5~r. ? ' : ELSEVIER Neuroscience Letters 202 (1996) 204-208 The neurosteroid dehydroepiandrosterone sulfate (DHEAS) enhances hippocampal primed burst, but not long-term, potentiation David M. Diamond a,b,*, Berrilyn J. Branch a, Monika Fleshner ~ aDepartment of Pharmacology, University of Colorado Health Sciences Center, Denver, CO, USA bMedical Research Service, Veterans Administration Medical Center, Denver, CO, USA CDepartment of Psychology, University of Colorado, Boulder, CO, USA Received 27 July 1995; revised version received 16 November 1995; accepted 21 November 1995 Abstract Dehydroepiandrosterone sulfate (DHEAS), which is synthesized in the brain and in the periphery, is known to affect the excitability of hippocampal neurons. However, its influence on electrophysiological plasticity has not been addressed. We have studied the effects of DHEAS on primed burst (PB) and long-term (LTP) potentiation, two electrophysiological models of memory. PB potentiation is a lasting increase in the amplitude of the CA1 population spike produced by minimal (threshold) electrical stimulation; LTP is produced by more extensive (supra-threshold) stimulation. Whereas intermediate doses (24 and 48 mg/kg, s.c.) of DHEAS given to rats enhanced PB potentiation, low (6 mg/kg) and high (96 mg/kg) doses were ineffective. LTP was not affected by any dose of DHEAS. The in- verted-U relationship between DHEAS and PB potentiatio.n is consistent with previous work demonstrating an inverted-U dose- dependent enhancement of memory by DHEAS. The present findings suggest that DHEAS could enhance memory by facilitating the induction of neural plasticity. Keywords: Neurosteroid; Long-term potentiation (LTP); Neuronal plasticity; CA1 ; Rat; Learning; Memory Dehydroepiandrosterone sulfate (DHEAS) is the most abundant adrenal steroid produced by young and mid- aged people [26,27]. Interest in this androgen precursor has increased in recent years because it appears to serve a protective role in pathological processes and it can an- tagonize the damaging effects of stress or glucocorticoids in a broad range of physiological systems [19,21]. For example, DHEAS counters the stress and glucocorticoid- induced suppression of immune function and increase in blood pressure [3,31]. It has also been shown that DHEAS increases neural excitability [15,23], improves memory [16,17,29] and enhances the survival of neurons in culture [29]. In the past decade Baulieu et al. have provided evidence that the brain synthesizes DHEAS de novo [2,5,28], with particularly high levels of the steroid taken up by the hippocampus [28], which is involved in learning and memory [4,33,35]. The behavioral and electrophysiological studies sug- * Corresponding author. Tel.: +1 303 3998020, ext. 2112; fax: +1 303 3775686; e-mail: d.diamond@uchsc.edu. gest that DHEAS can exert effects directly on the nervous system. However, there is little known concerning the functional consequences of DHEAS interactions with the central nervous system. One approach to address this is- sue is to evaluate the effects of DHEAS on learning- related neural plasticity. Two well-studied forms of plas- ticity are long-term (LTP), and primed burst (PB), poten- tiation [13,20,24,30]. In both cases electrical stimulation of the hippocampus induces a long-lasting enhancement of synaptic transmission, thereby providing a synaptic model of memory. LTP and PB differ, however, in their stimulation parameters. Whereas LTP involves extensive high frequency electrical stimulation (trains of at least 25-100 pulses) which typically results in a large increase in the magnitude of an evoked response, PB potentiation involves threshold stimulation (only five pulses patterned to mimic endogenous electrophysiological activity) and results in a smaller change in response. In this study we have tested the hypothesis that administration of DHEAS will affect hippocampal plasticity. We also investigated whether the effect of DHEAS on hippocampal plasticity 0304-3940/96/$12.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3940(95)12233-Q