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Apparatus and Response Measurements. This procedure induces anxiety and panic attacks in humans (47). Animals are briefly exposed to a mixture of O2 and CO2 in an hermetically closed box for 1 min.

Neurosteroid Concentrations. This stress induces an increase in the content of PREG and PROG in the cerebral cortex and the hippocampus (48). Although an increase in DOC was also reported, no changes in DHEA concentrations were observed. However, these increases could result not only from an enhancement of brain steroidogenesis but also from an increased adrenal steroid output (particularly for DOC). Further studies using ADX animals would thus be of interest in addressing these question.

Neurosteroid Expression Induced by Stress or Anxiety: A Synthesis

Taken together, these works demonstrate that a stressful event induces an increase in cerebral allopregnanolone, which could attenuate the corticosterone stress-related response via the modulation of GABAA receptors. However, the stress/anxiety-induced PREG and PROG increases in the brain (i.e., formed in situ) need to be confirmed.

Aggressive Behavior

Adult female mice display an aggressive behavior towards lactating intruders. This behavior does not depend on ovarian hormones because it persists after ovariectomy (49). This aggressive behavior is reduced in intact males but is amplified by castration (49). DHEA injected chronically (sc, 80 ^g/d/2 wk) significantly reduced the aggressive response of castrated males. This effect does not result from a transformation of DHEA into sex hormones (i.e., testosterone (T) or estradiol). Indeed the synthetic steroid CH3-DHEA (3p-methyl-A5-androstene-17-one)—which is devoid of hormonal action—had an inhibitory effect on the attack similar to that of DHEA (50). Interestingly, both molecules significantly decrease PREGS concentrations in the brain of treated, castrated mice (29). A possible explanation for the anti-aggressive effect of DHEA could be an increased GABAergic tone secondary to the decrease of PREGS. Indeed, high levels of GABA have been described in the hypothalamus, olfactory bulbs, and amygdala of some particularly aggressive strains of mice (51). However, the mechanism by which DHEA decreases brain levels of PREGS remains unknown.

Age-Related Effects of Neurosteroids on Stress and Anxiety

Previously described studies have been performed on adult rodents. In order to determine whether the anxiolytic effect of allopregnanolone could be demonstrated in infant animals, Zimmerberg et al. (52) investigated the consequence of icv injections of different doses of allopregnanolone (1.25-5 ^g) on ultrasonic vocalization production induced after maternal separation. These vocalizations classically occur following maternal deprivation (53) and anxiolytic compounds, such as BZD, reduce it (54,55). Allo-pregnanolone caused a dose-dependent decrease in these ultrasonic vocalizations in 1-wk-old Wistar rats. These results suggest that the GABAa receptor site for this neurosteroid is behaviorally active in neonates as well as in adult rats.

Concerning aging studies, the work of Guo et al. (45) (see earlier) has shown that anti-allopregnanolone treatment had no effect on corticosterone levels after stress in aged males or females rats, although the mechanisms underlying this phenomenon remain unclear. In fact, to date, the only report of an altered mechanism of steroidogenesis in aged animals (reproductive senescence) comes from a study of Hodges and Karavolas (56), which showed that 5a-reductase (5a-R; the enzyme that converts PROG into 5 a-DHPROG) and 3a hydroxysteroid oxydoreductase (3a-HOR; the enzyme that converts 5 a-DH PROG into allopregnanolone) are altered in the pituitary of anestrus females compared to constant estrus ones.

Concluding remarks in summary, studies using anxiety-like measurements have shown that

1. Peripheral/central allopregnanolone administration induces anxiolytic behavior or reverses the anxiogenic effects of CRH.

2. The anxiolytic effects of exogenous PROG are owing at least in part to its bioconversion into cerebral allopregnanolone.

3. Results obtained with PREGS and DHEA and its sulfate remain difficult to interpret in light of their biphasic modulation of the GABAa receptor.

Collectively, these results demonstrate that neurosteroids with a GABAA-agonist profile exhibit clear anxiolytic properties. Conversely neurosteroids with an antagonistlike action at the GABAA receptor seem to act as anxiogenic compounds although some of them display biphasic effects i.e., anxiogenic/anxiolytic depending of the dose used.

In addition to animal studies, a few studies has been performed in humans. Following a single oral dose of micronized PROG (1.2 mg) in female subjects (18-25 ye), the peak plasma level of PROG was correlated with plasmatic levels of allopregnanolone and pregnanolone (3a-hydroxy-5p-pregnan-20-one) (57). The levels of allopregnanolone were significantly correlated with measures of fatigue and confusion. Although these and pregnanolone levels correlated with reduced tension-anxiety, changes in these parameters were no greater than those observed with placebo. However the normal subjects used in this study had very low anxiety scores and had no mood distress at baseline. Studies in anxious patients may better demonstrate the anxiolytic effects of these molecules, as suggested by the authors.


The consequences of neurosteroid administration on learning and memory processes are not easy to summarize. In fact a great number of paradigms involving different memories (spatial/nonspatial, working/reference, and so on) have been used and different steps of the information processing (acquisition, consolidation, retention) have been studied. However, owing to the previously demonstrated effect of neurosteroids on the emotional status of the animals, we decided to use a classification based on the nature of the task in terms of avoidance vs approach.

Avoidance-Based Paradigms

In these paradigms, animals learn a behavior in order to avoid some noxious stimulus. However in these tasks, emotional factors may play a critical role (58), making it impossible to interpret solely the "memory" component of the animal's performance.

Passive Avoidance

In passive avoidance paradigms, the animals remember that a certain response terminated in an unpleasant event and will therefore hesitate to repeat it in the future. An increase in response latency reflects the strength of the memory trace for the aversive event (see ref. 59 for review).

Apparatus and Response Measurements. In some procedures called "step-through passive avoidance," a lighted compartment (naturally aversive) is coupled directly or through a runway to a dark opaque compartment (naturally secure). Following habituation trials, the animals are placed in the lighted compartment. They naturally quickly run to the dark compartment, where this time, they are confined and receive an electric shock that is applied through the floor (usually 0.3-0.4 mA, for a 2 s duration). The animal is then returned to its home cage. This trial is called the acquisition trial and following a variable time interval (hours, days, or even weeks) the animal is again placed in the lighted compartment and the latency to enter the dark compartment is measured. The longer is this latency, the better is the "memory" performance. Pharmacological treatments can be administered before the acquisition trial or after it (retention). Another procedure is called "step-down passive avoidance." In this procedure, there are no compartments or runways, only an insulated platform located in the center of an open field with a grid floor. The animal is placed onto the platform and when he steps down an electric shock is applied through the grid floor of the open-field. Following a variable time interval, the animal is again placed onto the platform and the latency to "step-down" is recorded.

Neurosteroid Administration Before the Acquisition Trial. In these experiments, the use of pre-training injection procedures limits the interpretation in terms of direct interactions with learning and memory process.

PREGS when injected alone (0.3-700 ng icv) had no effect on the acquisition or the retention (24 h later) performance in male Sprague-Dawley rats (60). However using the same procedure, PREGS (175 or 351 ng icv) reversed the deficit induced by prior administration of the competitive NMDA receptor antagonist CPP 3-([±]-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (60). The same effect was reported by Cheney et al. (61) in CPP (2.5 mg/kg) or dizocilpine (MK801, a noncompetitive NMDA receptor antagonist, 0.15 mg/kg)-treated adrenalectomized/castrated male rats following iv injections of PREGS (0.5-20 mg/kg) 30 min prior to the acquisition trial, and by Romeo et al. (62) in dizocilpine-treated intact male rats following an ip injection of PREGS (20 mg/kg). These results may be explained by the ability of PREGS to potentiate the activation of the NMDA subtype of excitatory amino-acid receptors as demonstrated in cultured rat hippocampal neurons (63,64).

DHEAS (10 or 20 mg/kg sc) was also shown to attenuate dizocilpine-induced impairments in this task (65); this effect was antagonized by the co-administration of the a antagonist BMY-14802 (5 mg/kg ip) or by a sub-chronic treatment with haloperidol (4 mg/kg/day sc for 7 d) suggesting an interaction between DHEAS and a1 receptors.

Allopregnanolone (15 ^mol iv) had the same effect as PREGS or DHEAS in dizocilpine-induced deficits (62). For these authors, this quite surprising cognitive-enhancing effect of a neurosteroid acting as a positive modulator at the GABAa receptor suggests that either another receptor mediates the allopregnanolone effect or perhaps the involvement of different GABAA receptor subtypes.

After the Acquisition Trial. These experiments focus mainly on the consolidation/ retrieval action of neurosteroids. When injected subcutaneously to male Wistar rats immediately following the avoidance trial, PREGS (1,10, and 100 ng) facilitates the retention of a passive avoidance 24 h later. With a delay of 48 h only the dose of 100 ng was effective (66). When PREGS was injected 1 h prior the retention trial (i.e., 23 h or 47 h after the acquisition) no clear effect was observed.

Active Avoidance

In active avoidance paradigms, the animals are required to make some measurable response in order to avoid a noxious stimulus (generally an electric footshock).

Apparatus and Response Measurements. The more simple paradigms require an animal to run from one compartment of an apparatus to another (one-way step through) or to jump onto a pole to avoid a footshock. Rats and mice can acquire the appropriate responses within a limited number of trials. In the two-way shuttle avoidance paradigm, the animal has to shuttle from one compartment of an avoidance chamber to another. On each trial, the direction of the response is reversed. In T-maze or Y-maze active avoidance paradigms, boxes are placed at the end of each alley (one start box and two goal boxes). The animal is placed in the start box and must learn to walk quickly through the maze in order to reach one of the goal boxes designated as correct; otherwise, an electric shock is applied through the floor of the maze. The animal is shocked until it reaches the correct box. In these tasks, it is possible to measure a temporal component (i.e., the latency to leave the start alley) and a discrimination component (i.e., to choose the correct goal box). Facilitating or deleterious effects of various drugs on the retention of these active avoidance paradigms can be evaluated by modulating the strength of the acquisition in control animals (for example, a low shock intensity during acquisition trials led to a poor performance in retention. Conversely, higher electrical shocks during acquisition trials induce an optimal retention performance).

Neurosteroid Administration. The effects of neurosteroids in these tasks were evaluated by retention performance (i.e., administration made at the end of acquisition trials). DHEAS enhances retention 1 wk after training in a T-maze active avoidance paradigm when injected subcutaneously in mice (67). This effect seems to follow an inverted U-shaped curve, i.e., intermediate doses having a significant effect on retention (525-700 ^g/mouse), whereas lower (175 and 350 ^g/mouse) or higher doses (875 and 1400 ^g/mouse) had no significant effect. Similar dose-effects were reported following icv (108-271 ng active, 55 and 324 ng inactive) or intra-hippocampal administration (0.4 ng active, 0.04 and 4 ng inactive) and also following an oral administration during 1 wk (0.7 and 1.4 mg/mouse active, 0.36 and 2-3 mg/mouse inactive) (67,68). Subcutaneous DHEAS (20 mg/kg) can also reverse spontaneous retention deficits in old mice (18 or 24 mo-old) (69). Experimentally-induced amnesia in these tasks is sensitive to treatment with DHEAS. Retention deficits induced by scopolamine, dimethyl sulfoxide (DMSO), or anisomycine (inhibitor of protein synthesis) are abolished by DHEAS (icv 162 ng) (67). DHEA and PREG (icv 350 pmol/mouse) reverse DMSO-induced amnesia in the

T-maze active avoidance paradigm (70). PREGS was shown to be very potent in these paradigms. When administered icv in mice, a dose of 1.47 pg is already active on memory performance (70). Local administration in various limbic structures (amygdala, hippocampus, mammillary bodies and septum) confirms the potency of this neurosteroid. Amygdala infusions reveal that 15 molecules of PREGS (2.4 x 10-23 mol, i.e., 10-20 g) are able to significantly enhance the retention of mice as compared to control animals (68). Effects seen in amygdala are 104 times more potent than those in the hippocampus or 105 times more potent than those in the septum or the mammillary bodies. In all these limbic structures, the effects of PREGS exhibit an inverted U-shaped dose response curve. If these U-shaped response curves are typical of memory-enhancing compounds, the range of effective doses of PREGS (4-6 orders of magnitude) extends the usual range (2-5). These results show that PREGS is by far the most potent memory enhancer in this task yet reported. For the authors, some effects of this compound could imply the existence of an as yet unidentified receptor that has a high affinity for PREGS. An action on NMDA receptors can also be envisaged in light of the work of Mathis et al. (71), which showed that in a Y-maze active avoidance paradigm icv infusions of PREGS (4.2-42 ng) blocked the retention deficits induced by the competitive NMDA receptor antagonist D-AP5 (D-2-amino-5-phosphonovalerate).

Water Maze

The learning of this task originally proposed by Morris (72), involves the storage and the retrieval of spatial information and the planning of navigational strategies.

Apparatus and Response Measurements. In this task, animals are trained to escape from the water of a swimming pool by swimming to a hidden platform. The location of this hidden platform needs the use of distal extra-maze cues. Normal animals learn the location of the platform rapidly (usually a dozen trials spaced over several days). At the end of the learning phase, the strength of the memory for the location of the platform can be assessed by removing the platform and measuring the time to find (or the distance traveled to) the previous location of the platform.

Neurosteroid Administration. When administered subcutaneously to female ova-riectomized rats, DHEAS or PREGS (3.2 or 6.4 mg/kg) have no effect on the latency to find the platform but reduce the distance to find this platform compared to control animals (73). When administered icv (1-2 ^g), they reduce both the latency and the distance to escape onto the platform during the first trials of the task. Allopregnanolone (sc 3.2 or 6.4 mg/kg) in the same experiment reduced the latency to find the platform but was devoid of effect when administered icv These results are difficult to interpret in terms of memory owing to the protocol used, i.e., icv administrations made before the first trial of a 1-d water-maze procedure. Nevertheless an indirect enhancing effect of some neurosteroids in this task can be derived from the work of Romeo et al. (62), which showed that administration of FGIN 1-27—a ligand at the mitochondrial diazepam-binding inhibitor receptor complex (MDRC) that stimulates neurosteroidogenesis—reverses the memory deficit induced by dizocilpine in this task.

Neurosteroids and Avoidance-Based Paradigms: A Synthesis

As previously mentioned, emotional factors can play a critical role in these tasks and the results obtained are difficult to interpret solely in terms of memory performance. However, when administered during the consolidation/retention phase, PREGS and

DHEAS facilitate the retention of the task. The facilitating effects of PREGS were obtained with extremely low dose, but in this case the mechanisms underlying this effect remains largely unknown.

Approach-Based Paradigms

In these tasks, animals usually learn a response in order to get some appetitive reinforcement. However some paradigms can imply spontaneous approach behaviors.

Spontaneous Exploration of Novelty

Apparatus and Response Measurements. Rodents have a natural drive to explore novel environments. This behavior implies that the animal must memorize a previously explored environment in order to discriminate it from a novel one. A classical paradigm for studying this behavior is the spontaneous alternation task in a Y-maze or a T-maze. The animal freely explores the maze during a period of time (usually 10 min) and the percentage of alternation (an entry into all three arms on consecutive occasions) is recorded. The alternation score reflects attentional and short-term memory abilities. Another procedure recently proposed by Dellu et al. (74) requires the animal to explore 2 of the 3 arms of a Y-maze during a period of time (usually 10 min) which corresponds to the acquisition phase. Following a variable time interval (usually several hours), the animal is then replaced in the maze but this time he can explore all the three arms. Increased exploration of the "novel" arm reflects memorization of the previously explored places.

Neurosteroid Administration. In the Dellu's task (two-trial recognition task) an infusion of PREGS (5 ng) into the nucleus basalis magnocellularis (NBM) of male rats immediately following the acquisition trial enhances recognition performance as compared to control (75). When administered before the acquisition trial, PREGS had no effect. These results suggest an action of PREGS mainly on consolidation/retrieval processes and not on acquisition. DHEAS (sc 10-20 mg/kg) attenuates the dizocilpine-induced impairment in a Y-maze alternation task (65). Conversely, allopregnanolone infused into the NBM (0.2 or 2 ng) disrupts performance in the two-trial recognition task. These results suggest a memory-enhancing action of neurosteroids acting as negative allosteric modulators at the GABAa receptor and, conversely, a deleterious action of positive modulators (i.e., allopregnanolone). The effect at the NBM level also suggests possible modulation of cholinergic systems by neurosteroids. Indeed the NBM is the major source of the cortical cholinergic innervation.

Spatial Food/Water-Search Tasks

Apparatus and Response Measurements. In these tasks, animals are required to find food reinforcement using spatial cues. The classical paradigm is the radial-maze task (76). This maze consists of an octagonal central area from which eight arms radiate outwards. A food cup is located at the end of each arm. Food-deprived rats must learn to avoid choosing arms they have already visited during the test session. Another paradigm of spatial food search uses a hole-board (77), where the animal must find food reinforcement placed in one hole. These paradigms require the use of spatial extra maze cues by the animal. Some procedures using delayed nonmatching to sample (DNMTS) involving spatial discriminations are also used (78); for example, a Y-maze in which the animal must choose the opposite arm from that which it forced down in a previous run.

Neurosteroid Administration. In a hole board task, PREGS when administered (100 ^g ip) 8 d before exposure to the test and during the 5 d of acquisition, failed to modify significantly acquisition performance as compared to control animals (79). A subsequent 10-d treatment of these animals with subcutaneous PREG pellets (100 ^g daily) until the retention phase, also failed to modify retention performance. Similar results were obtained in a second set of experiments in which the animals were implanted with PREG pellets during 21 d. However, when treated, animals of the two experiments were pooled and compared to controls for retention performance, a significant treatment-effect was noticed in the middle trials of the retention phase (trials 4-6). However, in view of the statistical analysis of these results (pooling of experimental groups) and the experimental design (PREGS and PREG administration), caution should be used when interpreting the results.

In the radial-maze paradigm, no direct investigations were done, however, Romeo et al. (62) have shown that the deficit induced in this task by dizocilpine (i.e., an increase in the number of errors made in the fifth to eighth visits) was abolished by pretreatment with FGIN 1-27 indicating a positive effect of an enhanced steroidogenesis on this pharmacologically induced spatial memory deficit.

Using a DNMTS procedure in a Y maze, Frye and Sturgis (73) showed in ovariecto-mized rats that DHEAS (6.4 mg/kg ip) enhanced the percentage of correct choices made on d 5 of the task, but when injected on d 3 (3.2 mg/kg), the latency to the goal box was increased. This apparent discrepancy could be explained by an anxiogenic effect of DHEAS on the third day and a promnesic effect on the fifth day. However, the use of different doses of DHEAS in the same animal complicates the interpretation of the data. Using a similar paradigm in a T maze, Melchior and Ritzman (80) have shown that subcutaneous injections in mice of neurosteroids with a GABA antagonist profile (DHEA, DHEAS, PREG, PREGS), enhance performance in the task with an inverted U-shaped dose-response curve. Moreover, each neurosteroid at a dose of 0.05 mg/kg blocked the amnesic effect of ethanol (0.5 g/kg). Conversely, neurosteroids with a GABA agonist profile, i.e., pregnanolone or epipregnanolone (3^,5^-THPROG) disrupted the memory performance in this DNTMS task. Epipregnanolone had no effect on ethanol-induced amnesia. Surprisingly pregnanolone, which disrupted memory by itself, was also effective, in a wide range of doses, in blocking the amnesic action of ethanol. The authors explain this paradoxical effect by the fact that low levels of ethanol could counteract the GABA agonist properties of pregnanolone, as has been previously demonstrated for allopregnanolone (81).

Nonspatial Food/Water Reinforced Tasks

Apparatus and Response Measurements. In these tasks the animal must discriminate between two (or more) differentiated compartments of an apparatus in order to find reinforcement. Two kinds of procedures are currently used in these tasks : the "forced choice," in which the two compartments are shown together and the animal must select one of them, and the "go/no go" procedure, in which the different compartments are shown one at a time and the subject decides whether or not to make a response. Another classical nonspatial food-reinforced task involves operant behavior in Skinner boxes. In the simplest procedures the animal must press a lever in order to receive a food pellet. The number of reinforced responses increases with time, reaching a plateau that reflects acquisition of the task. A retention test is administered following a variable delay (24 h or more) and the number of reinforced responses during the beginning of the retention test is compared to the number of reinforced responses obtained during the last phase of the acquisition.

Neurosteroid Administration. In a go/no go paradigm, Meziane et al. (82) showed that PREGS administered icv (0.2 ^g) to male mice after the first learning session enhanced the subsequent learning performance during the second and third learning sessions. Administration of 0.04 [ig or 0.4 ^g had no effect on learning performance reflecting an inverted U-shaped response curve. However all these doses are effective in blocking the amnesic action of scopolamine (3 mg/kg sc) in this task. In the lever-press task, PREGS administered to male mice (41.8 ng icv) immediately after the acquisition session had no effect on retention performance measured 24 h later (71). However, the same injection can block the D-AP5-induced deficit in the retention phase. This positive result can be explained by the fact that PREGS blocks the effect of D-AP5 through its positive modulatory action on NMDA receptors.

Neurosteroids and Approach-Based Paradigms: A Synthesis

The use of these paradigms demonstrate the memory-enhancing properties of PREGS and DHEAS. Conversely THPROG, pregnanolone, and epipregnanolone disrupted the memory performance, suggesting that the positive/negative effects of neurosteroids on memory processes could involve their positive/negative modulation of GABAa receptors. However, a modulation of NMDA receptors could also participate in the effects observed, particularly for PREGS.

Physiological Data

Despite the great number of pharmacological studies indicating a promnesic action of some neurosteroids, and particularly of those having a GABA antagonist profile, little if nothing is known about the link between the cerebral concentrations of these steroids and memory performances. In order to define this relationship, we have first evaluated the learning/memory performances of a group of old male rats (24 mo) in the water-maze task and in the Y-maze spontaneous recognition task. Classical variability in the performances of old rats was noticed. Performances in the two tasks were correlated, i.e., animals that explored preferentially the novel arm in the Y-maze covered a shorter distance to escape onto the platform in the water maze (Spearman's p = -0.67, p < 0.001). We then measured the concentrations of PREGS in various brain areas. A significant correlation was found between the performance of the animals in the water maze and the concentrations of PREGS in the hippocampus (r = -0.53, p < 0.003) (Fig. 1).

This relationship seems to be specific to the hippocampus. Indeed no correlation was found in the amygdala, prefrontal cortex, parietal cortex, or striatum (83).

In order to determine the causative role of hippocampal PREGS in memory performance, PREGS (5ng/0.5 ^L) was infused directly into the dorsal hippocampus of old cognitively impaired rats immediately after the acquisition trial in the two-trial recognition task (Y maze). Animals treated with PREGS performed better than the vehicle injected group (t = 3.1, df = 10, p < 0.01) (Fig. 2).

These results suggest that neurosteroids could be studied in the context of prevention and/or treatment of age-related memory disorders.


All these experiments clearly demonstrate that neurosteroids—particularly those having a GABA antagonist profile—have memory-enhancing properties. Among these,

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Fig 1. Learning performance of aged rats in the water-maze: correlation with PREGS levels in the hippocampus. PREGS concentrations were expressed in log (ng/g). Performance was expressed as the mean distance to reach the hidden platform during the last 3 d of the test. Low PREG S levels were linked with longer distances, i.e., worse performances (y = [-7.01 ± 2.18] x + 12.61).

Fig. 2. Effects of bilateral injection of PREG S into the hippocampus on the performance of impaired aged rats in the Y-maze. The subgroup treated with PREGS (n = 7) performed significantly above chance level 6 h post-injection (t = 4.1, df = 5, **p < 0.01), and returned to chance level 7 d later (t = 1.1, df = 5, ns).

Fig. 2. Effects of bilateral injection of PREG S into the hippocampus on the performance of impaired aged rats in the Y-maze. The subgroup treated with PREGS (n = 7) performed significantly above chance level 6 h post-injection (t = 4.1, df = 5, **p < 0.01), and returned to chance level 7 d later (t = 1.1, df = 5, ns).

PREGS is probably the most potent. The mechanisms underlying these properties are presently unknown, but it could be hypothesized that the neuromodulatory pathways of PREGS may reinforce neurotransmitter systems that decline with age. Central cholinergic transmission represents a plausible candidate for these steroid effects. Indeed cholinergic systems in the basal forebrain, thought to be involved in the regulation of memory processes, are altered in normal aging, and degenerative changes in cholinergic nuclei correlate with memory impairments in old rats (84). Previous results of Mayo (75) and Meziane (82) are in agreement with this hypothesis. Moreover, it has recently been demonstrated that icv infusions of PREGS stimulated, in a dose-dependent manner the release of acetylcholine in the cortex and the hippocampus (85). The effects of neurosteroid administration on cholinergic transmission in old, cognitively impaired rats are currently under investigation, and could provide new insights into therapeutic strategies against age-related degenerative diseases, including senile dementia of the Alzheimer's type.

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