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Memory-Enhancing Effects in Male Mice of Pregnenolone and Steroids Metabolically Derived from It

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Memory-Enhancing Effects in Male Mice of Pregnenolone and Steroids Metabolically Derived from It Proc. Nati. Acad. Sci. USA Vol. 89, pp. 1567-1571, March 1992 Neurobiology Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it (memory enhancement/pregnenolone sulfate/receptors/immediate-early genes/aging) JAMES F. FLOOD*t, JOHN E. MORLEY*, AND EUGENE ROBERTSt§ *Genatnc Research Education and Clinical Center, Veterans Administration Medical Center, St. Louis, MO 63106, and St. Louis University School of Medicine, Division of Geriatric Medicine, St. Louis, MO 63104; and tDepartment of Neurobiochemistry, Beckman Research Institute of the City of Hope, Duarte, CA 91010 Contributed by Eugene Roberts, November 8, 1991 ABSTRACT Immediate post-training intracerebroven- postmitotic differentiated states was favored in both neurons tricular administration to male mice of pregnenolone (P), and glia (7, 8). pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA), The water-soluble DHEAS, administered intracerebro- dehydroepiandrosterone sulfate (DHEAS), androstenedione, ventricularly (i.c.v.) or subcutaneously (s.c.) after training, testosterone, dihydrotestosterone, or aldosterone caused im- showed convincing memory-enhancing (ME) effects in foot- provement ofretention for footshock active avoidance training, shock active avoidance training (FAAT) in undertrained male while estrone, estradiol, progesterone, or 16.8-bromoepi- mice. DHEAS administered i.c.v. facilitated retention for androsterone did not. Dose-response curves were obtained for step-down passive avoidance training. Retention of FAAT P, PS, DHEA, and testosterone. P and PS were the most potent, was improved when DHEAS was given in taste-camouflaged PS showing significant effects at 3.5 fmol per mouse. The active drinking water for 1 week before and 1 week after training, steroids did not show discernible structural features or known while DHEAS in the drinking water for 2 weeks did not membrane or biochemical effects that correlated with their improve acquisition (9). DHEAS also completely counter- memory-enhancing capacity. The above, together with the acted the amnestic effects of anisomycin and scopolamine findings that DHEA acted even when given at 1 hr after training (9). A single s.c. injection of DHEAS after training improved and that P, PS, and DHEA improved retention over a much defective memory processes in aging mice, returning reten- wider dose range than do excitatory memory enhancers, led to tion of FAAT to the high levels observed in young mice (10). the suggestion that the effects of the active steroids converge at DHEA is insoluble in water but freely soluble in dimethyl the facilitation oftranscription ofimmediate-early genes. P and sulfoxide (DMSO). Pure DMSO (2 Al) administered i.c.v. PS, for which receptors have not yet been demonstrated, may caused amnesia. DHEA in DMSO (i.c.v., after training) was exert their effects by serving as precursors for the formation of active in impressively low amounts (3.5 pmol per mouse) in a panoply of different steroids, ensuring near-optimal modu- significantly improving retention relative to control groups lation of transcription of immediate-early genes required for receiving DMSO alone (9). Thus, inadequate availability of achieving the plastic changes of memory processes. Low serum DHEA, DHEAS, or steroids derived from them metaboli- levels of P in aging and the increases of cancer and behavioral cally could be rate-limiting in achievement of plastic changes disorders in individuals receiving drugs that block synthesis of required for retention of learning to take place. cholesterol, the immediate precursor of P, suggest possible The results cited above and those in the literature were clinical utility for P. compatible with the idea that these substances might be helpful in treatment of neurological diseases associated with Dehydroepiandrosterone (DHEA) and dehydroepiandroster- aging and metabolic or immune dysregulation. Clinical tests one sulfate (DHEAS), major circulating steroids in humans, with oral DHEA have been initiated in patients with multiple are largely adrenally derived substances which serve as sclerosis (11), Alzheimer disease (12), and benign memory precursors for both androgenic and estrogenic steroids (1). deficit. These substances appear to play important roles in many Cortisol, corticosterone, and dexamethasone previously aspects of cellular controls (1-5). Although molecular mech- had been shown to improve retention of FAAT (13). anisms of effects in particular instances have not yet been defined, the overall experimental results may be considered to be examples of pleiotropic facilitation of coordinative MATERIALS AND METHODS processes that enable immune, neural, and metabolic sys- Steroids Tested. The following substances obtained from tems, separately and together, to cycle freely through their the indicated suppliers were employed in the tests to be operational modes in solving problems of survival and re- described: DHEA from Searle; estradiol, estrone, testoster- production and in achieving rebalancing when malfunction- one, dihydrotestosterone, androstenedione, 17a-hydrox- ing occurs (4, 5). ypregnenolone, and pregnenolone sulfate (PS) from Steral- Blood levels ofDHEA and DHEAS are reduced in aging (6) oids (Wilton, NH); aldosterone, pregnenolone (P), proges- and during prolonged acute stress (1). We tested the suppo- sition (5) that raising extracellular levels of DHEA, DHEAS, Abbreviations: FAAT, footshock active avoidance training; i.c.v., or both might have some beneficial effects on aspects of intracerebroventricular(ly); s.c., subcutaneous(ly); DMSO, dimethyl nervous system function. Low concentrations of DHEA and sulfoxide; DHEA, dehydroepiandrosterone; DHEAS, dehydroepi- DHEAS reduced neuronal death and enhanced astrocytic androsterone sulfate; P, pregnenolone; PS, pregnenolone sulfate; differentiation while decreasing proliferation of astrocytes in IEG, immediate-early gene; ME, memory enhancement or memory- brain cell culture. Expression of cellular properties related to enhancing. tTo whom reprint requests and queries about behavioral aspects of the work should be addressed at: 151/JC, Veterans Administration The publication costs of this article were defrayed in part by page charge Medical Center, St. Louis, MO 63106. payment. This article must therefore be hereby marked "advertisement" §To whom queries about chemical and biochemical aspects of the in accordance with 18 U.S.C. §1734 solely to indicate this fact. work should be addressed. 1567 Downloaded by guest on September 27, 2021 1568 Neurobiology: Flood et al. Proc. Natl. Acad. Sci. USA 89 (1992) Table 1. Effects of 350 pmol of i.c.v.-administered steroids on 101, PREGNENOLONE retention of T-maze FAAT Substance tested Trials to P Substance icsted Trials to P critcrion* no cariterion*, no, valuct Saline 6.80±0.25 xamcrlhasonc DMSO 9.67±0.3* (14-Pregnadicnc-9a-luoro- 16a- P.........................m.:.......ethyl-I 113.17a.21-triol-3,20- Pregnenolone io) 9 (5-Pregnen-3p-ol-20-one) O 0 7.40±0.40 <0.01 0 ...................................... Dchydrocpiadroseronc Prcgnenolonc sulfaic (S-Androsln.31-oI-17-onc) 6.93±0.26 <0.01 (5-Pregnen-30-o1-20-onc § DEHYDROEPIANDROSTERONE z 0 osoto i16a-Bromoepiandrosicrone ...................................... (Sa-Androstanc-I6a-bromo-3p- l7a-Hydroxyprcgncnolonc 0l-17-onc0 Ij0 9.08±0.59 NS w 91 (5-Pregnene-30,17a-diol-20- one 0 7.27±0.37 <0.01.8 DchydropiandrosteronH sulfate HO P-V (5-Androsten-30ol-I1 7-one 8- ...................................... ..sulfat) 0 xx Progesterone oso2o I- 7I (4-Pregrnere-3.20-dione)000 (I) I° go 8.93±0.37 NSAndrosicncdion. 'El (4-Androstncric3,17-dionc) 6.93±0.37 <0.01 one)7~~~~~~~~~~~.2_.37<.01...... 0 7 -dionc) 6 I Corticosterone 0 (4-Pregnene-I 1 ,21-diol-3,20 Testosterone ....... ........ trione) OH (4-Androstcn- 170o-I3-onc) TESTOSTERONE OH11...°H . ........6.67±0.28 <0.01 ..... Dihydotestosteronc Aldostcrone (5a-Andrmtan- 170-oI-3-one) okicnc-3,(4-Pregncnec- 7..7.20±0.44 <0.01 110,21-diol-3,18 8] 20-trione) 7H7±.2O<No OX ......................................... °............ .. -.--.. ........ N'11.4 17p Estradiol 7 Sdk* xx 0 ~~~~~~~~~~~(l,3,5(l0)-Esatmriecn-3,l71§ 935043N ........diol)... OIl 0 9.351-0.43 NS Cortisol 6 (4-Pregnene- I 1 17 -rio1 l- r.o.......b:9 6 ..................................3¶20-dione) Estrone -15 -14 -13 -12 -11 -10 -9 ON (1 3.5(l0)-Esauicn-3-o1 17- | 19.20±0.42 NS LOG DOSE, mol per mouse *Data for trials to criterion are expressed as mean ± SEM. FIG. 1. Dose-response curves showing ME effects of P, DHEA, tP values for comparison with DMSO. NS, not significant. and testosterone on retention of T-maze FAAT measured in well- tP value for comparison with saline is <0.01. trained animals as the extent of prevention by substances dissolved §A memory enhancer (see Fig. 2). in DMSO of the amnesia produced by pure DMSO alone. Data for Previously shown to be memory enhancers in mice by the s.c. route, trials to criterion are expressed as mean + SEM. with dexamethasone being the most potent (13). Previously shown to be a memory enhancer in mice by i.c.v., s.c., substances dissolved in DMSO could prevent amnesia in- and oral routes (9). duced by DMSO alone. In these instances, training was performed under conditions that tend to maximize learning terone, and DMSO from Sigma. We received 16a- (five training trials; sound intensity, 65 decibels; footshock bromoepiandrosterone from Paul Talalay (Johns Hopkins current, 0.35 mA; intertrial interval, 45 s). To determine University School
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