Psychopharmacology

, Volume 196, Issue 4, pp 555–564

Improvement of contextual memory by S 24795 in aged mice: comparison with memantine

Authors

    • Centre de Neurosciences Intégratives et Cognitives (CNIC), CNRS UMR 5228Universités de Bordeaux 1 et 2
  • Aurelie Boucard
    • Centre de Neurosciences Intégratives et Cognitives (CNIC), CNRS UMR 5228Universités de Bordeaux 1 et 2
  • Caryn Trocme-Thibierge
    • Institut de Recherches Internationales Servier
  • Philippe Morain
    • Institut de Recherches Internationales Servier
Original Investigation

DOI: 10.1007/s00213-007-0987-5

Cite this article as:
Beracochea, D., Boucard, A., Trocme-Thibierge, C. et al. Psychopharmacology (2008) 196: 555. doi:10.1007/s00213-007-0987-5

Abstract

Results

In comparison with 5-month-old mice, 18- to 19-month-old mice exhibited a severe and specific memory impairment in a contextual serial discrimination (CSD) task involving the learning and remembering of two successive spatial discriminations carried out on two distinct floors. This impairment was specific, as spatial memory, simultaneously tested on a simple discrimination (SD) task, was not affected in these aged mice. This deficit was completely reversed by 9-day per os administration of S 24795, a partial agonist of α7 nicotinic receptors, at either 0.3 or 1.0 mg/kg. Memantine, an NMDA receptor antagonist, also had a memory-enhancing effect at a dose of 3.0 mg/kg, but not at 0.3 mg/kg.

Conclusions

The memory-enhancing effect of S 24795 was due to a strong enhancement of contextual memory as indicated by a decrease in interference rate, whereas memantine enhanced spatial/semantic memory. S 24795 was more effective than memantine and also appears to be more specific to flexible forms of memory, one of the first cognitive domains (i.e. episodic memory) affected in Alzheimer’s disease.

Keywords

AgeingMiceContextual memoryEpisodic memoryS 24795MemantineNicotinic receptors

Introduction

Histopathological and neurochemical studies have indicated that a cholinergic deficit is present in Alzheimer’s disease due to the degeneration of central cholinergic neurons, culminating in progressive alteration in memory, orientation, and attentional processes. To oppose this cholinergic hypoactivity, the central nicotinic receptors, which mediate numerous and diverse physiological processes in the brain (Jones et al. 1999) including learning and memory (Levin and Simon 1998), have now been identified as potentially novel therapeutic targets (Newhouse et al. 1996; Holladay et al. 1997; Kem 2000). Centrally acting nicotinic cholinergic ligands have been shown to improve the performance of memory-related tasks in a number of animal models (Buccafusco et al. 1995; Levin and Simon 1998; Levin et al. 2006).

The precise contribution of each nicotinic receptor subtype in cognition is still a matter of debate, and we chose to focus on alpha7 nicotinic subtype because, in addition to its involvement in memory processes (Broide and Leslie 1999; Levin et al. 2002), it has been identified as a potential target for a disease-modifying approach, as it is likely to be involved in the mechanism of beta-amyloid intracellular accumulation (Wang et al. 2000; Nagele et al. 2002).

From a series of bromophenyl pyridinium derivatives, S 24795 was selected as a new partial agonist of α7 nicotinic acetylcholine receptors (α7 nAChR). The neuromodulatory activity of S 24795 for α7 nAChR responses of hippocampal interneurons has been recently described by Lopez-Hernandez et al. (2007). To characterise the memory-enhancing profile of S 24795, it was decided to investigate its effect in a contextual serial discrimination (CSD) task. This task has been developed to study different forms of memory (i.e. flexible contextual memory vs stable spatial memory; Celerier et al. 2004a, b; Beracochea et al. 2004, 2007) simultaneously in mice. Performance accuracy in the CSD task does not require the use of the temporal relationships between the discriminations, nor planning strategy in novel situations. Thus, the CSD task cannot be considered as testing episodic memory as defined in humans because accurate performance is not based on an integrated “what–where–when” representation, as is the case in recent models developed to provide non-human models of episodic memory (see Clayton et al. 2003; Dere et al. 2006). Nevertheless, the CSD task involves cognitive processes which are essential for episodic memory because accurate performance in that task requires flexibility in using specific internal contextual cues associated with each separate discrimination, a process that is distinct from spatial reference memory performance based on the exclusive use of allocentric cues common to both discriminations; indeed, as opposed to spatial/semantic memory, we showed that contextual memory in the CSD task involved the hippocampus, a brain structure sustaining declarative (episodic) memory in humans (David et al. 2006).

A previous study where aged mice learned two successive discriminations (D1 and D2) in two different contexts showed that 18- to 19-month-old C57Bl/6 mice were unable to remember D1, as compared with 5- to 6-month-old mice, whereas memory of D2 was substantial and similar to that observed in young mice (Beracochea et al. 2007). These experiments showed that the memory deficits in aged mice stemmed from a difficulty in using the specific internal cues associated with each discrimination—a process which is one of the main components of episodic memory (see also Celerier et al. 2004a; Beracochea et al. 2007). Conversely, spatial learning based on the use of external cues common to both discriminations and involving a semantic-like memory component was substantial and only moderately impaired as compared with young mice. These findings were in agreement with the memory deficits observed in aged human subjects where one of the main factors responsible for the deleterious effects of ageing on episodic memory is the progressively weakening ability of the elderly to use the contextual and temporal cues of the information to be remembered (Shimamura 1994; Spencer and Raz 1995; Smith et al. 1998; Doyere et al. 2000; Bastin et al. 2004; Grady and Craik 2000). As shown by several authors, such contextual and temporal cues are key components of the declarative (episodic) memory system (see Eichembaum 2000).

Thus, using the CSD task, the goals of the present study were threefold: (1) to determine whether the already observed (Beracochea et al. 2007) effects of ageing on the CSD task in C57Bl/6 mice are specific, i.e. context-dependent, or whether they are also observed on a more simple spatial discrimination (SD) task involving only spatial semantic-like memory; (2) according to the results, to evaluate the memory-enhancing effects of S 24795 on D1 performance in CSD; and (3) to investigate in parallel the effects of memantine, an NMDA receptor antagonist, on the same task. The memory-enhancing properties of memantine have been extensively described in several reviews (Danysz and Parsons 2003; Rogawski and Wenk 2003). The effect of S 24795 will be compared with that of this well-known pharmacological compound used in Alzheimer patients.

Materials and methods

Animals

The subjects were naive male mice of the C57Bl/6 inbred strain obtained from Janvier (Le Genest-St.-Isle, France). They were either 4 to 5 or 18 to 20 months old at the time of experiments and weighed between 28 and 32 g.

The mice were housed individually, under a 12-h light–dark cycle in a temperature-controlled and ventilated room. They were partially food-deprived for 1 week prior to behavioural experimentation and were maintained at 85 to 90% of their body weight throughout the behavioural phase. All test procedures were conducted during the light phase of the cycle.

Apparatus

All testing was performed in a four-hole board apparatus, enclosed with grey Plexiglass walls (as described in Beracochea et al. 2007). Briefly, the floor of the four-hole board was interchangeable (white and rough; black and smooth). On the floor, four holes opening on a food cup were located 6 cm from the sidewalls. Photocells placed in each hole allowed us to measure (1) the number of head-dips in each hole (parameter 1), (2) the time spent head-dipping into each hole (parameter 2), (3) the total number of head-dips in the four holes (parameter 3), and (4) the total time spent head-dipping into the four holes (parameter 4).

Behavioural procedures

Contextual serial discrimination

The procedure is described in Fig. 1. The discrimination in the four-hole board was based on the search for a food reinforcement (Bioserv pellets, San Diego, CA, USA).
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Fig. 1

aSD simple discrimination: the acquisition phase consisted in the learning of one single discrimination performed on a grey Plexiglass floor, and the test phase was done 24 h later on the very same floor. Contextual serial discrimination (CSD) task: the acquisition phase consisted in the learning of two successive discriminations, each performed on a different floor, whereas the test phase was performed either on the floor of the first (D1 test) or the second (D2 test) floor. b Different types of responses (correct, interference responses and errors) studied according to the floor used at the test phase in the CSD task

Acquisition

In room A, mice were first placed at the centre of the board in a PVC tube for 15 s and then learned two successive spatial discriminations (D1 and D2) for 6 min each. The two serial discriminations differed by the colour (black vs white) and texture (rough vs smooth) of the floor and were each separated by a 2-min time interval during which the mouse was placed in its home cage in room B. For discrimination 1, ten 20-mg pellets were available only in one of the four holes in the board. The same hole was baited for discrimination 1. For discrimination 2, ten 20-mg pellets were located in the opposite symmetrical hole. Allocentric spatial cues remained at the same place for the two successive discriminations. Thus, the discriminations varied only by the internal contextual cues, i.e. the different colour and texture of the floor of the four-hole board. Further, the sequencing of the two different floors in the series (first vs second acquisition) was systematically alternated from one mouse to another within each group.

Test session

Retention testing either for discrimination 1 or for discrimination 2 was carried out on independent groups of mice 24 h after the acquisition phase. The food-deprived mice were replaced either on the floor of discrimination 1 or on the floor of discrimination 2. In each case, mice were allowed to explore the apparatus freely, and performance was assessed by measuring the exploration for each hole during 6 min without any pellets in the apparatus.

This procedure allowed us to measure exploration in the “correct” hole (i.e. “correct responses”: head-dips into the hole previously baited on the same floor-context), the “interference” response (i.e. head-dips into the hole previously baited on the other floor-context) and “errors” (i.e. head-dips into the two holes never previously baited during the acquisition phase). Parameters 1, 2, 3, and 4 allowed calculations of the percentage time spent head-dipping [(parameter 2/parameter 4) × 100], as well as percentages of correct or interfering responses [(parameter 1/parameter 3) × 100]. The percentage of errors was calculated likewise.

Spatial memory

Spatial memory performance was assessed as (correct responses + interfering responses/parameter 3) × 100. Spatial responses refer specifically to head-dips made into previously baited holes, regardless of the floor used at the acquisition and retention phases. Thus, within the framework of our analysis, performance depended exclusively on the knowledge of external contextual cues associated with food reinforcement at the acquisition phase. Accordingly, spatial memory was an index of the external/semantic contextual memory. Conversely, “correct” responses defined by head-dips into the hole previously baited on the same floor-context during the acquisition phase were used as an index of the internal/episodic contextual memory.

Gain or loss of internal contextual memory

To measure the relative “strength” of the enhancing internal contextual memory effects of the compounds, the following difference was calculated: (% correct responses − % interfering responses). A difference equal to “0” means that mice perform the same number of head-dips into the correct and the interfering holes. A negative difference means that mice perform a higher number of head-dips into the interfering hole as compared with the correct one. In contrast, a positive difference means that mice perform a higher number of head-dips into the contextually correct hole as compared with the interfering one. Thus, the trend toward a positive difference represents the gain of internal contextual memory at the expense of the external contextual memory.

Simple discrimination

The procedure is described in Fig. 1. In the acquisition phase of the SD task, mice learned only one discrimination instead of two successive discriminations in the CSD task. The SD task was performed in the same apparatus and room as for the CSD task, except that the acquisition phase was performed on a grey Plexiglas floor. The acquisition phase lasted 6 min, as in the CSD task. Then, mice were replaced in the colony room during the delay interval. The test phase was done 24 h later. Mice were replaced on the same four-hole board apparatus, which was free of food pellets, and were allowed to explore the apparatus freely for 6 min. Performance was assessed by recording correct responses and errors, as defined above.

The SD and CSD tasks were performed using independent groups of mice.

Drug administration

In the CSD task, mice were given placebo or S 24795 (Servier, Courbevoie Cedex, France; two doses: 0.3 and 1.0 mg/kg) or memantine (Sigma, St. Louis, MO, USA, two doses: 0.3 and 3.0 mg/kg). The doses of the two active compounds were chosen on the basis of a preliminary test of object recognition in adult Wistar rats showing comparable activity of the two compounds in these respective dose ranges. In particular a dose of 0.1 mg/kg of S 24795 was shown to be ineffective (unpublished data). S 24795 was dissolved in a solution of monopotassic phosphate buffer 0.025 M (prepared by dissolving 3.4 g of KH2PO4 in 1 L of purified water). For the 1-mg/kg dose, S 24795 chloride powder was weighed and diluted in an adequate volume of this buffer to obtain a solution at 0.1 mg/ml, administered by gavage at a volume of 10 mL/kg. This solution was further diluted in the same buffer to obtain the dosage of 0.3 mg/kg. Memantine hydrochloride (Sigma) was diluted in the same buffer accordingly. All solutions were prepared freshly each day.

In the SD task, aged mice received the same pharmacological treatments (placebo, S 24795—the same two doses, and memantine 0.3 mg/kg) and were compared with a 4- to 5-month-old placebo group.

Before behavioural testing, all mice received daily for 7 days either S 24795, memantine or placebo by oral gavage. These pharmacological treatments were also administered 1 h before behavioural testing, both at the acquisition and test phases. The pharmacological treatments were administered in a room (room C, see Fig. 1) different from that in which the acquisition and test phases were performed (room A).

Statistics

Results are expressed as percentages. Parameters 1, 2, 3 and 4 were used to calculate the percentage time spent head-dipping (parameter 2/parameter 4) × 100 and the percentage number of responses (parameter 1/parameter 3) × 100. The data were analysed using one-way or two-way factorial ANOVA followed when required by post hoc comparisons (Scheffe’s test). The significance level was set at p < 0.05. Statistical analysis was performed using Statview® 5.0.1 software.

Results

Simple discrimination task

Acquisition phase

SD acquisition: aged vs young placebo-treated mice

During the acquisition phase of SD, no significant difference was observed between the aged and young groups in the total time spent visiting the different holes of the apparatus, nor in the time spent visiting either the non-reinforced holes or the reinforced one. A similar analysis of the total number of head-dips in the different holes indicated no difference between aged and young placebo-treated mice.

SD acquisition: aged mice given placebo vs S 24795 or memantine

Treatment with S 24795 (0.3 and 1 mg/kg) and memantine (0.3 mg/kg) did not significantly alter parameters of acquisition during SD, as shown by a similar total time spent head-dipping into the four holes of the apparatus, a similar time spent head-dipping into the non-reinforced holes as well as into the reinforced one. Percentage time spent exploring the reinforced hole was also similar among the groups An analogous analysis of the total number of head-dips led to the same conclusions.

SD test phase

SD test phase: aged vs young placebo-treated mice

No significant differences were observed between aged mice and young mice given placebo in the percentage of correct responses (see Fig. 2), the number of errors, the percentage of the time spent head-dipping into the correct hole, the total time spent head-dipping, and the total number of head-dips.
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Fig. 2

Percentage of correct responses measured in the test phase of the SD task in young placebo-treated mice and aged placebo-, S 24795- and memantine-treated mice

SD test phase: aged mice given placebo vs S 24795- or memantine-treated mice

In aged animals treated with placebo, S 24795 or memantine, no significant between-group differences were observed in the percentage of correct responses (Fig. 2), the percentage errors, the percentage time spent head-dipping into the correct hole and the total number of head-dips (p > 0.10 in all comparisons).

In summary, ageing did not impair memory as compared with young mice in the SD task, and the pharmacological treatments did not modify performance in aged mice.

Contextual serial discrimination task

CSD: effect of age on acquisition phase

Number of head-dips

This analysis compared the number of head-dips performed by aged (N = 18) vs young mice (N = 20) given placebo during the learning of D1 and D2 discriminations. ANOVA of the pooled number of head-dips of D1 and D2 discriminations showed no significant between-group difference in pooled non-reinforced holes or pooled reinforced ones. No statistical significant between-group difference was observed in the total number of head-dips into the pooled four holes during the acquisition of D1 and D2. No significant between-group difference was observed for the three non-reinforced holes or for the baited one.

Duration of head-dipping

ANOVA of the pooled total number of head-dips into reinforced and non-reinforced holes of both acquisitions 1 and 2 showed a significantly shorter time spent head-dipping in aged mice than in young ones [aged mice: 12.3 ± 4.3 s vs young mice 26.3 ± 3.9 s; F(1,36) = 10.6; p = 0.0025]. This decrease was observed for both pooled non-reinforced holes [aged mice: 5.3 ± 0.7 s vs young mice: 9.4 ± 1.9 s; F(1,36) = 3.8; p = 0.05] and pooled reinforced ones [aged mice: 6.99 ± 0.6 s vs young mice: 16.8 ± 2.8 s; F(1,36) = 10.6; p = 0.003].

On D1, the mean time spent head-dipping was greater in young mice (13.3 ± 3 s) than in aged ones [4.9 ± 0.6 s; F(1,36) = 6.46; p = 0.01]. This was mainly due to the observed difference for the baited hole [young mice: 8.0 ± 2.1 s vs aged mice 2.8 ± 0.5 s; F(1,36) = 4.89; p = 0.03], whereas the difference failed to reach statistical significance for unbaited ones [young mice: 5.0 ± 1.51 s vs aged mice: 2.1 ± 0.26 s; F(1,36) = 3.72; p = 0.06]. On D2, the total time spent head-dipping was greater in young mice (12.9 ± 1.2 s) than in aged ones [7.4 ± 0.7 s; F(1,36) = 15.2; p = 0.0004], and there was a significant difference with the baited hole [young mice: 8.75 ± 1.0 s; aged mice: 4.1 ± 0.4 s; F(1,36) = 16.4; p = 0.0003]. In contrast, no significant difference was observed for unbaited holes [young mice: 4.2 ± 0.7 s; aged mice: 3.28 ± 0.5 s; F(1,36) = 1.1; p = 0.3 ns]. On D1 and D2, the percentage of head-dipping into the baited and unbaited holes was, however, similar in aged mice and young mice; F < 1.0 in all comparisons.

CSD: effect of age in the test phase

The main results are shown in Fig. 3. ANOVA of pooled D1 and D2 correct responses showed a significant discriminatory effect [F(1, 34) = 6.6; p = 0.01] and a significant age effect [F(1,34) = 7.9; p = 0.007] but a non-significant interaction between “age” and “discriminations”: [F(1,34) = 0.1]. This lack of statistical significance was due to a comparable enhancement of performance from D1 to D2 in both the young and aged groups. As a whole, aged mice exhibited a lower percentage of correct responses (47.7 ± 3.2) than young mice [61.6 ± 4.2; F(1,36) = 6.5; p = 0.014].
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Fig. 3

Percentage of correct responses measured at D1 and D2 discriminations in the test phase of the CSD task in young and aged placebo-treated mice; double asterisks p < 0.01

The percentage of correct responses at D1 was significantly lower in aged mice receiving placebo than in their young counterparts [40.1 ± 2.2 vs 56.5 ± 6.3; F(1,18) = 5.0; p = 0.03; N = 9 and N = 11 for, respectively, the aged and young groups]. In contrast, the difference observed between the aged and young groups failed to reach statistical significance at the second discrimination (D2: 55.3 ± 5 vs 67,88 ± 4.9) [F(1,16) = 3.1; p = 0.09; N = 9 in both groups].

No significant difference between the aged and young groups was observed in the number of interference responses (p > 0.05) or in the percentages of interference responses at the D1 session (28.6 ± 2.6 vs 28.4 ± 8 in aged and young mice, respectively; F < 1.0) and D2 session (18.1 ± 4.5 vs 18.0 ± 4.1, respectively; F < 1.0). In contrast, aged mice made more errors than young mice [pooled D1 and D2 sessions: F(1, 34) = 6.9; p = 0.01] during the D1 session [8.2 ± 2.6 vs 5.0 ± 0.88 F(1,18) = 1.4; p > 0.05; ns, however] and mainly during the D2 session [10.8 ± 2.0 vs 4.6 ± 1.1; F(1,16) = 6.7; p = 0.019] (see Table 1). The percentage of spatial responses (correct responses + interference responses) was significantly lower in aged mice than young ones [pooled D1 and D2 sessions: F(1,34) = 17.5; p = 0.0002] at both the D1 session [aged mice: 68.7 ± 3.9% vs young mice: 85.0 ± 2.1%; F(1,18) = 15.1; p = 0.001] and the D2 session [aged mice: 73.4 ± 4.5% vs young mice: 85.9 ± 3.1%; F(1,16) = 5.0; p = 0.03].
Table 1

Summary of the main data observed in aged and young mice in the test phase of the CSD task at D1 and D2 discriminations

 

% Correct responses

% Interference responses

% Spatial responses

% Errors

D1

Aged placebo

40.1 ± 2.2*

28.6 ± 2.6

68.7 ± 3.9*

8.2 ± 2.6 (ns)

Young placebo

56.5 ± 6.3

28.4 ± 8

85.0 ± 2.1

5.0 ± 0.88

D2

Aged placebo

55.3 ± 5

18.1 ± 4.5

73.4 ± 4.5*

10.8 ± 2.0*

Young placebo

67.88 ± 4.9

18.0 ± 4.1

85.9 ± 3.1

4.6 ± 1.1

In conclusion, ageing significantly impaired serial contextual memory. More specifically, ageing significantly decreased the percentage of correct responses at the first discrimination (D1) but not at the second (D2). Compared with young mice, aged mice had a substantial but weaker spatial memory and made significantly more errors.

CSD: effects of treatments with S 24795 and memantine

As ageing selectively impaired D1 response rate and spared the retrieval of D2, we specifically investigated the effects of S 24795 and of memantine on D1 performance in aged mice. Analysis was performed on the following groups: S 24795 at 0.3 mg/kg: N = 10; S 24795 at 1.0 mg/kg: N = 8; memantine at 0.3 mg/kg: N = 9; memantine at 3.0 mg/kg: N = 9; and aged mice given placebo: N = 9.

Effects of treatment on acquisition

The analysis showed no significant behavioural between-group differences at the D1 or D2 acquisition sessions in either the number of head-dips or in the time spent head-dipping into the reinforced and non-reinforced holes (p > 0.06 in all analyses). The overall analysis also failed to reveal statistically significant differences in the percentage of head-dipping at D1 and D2 (F < 1.0 in both cases) or in the percentage time spent head-dipping (p > 0.20 in all analyses).

Effects of treatments on test phase

Results are summarised in Fig. 4a,b. The percentage of correct responses differed significantly among the groups [F(4,41) = 4.0; p = 0.007]. S 24795 (73.5 ± 3.8 and 62.1 ± 8.6% for the 0.3 and 1.0 mg/kg doses, respectively) and memantine (54.18 ± 8.3 and 63.6 ± 6.0% at the 0.3 and 3.0 mg/kg doses, respectively) significantly improved the performance of aged mice, as compared with placebo (40.1 ± 2.2%). Improved performance was mainly observed in mice receiving the 0.3 mg/kg S 24795 dose (p < 0.007 as compared with placebo), whereas 1.0 mg/kg S 24795 and 3.0 mg/kg memantine induced significant but smaller effects (p < 0.01 vs placebo in both analyses). The lower memantine dose induced no significant effect as compared with placebo (p > 0.30) (see Fig. 4a).
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Fig. 4

a Percentage of correct responses at D1 in the CSD task in placebo-, S 24795- and memantine-treated mice; double asterisks p < 0.01. b Percentage of interference responses at D1 in the CSD task in placebo-, S 24795- and memantine-treated mice; single asterisks p < 0.05

S 24795 also induced a dramatic reduction in interference responses as compared with placebo (10.7 ± 2.3 and 11.1 ± 4.3% for the 0.3 and 1.0 mg/kg S 24795 doses, respectively, as compared with placebo: 28.6 ± 2.6%; p = 0.02 and p = 0.03, respectively). In contrast, the two memantine doses did not reduce the number of interference responses as compared with placebo (22.7 ± 7.4 and 25.6 ± 8.6%; p > 0.20 in both comparisons; see Fig. 4b and Table 2). The improved performance in the 3.0 mg/kg memantine group was due to a reduction in the percentage errors (i.e. head-dips into the previously non-reinforced holes) as compared with placebo (13.6 ± 3.4 vs 31.4 ± 3.8%, respectively; p = 0.007), a finding also observed in the 0.3 mg/kg S 24795 group (15.7 ± 2.8%; p = 0.01 as compared with placebo).
Table 2

Summary of the main data observed in the test phase of the CSD task at D1 in aged placebo-, S 24795- and memantine-treated mice

D1

% Correct responses

% Interference responses

% Spatial responses

% Errors

Aged placebo

40.1 ± 2.2

28.6 ± 2.6

68.7 ± 3.9

31.4 ± 3.8

Aged S 24795 0.3 mg/kg

73.5 ± 3.8**

10.7 ± 2.3*

84.2 ± 2.8**

15.7 ± 2.8**

Aged S 24795 1 mg/kg

62.1 ± 8.6**

11.1 ± 4.3*

73.2 ± 5.5

26.7 ± 5.5

Aged memantine 0.3 mg/kg

54.18 ± 8.3

25.6 ± 8.6

79.8 ± 5.9

20.1 ± 5.9

Aged memantine 3 mg/kg

63.6 ± 6.0**

22.7 ± 7.4

86.3 ± 3.4**

13.6 ± 3.4**

To measure the relative “strength” of the enhancing memory effects of the compounds on internal contextual cues, we calculated percentage correct responses − percentage interference responses. Interference responses are an index of the memory of the second discrimination during testing of the first one, and therefore expressed a spatial semantic memory component. The greater the positive difference, the greater the gain in internal/episodic contextual memory at the expense of the external/semantic contextual memory.

Using this index, we observed a significant treatment effect [F(4,41) = 3.2; p = 0.02]. The positive difference increased significantly in both S 24795 groups (0.3 mg/kg: +62.5 ± 5; 1.0 mg/kg: +51.0 ± 12.5) compared with placebo (+11.5 ± 3.0; p < 0.001 and p < 0.01, respectively). Memantine at 3.0 mg/kg (+40.0 ± 13.0) and 0.3 mg/kg (+28.0 ± 16) did not differ significantly from placebo (p > 0.07 and p > 0.10, respectively) (see Fig. 5).
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Fig. 5

Difference between percentage correct responses and percentage interference responses in placebo-, S 24795- and memantine-treated mice; triple asterisks p < 0.001 and double asterisks p < 0.01 as compared with placebo

An additional analysis showed that the percentage of spatial responses was significantly improved by the pharmacological treatments [F(4,41) = 2.7; p = 0.04]. This improvement was statistically significant in the 0.3 mg/kg S 24795 group (84.2 ± 2.8%; p < 0.01 as compared with placebo: 68.7 ± 3.9%), as well as in mice treated with 3.0 mg/kg memantine (86.3 ± 3.4%; p = 0.008) (see Table 2).

The percentage time spent head-dipping into the previously reinforced hole was similar among the groups [F(4,41) = 1.3; p = 0.27], as was the percentage time spent head-dipping into the previously non-reinforced ones [F(4,41) = 1.15; p = 0.34].

Discussion

The main results of the study are as follows: (1) ageing (18- to 19-month-old mice) did not impair memory in a simple discrimination (SD) task but induced a selective retrieval memory deficit for the first discrimination but not the second one in the CSD task, as compared with young (5-month-old) mice; (2) this memory deficit was totally suppressed by chronic (nine consecutive days) per os administration of two S 24795 doses (0.3 and 1.0 mg/kg); and (3) S 24795 had greater memory-enhancing effects on contextual memory than memantine (0.3 and 3.0 mg/kg) in aged mice.

Effects of ageing on memory in the SD and CSD tasks

Ageing (18- to 19-month-old mice) induced no deficit in the learning and memory of a simple spatial discrimination (SD) task performed in a four-hole board apparatus. In contrast, in the contextual serial discrimination task (CSD), which involved the learning and remembering of two successive spatial discriminations (D1 and D2) carried out on two distinct floors (internal contexts), aged mice exhibited a severe memory deficit in remembering the first discrimination, as compared with young (5- to 6-month-old) mice (as seen in Beracochea et al. 2007). The memory deficit of aged mice consisted of a large reduction in the percentage of correct responses and in a concomitant increase in errors during the retrieval of D1, as compared with young mice. In contrast, the retrieval of D2 was similar to that of young mice. Thus, increasing the memory load of the task from SD (one single discrimination) to CSD (two successive discriminations) induced a dramatic serial contextual memory deficit in aged mice, with D2 interfering with retention of D1.

It does not seem that the modest behavioural differences observed at the acquisition phase between young and old mice could be responsible for the memory deficit of aged mice. Indeed, young and aged mice performed a similar number of head-dips into the reinforced and non-reinforced holes, at both acquisitions 1 and 2. In contrast, the mean duration of head-dipping was significantly greater in young mice than in aged mice, this between-group difference being observed for both baited and unbaited holes. However, this difference was much greater at acquisition 2 than at acquisition 1, and memory of the second discrimination (D2) was totally spared in aged mice, as opposed to the first one (D1).

Interestingly, even though it was weaker than in young mice, spatial/semantic-like memory in CSD in aged mice was substantial. This analysis is of interest in so far as it indicates that aged mice are able to locate the previously reinforced holes in relation to their spatial allocentric environment, a searching strategy which did not require the use of the internal contextual cues associated with each discrimination. The use of such a spatial allocentric “strategy” may be the consequence of either accelerated forgetting of the contextual discrete information associated with D1 or a weakness in the effortful processes required to remember specific internal contextual cues in the CSD task. Overall, our data drawn from the SD and CSD tasks are in agreement with numerous clinical studies showing that ageing induced detrimental effects on episodic memory tasks involving either an important memory load component (SD vs CSD) or different temporal or contextual cues associated with the information to be remembered (Hasselhorn et al. 1989; Earles et al. 1996; Thomas and Bulevich 2006; Kessels et al. 2007).

Effects of S 24795 and memantine on memory in aged mice in the SD and CSD tasks

Chronic (9 days) per os administration of either S 24795 (at 0.3 or 1.0 mg/kg) or memantine (0.3 mg/kg) did not significantly improve memory performance in the SD task, as compared with placebo-treated mice. This lack of effect of the pharmacological treatments may be due to a ceiling effect or to the fact that the SD task involved spatial semantic-like memory, which is relatively resistant or less sensitive to pharmacological compounds than more flexible forms of memory.

In contrast, the two doses of S 24795 (but mainly the 0.3-mg/kg dose) totally reversed the contextual memory deficit exhibited by placebo-treated aged mice at the D1 test session of the CSD task. Aged mice treated with 0.3 and 1 mg/kg S 24795 and with 3 mg/kg memantine had performances that were better than or at least as good as those of young mice given placebo in the same test (% of correct responses of, respectively, 73.5 ± 3.8, 62.1 ± 8.6, 63.6 ± 6.0% vs 56.5 ± 6.3% in young mice given placebo).

The memory-enhancing effect of S 24795 was due to a significant reduction in interference responses indicating that, unlike the placebo-treated aged mice, which used a simple spatial/semantic-like memory searching strategy, mice administered S 24795 were able to use the internal contextual component of the task to increase the number of correct responses. S 24795 facilitated the use of a flexible form of memory in aged mice. This conclusion is strengthened by further analysis, aimed at measuring the relative “strength” of the memory-enhancing effects of the pharmacological compounds. Thus, we calculated the difference between the percentage of contextual correct responses and the percentage of interference ones at the D1 session. We found that 0.3 mg/kg S 24795 induced a greater positive difference (+62.5 ± 5.0) than 1.0 mg/kg S 24795 (+51.0 ± 12.0), both indices being significantly greater than that of placebo-treated aged mice (+11.5 ± 3.0).

In contrast, 3.0 mg/kg memantine increased the number of correct responses and decreased the number of errors, as compared with the lower dose of memantine (0.3 mg/kg). The higher memantine dose had a more significant effect in the CSD task than the lower dose, but this memory-enhancing effect remained weaker than that of 0.3 mg/kg S 24795 (see Fig. 4), and it appears to be of a different cognitive nature. Whereas S 24795 increased contextual memory, as indicated by the difference between correct and interference responses, memantine emphasised much more spatial memory, as indicated both by the significant reduction of errors (i.e. head-dips into the previously non-reinforced holes, in the acquisition phase) and the persistence of interference responses.

One could argue that the 3-mg/kg dose of memantine is rather low compared with the 20–30-mg/kg range in which memantine has been reported to be active (Barnes et al. 1996; Minkeviciene et al. 2004). In our hands, a 10-mg/kg per os dose induced behavioural disturbances in NMRI mice (unpublished data) precluding the testing of this dose. Accordingly, other teams have reported behavioural disturbances in rats and learning impairment with a 10-mg/kg dose (Zajaczowski et al. 1997; Creeley et al. 2006; Zoladz et al. 2006). As stated in the “Materials and methods” section, the doses for each drug were chosen after a preliminary dose-range experiment in the rat object recognition paradigm, and therefore, the 3-mg/kg per os dose of memantine in the present study was deemed appropriate. Zajaczowski et al. (1997), Van Dam et al. (2005) and Zoladz et al. (2006) reported positive effects of memantine in different memory paradigms in rodents in the range 3–5 mg/kg, confirming our results.

The possible mechanism by which memantine can enhance memory has been discussed elsewhere (Danysz and Parsons 2003; Rogawski and Wenk 2003). Concerning α7 compounds, it has been shown that they can mediate fast cholinergic transmission within the hippocampus (Alkondon et al. 1998; Frazier et al. 1998), and they also may have an important role in modulating neurotransmitters release, such as glutamate (Radcliffe and Dani 1998; Alkondon et al. 2003) or noradrenaline (Barik and Wonnacott 2006), and GABA from interneurons controlling the neuronal excitability of CA1 pyramidal cells (Kanno et al. 2005) thereby potentially contributing to synaptic plasticity processes.

Thus, in conclusion, S 24795, a partial agonist of α7 nicotinic receptors, appears to be more pharmacologically powerful than memantine in improving contextual memory in aged mice. Given the importance of contextual cues in episodic memory, S 24795 can be proposed as a potentially powerful compound for attenuating episodic memory dysfunction associated with Alzheimer’s disease.

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© Springer-Verlag 2007