Elsevier

Brain Research

Volume 951, Issue 2, 4 October 2002, Pages 237-242
Brain Research

Research report
The neurosteroid pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats

https://doi.org/10.1016/S0006-8993(02)03166-9Get rights and content

Abstract

The effects of an infusion of the neurosteroid pregnenolone sulfate into the medial septum on acetylcholine release in the hippocampus and on spatial memory were evaluated in two experiments. Results show that pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline and improved recognition memory of a familiar environment. Therefore, our results suggest that the septo-hippocampal pathway could be involved in the promnesic properties of this neurosteroid.

Introduction

Alzheimer’s disease (AD) is the most common degenerative disorder of elderly characterized by a heterogenous etiopathogenesis. Although the pathogenesis of AD is not completely understood, several lines of evidence suggest that the decline of cholinergic transmission caused by the destruction of basal forebrain plays a critical role in cognitive disorders observed in AD patients [2], [9], [26]. The cholinergic basal forebrain includes the medial septal nucleus and the nucleus basalis of Meynert, projecting mainly respectively to the hippocampus and to the cerebral cortex [21], two areas playing a major role in various aspects of cognition [29]. Currently available therapies for AD are limited to cholinergic drugs that augment impaired cholinoceptive mechanisms and can alleviate some of the symptoms for a subset of patients with such disease [31]. In this view, converging evidence from animals studies suggests that neurosteroids (mainly pregnenolone, dehydroepiandrosterone and their sulfate derivatives), which are steroids synthesized in the brain, may have some therapeutical interest for age-related disorders [22], [30], [34]. Pregnenolone sulfate (PREG-S), which was one of the first neurosteroid characterized in the rat brain, has been particularly studied for its action on memory processes [34]. Numerous behavioral studies have demonstrated in rodents that PREG-S administrations improve retention abilities in young [1], [7], [16] as well in old animals [33] and antagonize pharmacologically-induced amnesia [15], [18], [27], [32]. In vitro studies have demonstrated that PREG-S acts as a non-competitive antagonist of GABAA receptor [24] and as an allosteric agonist of the NMDA receptor [35].

Using microdialysis in freely moving rats, our recent studies suggest that PREG-S could modulate cholinergic neurotransmission. Indeed, we have previously observed that intracerebroventricular administrations of PREG-S enhance acetycholine (ACh) release in the cortex and in the hippocampus, without effect on striatal levels [3], [5]. In rats, the cell bodies of cholinergic neurons projecting to the cortex and to the amygdala are localized in the nucleus basalis magnocellularis (NBM), whereas those projecting to the hippocampus are found in the medial septum [17], [19]. We have previously reported an enhancement of ACh in cortex and amygdala after PREG-S infusion into the NBM [23]. Therefore, the aim of the present study, was to examine the implication of the medial septum in the PREG-S induced hippocampal ACh release. In addition, we investigated the effect of medial septum infusion of PREG-S on spatial memory recognition.

Section snippets

Animals housing and surgery

Male adult Sprague–Dawley rats (Iffa-Credo, France) weighing 260–280 g were housed individually under a 12 h light/12 h dark cycle with free access to food and water. Animals were i.p. anesthesized with ketamine (100 mg/kg) plus xylazine (4 mg/kg) and were placed in a stereotaxic apparatus (Kopf instruments) with the incisor bar set 3.3 mm below the interaural line. Two groups of subjects were used to evaluate the effects of PREG-S infusion into the medial septum, one set was used for

Effect of PREG-S infusion into the septal medial nucleus on hippocampal ACh release

Before any treatment baseline mean efflux of ACh in the hippocampus were respectively 10.66±2.19 and 9.35±0.87 fmol/min in the two experimental groups (ANOVA, F(1,11)=0.34, ns). Results shown in Fig. 2 depicted extracellular ACh variation expressed in percent of baseline levels. ANOVA conducted on the 13 ACh measures revealed a treatment×time effect (F(12,132)=2.06, P<0.02). Thus, PREG-S administrations into the medial septum enhanced extracellular concentrations of ACh in the hippocampus

Discussion

Our results demonstrate that PREG-S administrations into the medial septum stimulate cholinergic neurotransmission in the hippocampus. This observation is consistent with previous data showing that some neurosteroids could affect cholinergic transmission. Indeed, intracerebroventricular administrations of PREG-S and intraperitoneal administrations of dehydroepiandrosterone sulfate (DHEA-S) enhanced ACh release [3], [5], [28], while intracerebroventricular administrations of allopregnanolone

Acknowledgements

This study was supported y the European Community (BIOMED2, BMH4-CT, 97-2359), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Bordeaux 2 and the Conseil Régional d’Aquitaine.

References (35)

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