Research reportThe neurosteroid pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats
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.
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2016, Neurobiology of Learning and MemoryCitation Excerpt :It is possible that PREG interacts with the activity of cholinergic systems, since application of PREG-S induced acetylcholine release in hippocampal and cortical areas (Darnaudéry, Koehl, Pallarés, Moal, & Mayo, 1998; Darnaudéry, Pallarés, Pizza, Le Moal, & Mayo, 2002; Darnaudéry et al., 2000; Pallarés, Darnaudéry, Day, Le Moal, & Mayo, 1998; Vallée et al., 1997). The promnestic actions of IN-PREG may refer to a direct steroid modulatory effect on cholinergic neurons, since PREG was also shown to have memory-enhancing effects when locally injected into the medial septum or nucleus basalis magnocellularis, the main sources of cholinergic innervation to the forebrain (Darnaudéry et al., 2002; Pallarés et al., 1998), although deleterious effects were also reported (Nanfaro, Cabrera, Bazzocchini, Laconi, & Yunes, 2010). The main findings here are unlikely to be confounded by attentional, sensorimotor, or anxiety-related factors, since all of the animals exhibited comparable performance during water maze extinction in swimming speed, and time to find the cued platform.
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2011, NeuroscienceCitation Excerpt :Perhaps particularly relevant to schizophrenia are reported pregnenolone actions on learning and memory in rodent models, as cognitive symptoms profoundly influence long-term outcome and quality of life in patients with schizophrenia (Green et al., 2000; Harvey et al., 2004; Marder and Fenton, 2004; Buchanan et al., 2005; Buchanan, 2006; Green, 2006; Marder, 2006). Importantly, pregnenolone and pregnenolone sulfate exhibit these actions on learning and memory (Flood et al., 1992, 1995; Mayo et al., 1993; Meziane et al., 1996; Vallée et al., 1997, 2001; Pallarés et al., 1998; Ladurelle et al., 2000; Akwa et al., 2001; Darnaudéry et al., 2002) at concentrations that appear to be physiologically relevant (Weill-Engerer et al., 2002; Marx et al., 2006c). Further, learning and memory improvements in response to these two neurosteroids have been reported in several different behavioral models (e.g., T-maze, Morris water maze, Y-maze) (Flood et al., 1992, 1995; Vallée et al., 1997; Akwa et al., 2001), and pregnenolone sulfate administration prevents learning and memory deficits induced by NMDA receptor antagonists, including MK-801 and DAP-V (Mathis et al., 1994, 1996; Romeo et al., 1994; Cheney et al., 1995; Akwa et al., 2001).
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2010, Pharmacological ReportsCitation Excerpt :This is not surprising, since neuroactive steroids have been proposed to exert a well tuned balance between excitatory (primarily glutamatergic systems) [8] and inhibitory systems (primarily GABAergic systems) [1, 25], acting in both cases as allosteric regulators of the correspondent receptors [7]. Regarding the effects of Preg-S on memory tasks, it has been reported a better response regarding spatial memory tasks in rats, associated to an increase in hippocampal acetylcholine [4]. In addition, a review dealing with neuroactive steroids and their sulfated variants [27] has summarized information regarding the promnesic effects of Preg-S in aging rats correlated with an increase of the levels of Preg-S in the hippocampus.