–8219
Irwin RP, Maragakis NJ, Rogawski MA, Purdy RH, Farb DH, Paul SM (1992) Pregnenolone sulfate augments NMDA receptor mediated increases in intra cellular Ca2+ in cultured rat hippocampal neurons. Neurosci Lett 141:30–34
Lehmann J, Hutchison AJ, McPherson SE, Mondadori C, Schmutz M, Sinton CM, Tsai C, Murphy DE, Steel DJ, Williams M, Cheney DL, Wood PL (1988) CGS 19755, a selective and competitiveN-methyl-d-aspartate-type excitatory amino acid receptor antagonist. J Pharmacol Exp Ther 246:65–75
Maione S, Berrino L, Vitagliano S, Leyva J, Rossi F (1992) Pregnenolone sulfate increases the convulsant potency of N-methyl-d-aspartate in mice. Eur J Pharmacol 219:477–479
Majewska MD (1987) Steroids and brain activity: essential dialogue between body and mind. Biochem Pharmacol 36:3781–3788
Majewska MD, Schwartz RD (1987) Pregnenolone-sulfate: an endogenous antagonist of the γ-aminobutyric acid receptor complex in brain? Brain Res 404:355–360
Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232:1004–1007
Mathis C, De Barry J, Ungerer A (1991) Memory deficits induced by γ-l-glutamyl-l-aspartate andd-2-amino-5-phosphonovalerate in a Y-maze avoidance task: relationship to NMDA receptor antagonism. Psychopharmacology 105:546–552
Mathur C, Prasad VVK, Raju VS, Welch M, Lieberman S (1993) Steroids and their conjugates in the mammalian brain. Proc Natl Acad Sci USA 90:85–88
Mayo W, Dellu F, Robel P, Cherkaoui J, Le Moal M, Baulieu E-E, Simon H (1993) Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat. Brain Res 607:324–328
Mendelson WB, Martin JV, Perlis M, Wagner R, Majewska MD, Paul SM (1987) Sleep induction by an adrenal steroid in the rat. Psychopharmacology 93:226–229
Mienville J-M, Vicini S (1989) Pregnenolone sulfate antagonizes GABAA receptor-mediated currents via a reduction of channel opening frequency. Brain Res 489:190–194
Mondadori C, Weiskrantz L, Buerki H, Petschke F, Fagg GE (1989) NMDA receptor antagonists can enhance or impair learning performance in animals. Exp Brain Res 75:449–456
Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by anN-methyl-d-aspartate antagonist, AP5. Nature 319:774–776
Morrow AL, Pace JR, Purdy RH, Paul SM (1990) Characterization of steroid interactions with γ-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites. Mol Pharmacol 37:263–270
Nakahiro M, Arakawa O, Narahashi T, Ukai S, Kato Y, Nishinuma K, Nishimura T (1992) Dimethyl sulfoxide (DMSO) blocks GABA-induced current in rat dorsal root ganglion neurons. Neurosci Lett 138:5–8
Parada-Turska J, Turski WA (1990) Excitatory amino acid antagonists and memory: effect of drugs acting atN-methyl-d-aspartate receptors in learning and memory tasks. Neuropharmacology 29:1111–1116
Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J 6:2311–2322
Prince RJ, Simmonds MA (1993) Differential antagonism by epipregnanolone of alphaxalone and pregnanolone potentiation of [3H]flunitrazepam binding suggests more than one class of binding site for steroids at the GABAA receptors. Neuropharmacology 32:59–63
Purdy RH, Moore PH Jr, Rao PN, Hagino N, Yamaguchi T, Schmidt P, Rubinow DR, Morrow AL, Paul SM (1990) Radioimmunoassay of 3α-hydroxy-5α-pregnane-20-one in rat and human plasma. Steroids 55:290–296
Purdy RH, Morrow AL, Moore PH, Paul SM (1991) Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 88:4553–4557
Staubli U, Thibault O, DiLorenzo M, Lynch G (1989) Antagonism of NMDA receptors impairs acquisition but not retention of olfactory memory. Behav Neurosci 103:54–60
Takashima A, Maeda Y, Itoh S (1990) Effect of caerulein on decreased latency of passive avoidance response in rats treated with NMDA receptor antagonists. Peptides 11:1263–1267
Ungerer A, Mathis C, Mélan C, De Barry J (1991) The NMDA receptor antagonists, CPP and γ-l-glutamyl-l-aspartate, selectively block post-training improvement of performance in a Y-maze avoidance learning task. Brain Res 549:59–65
Venable N, Kelly PH (1990) Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice. Psychopharmacology 100:215–221
Walker DL, Gold PE (1991) Effects of the novel NMDA antagonist, NPC 12626, on long-term potentiation, learning and memory. Brain Res 549:213–221
Wieland S, Lan NC, Mirasedeghi S, Gee KW (1991) Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Brain Res 565:263–268
Wu F-S, Gibbs TT, Farb DH (1991) Pregnenolone sulfate: a positive allosteric modulator at theN-methyl-d-aspartate receptor. Mol Pharmacol 40:333–336
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mathis, C., Paul, S.M. & Crawley, J.N. The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task. Psychopharmacology 116, 201–206 (1994). https://doi.org/10.1007/BF02245063
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245063