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Involvement of the glutamatergic system in behavioral disorders in senescence-accelerated mice (SAMP8)
International Congress Series 1260 (2004) 303 – 308
www.ics-elsevier.com
Involvement of the glutamatergic system in behavioral disorders in senescence-accelerated mice (SAMP8) Yuu Fujiwara a,*, Hideki Takahashi a, Keisuke Hirai a, Masaomi Miyamoto b a
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan b Pharmacology Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 10 Wadai, Tsukuba, Ibaraki 300-4293, Japan Received 1 July 2003; received in revised form 14 October 2003; accepted 14 October 2003
Abstract. We previously reported that senescence-accelerated mice (SAMP8) showed age-related behavioral disorders such as learning and memory deficits and low anxiety-like behavior. To investigate the involvement of the brain glutamatergic system in the behavioral disorders observed in SAMP8, we examined the effects of MK-801, a non-competitive N-methyl-D-aspartic acid (NMDA) antagonist, on the behavior of a senescence-resistant control, SAMR1/TaSlc (SAMR1), and we tested the effects of D-cycloserine (DCS), a glycine site partial agonist, on behavioral disorders in SAMP8/ TaSlc (SAMP8). In the elevated plus-maze test, MK-801 significantly increased the number of entries into open arms and the time spent on open arms compared with the control group treated with saline. Furthermore, in the passive avoidance task, MK-801 caused dose-dependent decreases in avoidance latency in SAMR1. SAMP8 showed significant impairment in the acquisition of the passive avoidance response compared with SAMR1, even though they were trained repeatedly. DCS (3 or 10 mg/kg, intraperitoneally) tended to reduce the increased time spent on the open arms in SAMP8, and the administration of DCS (10 mg/kg, intraperitoneally) before each trial also tended to extend the avoidance latencies observed in SAMP8. These results indicate that the MK-801-induced behavioral disorders in SAMR1 are similar to those in SAMP8 and suggest that the glutamatergic system might be involved in the behavioral disorders observed in SAMP8. D 2003 Elsevier B.V. All rights reserved. Keywords: SAMP8; Glutamate; Passive avoidance; Elevated plus-maze; Behavioral disorder
1. Introduction Our previous studies of the behavioral characteristics of senescence-accelerated mice (SAMP8) have demonstrated age-related learning and memory impairments as com* Corresponding author. Tel.: +81-6-6300-6824; fax: +81-6-6300-6306. E-mail address: [email protected] (Y. Fujiwara). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)01730-8
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pared with a senescence-resistant control, SAMR1 mice, and we have shown that SAMP8 mice exhibit age-related emotional disorders including low anxiety-like behavior [1,2]. Our findings suggest that the SAMP8 strain is a useful animal model for studying age-related emotional disorders and memory impairments observed in senile dementia. Recent studies have demonstrated increases in the content of glutamate and decreases in the number of NMDA receptors in the SAMP8 brain, and these reports have suggested the involvement of these receptors in behavioral disorders [3,4]. In the present study, we investigated the involvement of the brain glutamatergic system in the behavioral disorders observed in SAMP8 by testing the behavioral effects of MK-801 on SAMR1 and those of D-cycloserine (DCS) on SAMP8. 2. Method 2.1. Subjects and experimental procedure The subjects were SAMP8/TaSlc (SAMP8) and SAMR1/TaSlc (SAMR1) mice at 4– 5 months of age (Japan SLC). Each mouse was individually housed in a stainless steel cage with free access to food (CE-2, Japan CLEA) and tap water, in a temperature-and light-controlled room (24 F 1 jC with a 12-h light –dark cycle, with lights on from 7:00 a.m. to 7:00 p.m.). Two different experiments were carried out. In experiment 1, the elevated plus-maze test and the passive avoidance task were performed with SAMR1 after administration of MK-801 (0.05 or 0.1 mg/kg, subcutaneously) or saline. Twenty-five SAMR1 mice were divided into three groups each: the first group was treated with MK-801 0.05 mg/kg (n = 8), the second group was treated with MK-801 0.1 mg/kg (n = 8), and the third group was treated with saline (n = 9). Ten SAMP8 mice were treated with saline and served as the control. MK-801 (Sigma) was dissolved in saline and administered subcutaneously 30 min before the test. For experiment 2, we used SAMP8 to perform an elevated plus-maze test and passive avoidance response test by repeated acquisition trials after the administration of DCS (1, 3, or 10 mg/kg) or saline. Thirty-eight SAMP8 mice were divided into four groups each: the first group was treated with DCS 1 mg/kg (n = 9), the second group was treated with DCS 3 mg/kg (n = 9), the third group was treated with DCS 3 mg/kg (n = 10), and the fourth group was treated with saline (n = 10). Ten SAMR1 mice were treated with saline and served as the control. DCS (Wako) was administered intraperitoneally 30 min before the test. Each drug was administered to the mice in a volume of 0.1 ml/10 g body weight. 2.2. Elevated plus-maze test The elevated plus-maze was comprised of two open arms measuring 50 10 cm, and two arms of the same size that were enclosed with walls 40 cm high, the two arms of each type being opposite each other. The maze was elevated to a height of 50 cm. Each mouse was placed at the center of the maze facing one of the enclosed arms, and it was allowed to explore the maze freely for 5 min. We then measured the number of entries into open or enclosed arms, and the time spent on the open arms.
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2.3. Passive avoidance task We used a two-compartment step-through passive avoidance apparatus for the passive avoidance task. An illuminated front chamber (9 9 25) was connected to a rear dark chamber (25 25 30 cm) equipped with a grid floor, with the two chambers separated by a sliding door (5 5 cm). On the initial acquisition trial, the mouse was placed in the front chamber and the sliding door was opened 20 s later. As soon as all four paws of the mouse entered the rear dark compartment, the door was closed and an AC 0.4 mA scrambled footshock was applied to the floor grid for 3 s. The mouse was then removed and returned to its home cage. The retention test was performed by replacing the mouse in the front chamber 24 h after the acquisition trial and measuring the latency to enter the dark compartment. If the mouse did not enter the dark compartment within 300 s, the retention test was terminated and a ceiling score of 300 s was assigned. In experiment 2, the mouse received a second foot shock when it entered the dark compartment in the retention test, and similar retention tests associated with repeated training were carried out at 48 h intervals. 3. Results 3.1. Experiment 1: behavioral changes in SAMR1 after administration of MK-801 Fig. 1A shows the number of entries into open arms and the number of total entries in the elevated plus-maze test. SAMP8 showed significant increases in the number of entries into open arms and total entries, which is consistent with our previous report. SAMP8 also showed significant increases in the mean time spent on open arms (Fig. 1B). The administration of MK-801 induced significant increases in the number of
Fig. 1. The effects of MK-801 on the behavioral performance of SAMR1 in the elevated plus-maze test and passive avoidance task. The mean number of entries (A) and the mean time spent on open arms (B) during 5 min of the plus-maze test are shown. The effects of MK-801 on the passive avoidance task in SAMR1 are shown in C. MK-801 was administered subcutaneously 30 min before each test. The retention test was performed 24 h after an acquisition trial. Each value shows the mean latency to enter the dark chamber in the acquisition trial or in the retention test. Vertical bars show the standard errors. Eight to 10 mice were used in each group. +P < 0.05, ++ P < 0.01, compared with the SAMR1 control (Student’s t-test); *P < 0.025, compared with the SAMR1 control (one-tailed Williams’ test).
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entries into open arms and in the time spent in open arms, compared with the SAMR1 control. Fig. 2C shows the effect of MK-801 on the passive avoidance response in SAMR1 mice. In the retention test carried out 24 h after the acquisition trial, the SAMR1 control exhibited long retention latencies. However, SAMP8 showed significantly shorter retention latencies compared with the SAMR1 control (SAMR1 control: 268.7 F 29.6; SAMP8 control: 13.3 F 2.4 s). The SAMR1 groups treated with MK-801 exhibited short retention latencies, and the higher-dose group (0.1 mg/kg) showed a significant deficit in the passive avoidance response ( p < 0.025, one-tailed Williams’ test). 3.2. Experiment 2: behavioral changes in SAMP8 after administration of DCS In the plus-maze test, the SAMP8 controls showed significant increases in the number of open-arm entries (Fig. 2A) and time spent on open arms (Fig. 2B) compared with SAMR1 mice. DCS reduced the increased time spent on open arms in the SAMP8 control, although the effect was not statistically significant (DCS 3 mg/kg: p = 0.036; DCS 10 mg/kg: p = 0.034; one-tailed Williams’ test). Fig. 2C shows the acquisition of the passive avoidance response by repeated training and passive avoidance retention after DCS administration. The SAMR1 mice showed a marked avoidance response, as demonstrated by long latencies in the first retention test (Acq1). However, all SAMP8 mice showed short latencies and received a second foot shock. Thereafter, similar retention tests were repeated at 48 h intervals. The SAMP8 mice gradually acquired the response, but the acquisition was relatively slow. By contrast, the group treated with DCS 10 mg/kg, tended to show an improved avoidance response, although the effect was not statistically significant.
Fig. 2. The effects of DCS on the behavioral performance in SAMP8 in the elevated plus-maze test and passive avoidance task. The mean number of entries (A) and the mean time spent on open arms (B) during 5 min of the plus-maze test are shown. The effects of DCS on acquisition of the passive avoidance response by repeated acquisition trials in SAMP8 mice are shown in C. DCS was administered intraperitoneally 30 min before each test. The first retention trial (Acq 1) associated with repeated training was carried out 24 h after the initial acquisition trial (Acq 0), and subsequent acquisition trials were performed at 48 h intervals. Each value shows the mean latency to enter the dark compartment. Vertical bars show the standard errors. +P < 0.05, + +P < 0.01, compared with the SAMP8 control (Student’s t-test).
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4. Discussion In the present study, we performed two experiments to investigate the involvement of the glutamatergic system in behavioral disorders in SAMP8. First, we observed the behavioral changes in SAMR1 after the administration of MK-801, and we then examined the behavioral changes in SAMP8 after the administration of DCS. In experiment 1, the SAMR1 mice treated with MK-801 exhibited low anxiety-like behaviors wherein the number of open-arm entries in the elevated plus-maze was significantly increased by the treatment, and the time spent on open arms was also markedly increased. In the passive avoidance task, MK-801 markedly impaired the passive avoidance response. In experiment 2, the SAMP8 mice treated with DCS showed changes in their reduced anxiety-like behaviors, such that they spent less time on the open arms in the plus-maze test. In the passive avoidance task by repeated acquisition training, the SAMP8 mice showed significantly shorter latencies compared with SAMR1. By contrast, 10 mg/kg of DCS prolonged the avoidance latencies in all trials, although the effect was not statistically significant. It has been shown that NMDA antagonists, including MK-801, induced memory deficits and low anxiety-like behaviors [5,6], and this is consistent with the present findings. Furthermore, the changes in SAMR1 treated with MK-801 were similar to those of SAMP8. Therefore, we suggest that the dysfunction of the glutamatergic system mediated by NMDA receptors might be the cause of the observed behavioral abnormalities in SAMP8. DCS is a partial agonist of glycine-B binding sites at the NMDA receptor complex. DCS has been shown to induce the behavioral amelioration of memory deficits in animal models involving brain lesions and aged rats [7,8], and it is expected that the NMDA receptor agonist might reduce the memory impairment in mammals. It has been well established that glutamate plays a key role in learning and memory, and that excessive release of glutamate by various insults has neurotoxic effects. Furthermore, previous neurochemical studies have demonstrated increases in the content or release of glutamate in the hippocampus in SAMP8 [3,4]. Thus, we consider that the neuronal damage caused by such an excessive release of glutamate might be involved in the behavioral disorders observed in SAMP8. Indeed, it has been reported that the release of [3H]-norepinephrine and [3H]-ACh stimulated by NMDA was attenuated in SAMP8 compared with SAMR1 [9,10]. In summary, the present study showed that the MK-801-induced behavioral disorders in SAMR1 are similar to those in SAMP8. These results suggest that the glutamatergic system might be involved in the behavioral disorders observed in SAMP8. References [1] M. Miyamoto, Y. Kiyota, N. Yamazaki, A. Nagaoka, T. Matsuo, Y. Nagawa, T. Takeda, Age related changes in learning and memory in the senescence-accelerated mouse (SAM), Physiol. Behav. 38 (1986) 399 – 406. [2] M. Miyamoto, Y. Kiyota, M. Nishiyama, A. Nagaoka, Senescence-accelerated mouse (SAM): age related reduced anxiety-like behavior in the SAM-P/8 strain, Physiol. Behav. 51 (1992) 979 – 985. [3] Y. Kitamura, X.H. Zhao, T. Ohnuki, M. Takei, Y. Nomura, Age-related changes in transmitter glutamate and NMDA receptor/channels in the brain of senescence-accelerated mouse, Neurosci. Lett. 137 (1992) 169 – 172. [4] Y. Nomura, Experimental techniques for developing new drugs acting on dementia (1)-senescence-accelerated mouse: neurochemical approaches and the findings, Jpn. J. Psychopharmacol. 14 (1994) 139 – 146.
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[5] Z. Hlinak, I. Krejci, MK-801 induced amnesia for the elevated plus-maze in mice, Behav. Brain Res. 131 (2002) 221 – 225. [6] K. Kawabe, T. Yoshida, Y. Ichitani, T. Iwasaki, Intrahippocampal D-cycloserine improves MK-801-induced memory deficits: radial-arm maze performance in rats, Brain Res. 814 (1998) 226 – 230. [7] P. Riekkinen Jr., S. Ikonen, M. Riekkinen, Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation, NeuroReport 9 (1998) 1633 – 1637. [8] M.G. Baxter, T.H. Lanthorn, K.M. Frick, S. Golski, R.Q. Wan, D.S. Olton, D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats, Neurobiol. Aging 15 (1994) 207 – 213. [9] X.H. Zhao, Y. Nomura, Age-related changes in uptake and release on L-[3H]noradrenaline in brain slices of senescence accelerated mouse, Int. J. Dev. Neurosci. 8 (1990) 267 – 272. [10] X.H. Zhao, Y. Kitamura, Y. Nomura, Age-related changes in NMDA-induced [3H]acetylcholine release from brain slices of senescence-accelerated mouse, Int. J. Dev. Neurosci. 10 (1992) 121 – 129.
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Involvement of the glutamatergic system in behavioral disorders in senescence-accelerated mice (SAMP8) Yuu Fujiwara a,*, Hideki Takahashi a, Keisuke Hirai a, Masaomi Miyamoto b a
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan b Pharmacology Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 10 Wadai, Tsukuba, Ibaraki 300-4293, Japan Received 1 July 2003; received in revised form 14 October 2003; accepted 14 October 2003
Abstract. We previously reported that senescence-accelerated mice (SAMP8) showed age-related behavioral disorders such as learning and memory deficits and low anxiety-like behavior. To investigate the involvement of the brain glutamatergic system in the behavioral disorders observed in SAMP8, we examined the effects of MK-801, a non-competitive N-methyl-D-aspartic acid (NMDA) antagonist, on the behavior of a senescence-resistant control, SAMR1/TaSlc (SAMR1), and we tested the effects of D-cycloserine (DCS), a glycine site partial agonist, on behavioral disorders in SAMP8/ TaSlc (SAMP8). In the elevated plus-maze test, MK-801 significantly increased the number of entries into open arms and the time spent on open arms compared with the control group treated with saline. Furthermore, in the passive avoidance task, MK-801 caused dose-dependent decreases in avoidance latency in SAMR1. SAMP8 showed significant impairment in the acquisition of the passive avoidance response compared with SAMR1, even though they were trained repeatedly. DCS (3 or 10 mg/kg, intraperitoneally) tended to reduce the increased time spent on the open arms in SAMP8, and the administration of DCS (10 mg/kg, intraperitoneally) before each trial also tended to extend the avoidance latencies observed in SAMP8. These results indicate that the MK-801-induced behavioral disorders in SAMR1 are similar to those in SAMP8 and suggest that the glutamatergic system might be involved in the behavioral disorders observed in SAMP8. D 2003 Elsevier B.V. All rights reserved. Keywords: SAMP8; Glutamate; Passive avoidance; Elevated plus-maze; Behavioral disorder
1. Introduction Our previous studies of the behavioral characteristics of senescence-accelerated mice (SAMP8) have demonstrated age-related learning and memory impairments as com* Corresponding author. Tel.: +81-6-6300-6824; fax: +81-6-6300-6306. E-mail address: [email protected] (Y. Fujiwara). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)01730-8
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pared with a senescence-resistant control, SAMR1 mice, and we have shown that SAMP8 mice exhibit age-related emotional disorders including low anxiety-like behavior [1,2]. Our findings suggest that the SAMP8 strain is a useful animal model for studying age-related emotional disorders and memory impairments observed in senile dementia. Recent studies have demonstrated increases in the content of glutamate and decreases in the number of NMDA receptors in the SAMP8 brain, and these reports have suggested the involvement of these receptors in behavioral disorders [3,4]. In the present study, we investigated the involvement of the brain glutamatergic system in the behavioral disorders observed in SAMP8 by testing the behavioral effects of MK-801 on SAMR1 and those of D-cycloserine (DCS) on SAMP8. 2. Method 2.1. Subjects and experimental procedure The subjects were SAMP8/TaSlc (SAMP8) and SAMR1/TaSlc (SAMR1) mice at 4– 5 months of age (Japan SLC). Each mouse was individually housed in a stainless steel cage with free access to food (CE-2, Japan CLEA) and tap water, in a temperature-and light-controlled room (24 F 1 jC with a 12-h light –dark cycle, with lights on from 7:00 a.m. to 7:00 p.m.). Two different experiments were carried out. In experiment 1, the elevated plus-maze test and the passive avoidance task were performed with SAMR1 after administration of MK-801 (0.05 or 0.1 mg/kg, subcutaneously) or saline. Twenty-five SAMR1 mice were divided into three groups each: the first group was treated with MK-801 0.05 mg/kg (n = 8), the second group was treated with MK-801 0.1 mg/kg (n = 8), and the third group was treated with saline (n = 9). Ten SAMP8 mice were treated with saline and served as the control. MK-801 (Sigma) was dissolved in saline and administered subcutaneously 30 min before the test. For experiment 2, we used SAMP8 to perform an elevated plus-maze test and passive avoidance response test by repeated acquisition trials after the administration of DCS (1, 3, or 10 mg/kg) or saline. Thirty-eight SAMP8 mice were divided into four groups each: the first group was treated with DCS 1 mg/kg (n = 9), the second group was treated with DCS 3 mg/kg (n = 9), the third group was treated with DCS 3 mg/kg (n = 10), and the fourth group was treated with saline (n = 10). Ten SAMR1 mice were treated with saline and served as the control. DCS (Wako) was administered intraperitoneally 30 min before the test. Each drug was administered to the mice in a volume of 0.1 ml/10 g body weight. 2.2. Elevated plus-maze test The elevated plus-maze was comprised of two open arms measuring 50 10 cm, and two arms of the same size that were enclosed with walls 40 cm high, the two arms of each type being opposite each other. The maze was elevated to a height of 50 cm. Each mouse was placed at the center of the maze facing one of the enclosed arms, and it was allowed to explore the maze freely for 5 min. We then measured the number of entries into open or enclosed arms, and the time spent on the open arms.
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2.3. Passive avoidance task We used a two-compartment step-through passive avoidance apparatus for the passive avoidance task. An illuminated front chamber (9 9 25) was connected to a rear dark chamber (25 25 30 cm) equipped with a grid floor, with the two chambers separated by a sliding door (5 5 cm). On the initial acquisition trial, the mouse was placed in the front chamber and the sliding door was opened 20 s later. As soon as all four paws of the mouse entered the rear dark compartment, the door was closed and an AC 0.4 mA scrambled footshock was applied to the floor grid for 3 s. The mouse was then removed and returned to its home cage. The retention test was performed by replacing the mouse in the front chamber 24 h after the acquisition trial and measuring the latency to enter the dark compartment. If the mouse did not enter the dark compartment within 300 s, the retention test was terminated and a ceiling score of 300 s was assigned. In experiment 2, the mouse received a second foot shock when it entered the dark compartment in the retention test, and similar retention tests associated with repeated training were carried out at 48 h intervals. 3. Results 3.1. Experiment 1: behavioral changes in SAMR1 after administration of MK-801 Fig. 1A shows the number of entries into open arms and the number of total entries in the elevated plus-maze test. SAMP8 showed significant increases in the number of entries into open arms and total entries, which is consistent with our previous report. SAMP8 also showed significant increases in the mean time spent on open arms (Fig. 1B). The administration of MK-801 induced significant increases in the number of
Fig. 1. The effects of MK-801 on the behavioral performance of SAMR1 in the elevated plus-maze test and passive avoidance task. The mean number of entries (A) and the mean time spent on open arms (B) during 5 min of the plus-maze test are shown. The effects of MK-801 on the passive avoidance task in SAMR1 are shown in C. MK-801 was administered subcutaneously 30 min before each test. The retention test was performed 24 h after an acquisition trial. Each value shows the mean latency to enter the dark chamber in the acquisition trial or in the retention test. Vertical bars show the standard errors. Eight to 10 mice were used in each group. +P < 0.05, ++ P < 0.01, compared with the SAMR1 control (Student’s t-test); *P < 0.025, compared with the SAMR1 control (one-tailed Williams’ test).
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entries into open arms and in the time spent in open arms, compared with the SAMR1 control. Fig. 2C shows the effect of MK-801 on the passive avoidance response in SAMR1 mice. In the retention test carried out 24 h after the acquisition trial, the SAMR1 control exhibited long retention latencies. However, SAMP8 showed significantly shorter retention latencies compared with the SAMR1 control (SAMR1 control: 268.7 F 29.6; SAMP8 control: 13.3 F 2.4 s). The SAMR1 groups treated with MK-801 exhibited short retention latencies, and the higher-dose group (0.1 mg/kg) showed a significant deficit in the passive avoidance response ( p < 0.025, one-tailed Williams’ test). 3.2. Experiment 2: behavioral changes in SAMP8 after administration of DCS In the plus-maze test, the SAMP8 controls showed significant increases in the number of open-arm entries (Fig. 2A) and time spent on open arms (Fig. 2B) compared with SAMR1 mice. DCS reduced the increased time spent on open arms in the SAMP8 control, although the effect was not statistically significant (DCS 3 mg/kg: p = 0.036; DCS 10 mg/kg: p = 0.034; one-tailed Williams’ test). Fig. 2C shows the acquisition of the passive avoidance response by repeated training and passive avoidance retention after DCS administration. The SAMR1 mice showed a marked avoidance response, as demonstrated by long latencies in the first retention test (Acq1). However, all SAMP8 mice showed short latencies and received a second foot shock. Thereafter, similar retention tests were repeated at 48 h intervals. The SAMP8 mice gradually acquired the response, but the acquisition was relatively slow. By contrast, the group treated with DCS 10 mg/kg, tended to show an improved avoidance response, although the effect was not statistically significant.
Fig. 2. The effects of DCS on the behavioral performance in SAMP8 in the elevated plus-maze test and passive avoidance task. The mean number of entries (A) and the mean time spent on open arms (B) during 5 min of the plus-maze test are shown. The effects of DCS on acquisition of the passive avoidance response by repeated acquisition trials in SAMP8 mice are shown in C. DCS was administered intraperitoneally 30 min before each test. The first retention trial (Acq 1) associated with repeated training was carried out 24 h after the initial acquisition trial (Acq 0), and subsequent acquisition trials were performed at 48 h intervals. Each value shows the mean latency to enter the dark compartment. Vertical bars show the standard errors. +P < 0.05, + +P < 0.01, compared with the SAMP8 control (Student’s t-test).
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4. Discussion In the present study, we performed two experiments to investigate the involvement of the glutamatergic system in behavioral disorders in SAMP8. First, we observed the behavioral changes in SAMR1 after the administration of MK-801, and we then examined the behavioral changes in SAMP8 after the administration of DCS. In experiment 1, the SAMR1 mice treated with MK-801 exhibited low anxiety-like behaviors wherein the number of open-arm entries in the elevated plus-maze was significantly increased by the treatment, and the time spent on open arms was also markedly increased. In the passive avoidance task, MK-801 markedly impaired the passive avoidance response. In experiment 2, the SAMP8 mice treated with DCS showed changes in their reduced anxiety-like behaviors, such that they spent less time on the open arms in the plus-maze test. In the passive avoidance task by repeated acquisition training, the SAMP8 mice showed significantly shorter latencies compared with SAMR1. By contrast, 10 mg/kg of DCS prolonged the avoidance latencies in all trials, although the effect was not statistically significant. It has been shown that NMDA antagonists, including MK-801, induced memory deficits and low anxiety-like behaviors [5,6], and this is consistent with the present findings. Furthermore, the changes in SAMR1 treated with MK-801 were similar to those of SAMP8. Therefore, we suggest that the dysfunction of the glutamatergic system mediated by NMDA receptors might be the cause of the observed behavioral abnormalities in SAMP8. DCS is a partial agonist of glycine-B binding sites at the NMDA receptor complex. DCS has been shown to induce the behavioral amelioration of memory deficits in animal models involving brain lesions and aged rats [7,8], and it is expected that the NMDA receptor agonist might reduce the memory impairment in mammals. It has been well established that glutamate plays a key role in learning and memory, and that excessive release of glutamate by various insults has neurotoxic effects. Furthermore, previous neurochemical studies have demonstrated increases in the content or release of glutamate in the hippocampus in SAMP8 [3,4]. Thus, we consider that the neuronal damage caused by such an excessive release of glutamate might be involved in the behavioral disorders observed in SAMP8. Indeed, it has been reported that the release of [3H]-norepinephrine and [3H]-ACh stimulated by NMDA was attenuated in SAMP8 compared with SAMR1 [9,10]. In summary, the present study showed that the MK-801-induced behavioral disorders in SAMR1 are similar to those in SAMP8. These results suggest that the glutamatergic system might be involved in the behavioral disorders observed in SAMP8. References [1] M. Miyamoto, Y. Kiyota, N. Yamazaki, A. Nagaoka, T. Matsuo, Y. Nagawa, T. Takeda, Age related changes in learning and memory in the senescence-accelerated mouse (SAM), Physiol. Behav. 38 (1986) 399 – 406. [2] M. Miyamoto, Y. Kiyota, M. Nishiyama, A. Nagaoka, Senescence-accelerated mouse (SAM): age related reduced anxiety-like behavior in the SAM-P/8 strain, Physiol. Behav. 51 (1992) 979 – 985. [3] Y. Kitamura, X.H. Zhao, T. Ohnuki, M. Takei, Y. Nomura, Age-related changes in transmitter glutamate and NMDA receptor/channels in the brain of senescence-accelerated mouse, Neurosci. Lett. 137 (1992) 169 – 172. [4] Y. Nomura, Experimental techniques for developing new drugs acting on dementia (1)-senescence-accelerated mouse: neurochemical approaches and the findings, Jpn. J. Psychopharmacol. 14 (1994) 139 – 146.
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[5] Z. Hlinak, I. Krejci, MK-801 induced amnesia for the elevated plus-maze in mice, Behav. Brain Res. 131 (2002) 221 – 225. [6] K. Kawabe, T. Yoshida, Y. Ichitani, T. Iwasaki, Intrahippocampal D-cycloserine improves MK-801-induced memory deficits: radial-arm maze performance in rats, Brain Res. 814 (1998) 226 – 230. [7] P. Riekkinen Jr., S. Ikonen, M. Riekkinen, Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation, NeuroReport 9 (1998) 1633 – 1637. [8] M.G. Baxter, T.H. Lanthorn, K.M. Frick, S. Golski, R.Q. Wan, D.S. Olton, D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats, Neurobiol. Aging 15 (1994) 207 – 213. [9] X.H. Zhao, Y. Nomura, Age-related changes in uptake and release on L-[3H]noradrenaline in brain slices of senescence accelerated mouse, Int. J. Dev. Neurosci. 8 (1990) 267 – 272. [10] X.H. Zhao, Y. Kitamura, Y. Nomura, Age-related changes in NMDA-induced [3H]acetylcholine release from brain slices of senescence-accelerated mouse, Int. J. Dev. Neurosci. 10 (1992) 121 – 129.