Acute stress impairs spatial memory in male but not female rats: influence of estrous cycle

We investigated how sex and estrous cycle influenced spatial recognition memory in the Y-maze after exposure to acute restraint stress. In Experiment 1, intact male and female rats were restrained for 1 h and then 2 h after the start of restraint, rats were trained on the Y-maze. After a 4 h delay, hippocampal-dependent spatial recognition memory was assessed. Acute stress produced opposite patterns between the sexes with spatial memory being impaired in males and facilitated in females. Serum corticosterone measures indicated that both sexes showed a robust corticosterone response after restraint and a moderate corticosterone response after Y-maze exposure. Serum corticosterone levels in response to restraint and Y-maze were not statistically different between the sexes. Experiment 2 examined the influence of the estrous cycle on spatial memory ability after acute stress. Acute stress facilitated spatial memory in females compared to controls, regardless of the estrous cycle phase (estrus and proestrus). Moreover, females in proestrus showed higher serum corticosterone levels during restraint compared to females in estrus. No differences in corticosterone levels were observed at baseline or following 2 h of recovery from restraint. These data show important differences in how sex and estrous cycle influence cognitive functions following acute stress.     

Behavioral responses to ethanol in rats perinatally exposed to low lead levels.

Wistar rats were exposed to 220 ppm of lead (Pb) in the drinking water from conception to the end of the nursing period (postnatal day 25). Maternal blood Pb levels at this time were 25 microg/dl. Male offspring were tested at the age of 35 or 70 days. We studied the anxiolytic response to 0.5-2.0 g/kg ethanol in an elevated plus maze test and preference for increasing ethanol solutions (2%, 4%, and 6%, v/v) in a free-choice paradigm; we also determined basal blood levels of corticosterone. Results demonstrated that, at 35 days of age, experimental rats were hypersensitive to the anxiolytic effect of ethanol and showed greater voluntary intake of this drug. In addition, 35-day-old Pb-treated rats exhibited higher basal levels of corticosterone as compared with those of controls. These differences disappeared at 70 days. Our findings are discussed in terms of either Pb-induced alterations in the development of the CNS or higher levels of corticosterone in experimental animals. Possible Pb-ethanol effects interactions are also considered.     

Corticosterone concentrations in blood and excretion in faeces after ACTH administration in male Sprague-Dawley rats

The aim of the present study was to analyse the corticosterone response to exogenous ACTH in the circulation of catheterised male rats and to investigate the sensitivity of faecal corticosterone output as a measure of preceding elevated levels in the circulation. A total of 21 adult male Sprague-Dawley rats permanently catheterised (v. jugularis externa for intravenous administration of ACTH and a. carotis communis for blood sampling), were used. Administration of both 10 and 100 microg/kg ACTH resulted in a rapid and pronounced corticosterone increase three minutes after injection (226 and 220 ng/ml, respectively), but the duration of the response was different. In the 10 microg/kg group, corticosterone levels were significantly elevated for 3-90 min after injection, while in the 100 microg/kg group, the levels remained elevated for 240 min after injection. In faeces, a significant increase during eight hours after ACTH injection was found in the group treated with 100 microg/kg, but not in the group treated with 10 microg/kg. In conclusion, quantification of faecal excretion of corticosteroids is a useful non-invasive measure of prior substantial stress (e.g. surgery), but not sufficiently sensitive to reveal minor stress or acute stress of short duration.     

Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response

RATIONALE: Acute and chronic systemic nicotine administration has been shown to cause significant spatial memory improvement. The critical nicotinic receptor subtypes for this effect and their location are still being determined. Nicotinic receptors in the ventral hippocampus have been found to be critically involved in memory. Acute ventral hippocampal infusions of dihydro-beta-erythroidine (DHbetaE), an alpha4beta2 nicotinic receptor antagonist, impaired spatial memory of rats in the radial-arm maze. OBJECTIVES: The current study used chronic ventral hippocampal infusion of DHbetaE as a model of nicotinic receptor loss such as that which occurs in Alzheimer's disease. The therapeutic effect of systemic nicotine treatment in reversing the DHbetaE-induced memory impairment was determined. METHODS: Rats were pretrained to asymptotic levels of performance on the eight-arm radial maze. Then, they were implanted with bilateral infusion cannulae in the ventral hippocampus, through which 0, 33.3, or 100 microg/side/day of DHbetaE was continuously infused for 4 weeks. The rats were retested on the eight-arm maze throughout infusion period and after withdrawal, and the interaction of acute systemic nicotine injections on memory was tested. RESULTS: The higher (100 microg/side/day) but not the lower (33.3 microg/side/day) DHbetaE dose caused a significant spatial memory impairment. Acute systemic nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg, subcutaneous) attenuated the memory impairing effects of 100 microg/side/day of DHbetaE. There was no significant effect on response latency with the chronic DHbetaE infusion. Acute systemic nicotine infusions did significantly speed responding, an effect which was reversed by chronic hippocampal infusions of DHbetaE. After withdrawal there were no significant lasting effects on choice accuracy or response latency. Wet-dog shakes were significantly elevated during chronic hippocampal DHbetaE administration with no effect during the withdrawal period. CONCLUSIONS: These results indicate that chronic inhibition of a subset of nicotinic receptors in the hippocampus results in a significant impairment in the spatial memory choice accuracy. The ability of nicotine to attenuate the impairment supports the development of nicotinic agonist therapy of syndromes, such as Alzheimer's disease, that involve a chronic decrease in the activity of the alpha4beta2 nicotinic receptors and memory impairment.     

Gingko biloba extract diminishes stress-induced memory deficits in rats

Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and undesired effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2 h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg/kg) impaired nonspatial memory as measured by an object recognition test. In control rats, EGB 761 improved spatial and nonspatial memory in Morris water maze and object recognition tests. Preventive doses of EGB 761 (100 mg/kg) normalized cognitive deficits, seen in rats chronically stressed or treated with corticosterone in object recognition test, and improved memory processes in these rats measured by Morris water maze test. There was no influence of our treatments on locomotor exploratory activity and anxiety measured in open field and elevated 'plus' maze tests, making a contribution of unspecific motor and emotional effects of the used drugs to their performance in the memory tests improbable.     

Stress at Learning Facilitates Memory Formation by Regulating AMPA Receptor Trafficking Through a Glucocorticoid Action

Stress and glucocorticoids (GCs) can facilitate memory formation. However, the molecular mechanisms mediating their effects are largely unknown. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) trafficking has been implicated in the changes in synaptic strength at central glutamatergic synapses associated with memory formation. In cell cultures, corticosterone has been shown to condition the synaptic trafficking of the AMPAR GluA2 subunit. In this study, we investigated the involvement of GluA2 trafficking in the facilitation of learning by stress. Using the water maze spatial task involving different stress levels, mice trained under more stressful conditions (water at 22°C) showed better learning and memory, and higher post-training corticosterone levels, than mice trained under lower stress (water at 30°C). Strikingly, this facilitated learning by stress was accompanied by enhanced synaptic expression of GluA2 AMPARs that was not observed in mice trained under less stressful conditions. Interfering with GC actions by injecting the GC synthesis inhibitor, metyrapone, blocked both the memory facilitation and the enhanced GluA2 trafficking induced by stressful learning. Intracerebroventricular infusion of the peptide, pep2m, that blocks GluA2 synaptic trafficking by interfering with the interaction between N-ethylmaleimide-sensitive factor and GluA2, impaired immediate performance at learning as well as long-term memory retrieval, supporting a causal role for GluA2 trafficking in stress-induced facilitation of spatial learning and memory. Evidence for the involvement of the neural cell adhesion molecule N-cadherin in interaction with GluA2 is also provided. These findings underscore a new mechanism whereby stress can improve memory function.     

Phencyclidine disrupts long- but not short-term memory within a spatial learning task

In the first experiment rats with 1, 2, 3 or 4 mg/kg phencyclidine (PCP), or saline injections were tested for acquisition or retention of a cheese board spatial task (dry land version of a water maze). Results indicate that relative to controls or rats with injections of 1 and 2 mg/kg PCP, rats with 3 or 4 mg/kg PCP injections were impaired in acquisition and retention of the task as measured by increased distances traveled to find the correct food location. This impairment was primarily observed in between days but not within days performance. In the second experiment rats with 4 mg/kg PCP or saline injections were tested for memory performance of a delayed spatial matching-to-sample task. Results indicate that relative to controls rats with 4 mg/kg PCP injections were not impaired at either 1–5 or 30 s delays. It is suggested that PCP through its blocking action of the NMDA receptor mediates long- but not short-term memory for spatial location information as well as the ability to retrieve previously learned spatial location information.     

Stress modulation of the memory retrograde-enhancing effects of the awakening drug modafinil in mice

Purpose This study investigated the dose–effect relationship of modafinil administration on contextual memory processes, in parallel with the measurements of plasma corticosterone levels in acutely stressed mice. Materials and methods Memory was first evaluated in normal (nonstressed) mice either in contextual (CSD) or spatial (SSD) tasks. Thus, C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board. The discriminations occurred on either distinct (CSD) or identical (SSD) floors (internal contextual cues). All mice received a vehicle intraperitoneal injection before learning and were injected 24 h later (20 min before the test session) either with vehicle or modafinil. Results Results showed that modafinil-treated mice behaved similarly as vehicles in the spatial SSD task, whereas in contrast, memory of the first-learned discrimination (D1) in the CSD task was enhanced by a 32- but not a 16-mg/kg modafinil dose. Hence, we studied the effect of a pretest acute stress (electric footshocks) specifically on D1 performance in modafinil-treated subjects. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels. Conclusions Results showed that: (1) stress significantly improved performance in vehicles, (2) stress decreased the efficiency threshold of modafinil, as performance was enhanced at the low dose (16 mg/kg), whereas this enhancement was obtained for the high dose (32 mg/kg) under nonstress conditions, (3) the performance was impaired at the high (32 mg/kg) dose, and (4) modafinil significantly reduced the magnitude of the stress-induced corticosterone secretion, mainly at the dose of 32 mg/kg.     

Effect of diphenhydramine on stress-induced changes in brain histidine decarboxylase activity,histamine and plasma corticosterone levels

Exposure of rats to platform stress induced a significant elevation in hypothalamic histamine levels. Air blast-stress resulted in a significant increase in hypothalamic histamine concentration and in histidine decarboxylase activity. No significant changes were noted either in the enzyme activity or in histamine levels in the midbrain or cortex of stressed rats. In the nonstressed rats, diphenhydramine (7.5 mg/kg intragastrically), a H₁-receptor antagonist, did not influence histidine decarboxylase activity or histamine concentration in any of the three brain regions investigated. However, diphenhydramine pretreatment prevented the increase in histidine decarboxylase activity induced by air blasts. In untreated rats, plasma corticosterone levels were significantly elevated following either platform stress (4.5-fold) or air blasts (7.8-fold). A significant increase was also noted in saline and diphenhydramine-treated animals following these stressors, however, the increase in saline or diphenhydramine treated rats following air blasts was significantly less than that seen in untreated stressed controls.     

Age-dependent effects of neonatal methamphetamine exposure on spatial learning

Neonatal rats exposed to (+)-methamphetamine (MA) display spatial learning and reference memory deficits in the Morris water maze. In separate experiments the emergence and permanence of these effects were determined. Twenty litters were used in each experiment, and two male/female pairs/litter received saline or MA (5 mg/kg four times a day) on postnatal days (P) 11-20. In experiment 1, one MA and one saline pair from each litter began testing on either P30 or P40, whereas in experiment 2, testing began on P180 or P360. Animals received trials in a straight swimming channel and then in the Morris maze (acquisition, reversal, and reduced platform phases). In both experiments, MA-treated groups showed impaired learning in the platform trials and impaired reference memory in the probe trials, which were largely independent of age. The P30 and P40 MA impairments were seen on acquisition and reduced platform trials but not on reversal. In the probe trials, MA effects were seen during all phases. The P180 and P360 MA-induced deficits were seen in all phases of the platform trials. In probe trials, deficits were only seen during the reversal and reduced platform phases. The results demonstrate that neonatal MA treatment induces spatial learning and reference memory deficits that emerge early and persist until at least 1 year of age, suggesting permanence.     

组胺对地佐环平诱发的SD大鼠八臂迷宫空间记忆障碍的改善作用

AIM: To investigate whether or not histamine is involved in spatial memory deficits induced by dizocilpine (MK-801) as evaluated by 8-arm radial maze of rats. METHODS: 8-Arm (4-arm baited) radial maze was used to measure spatial memory in rats. RESULTS: Bilaterally intrahippocampal (ih) injection of MK-801 (0.3μg/site) impaired working memory and reference memory in rats. Both histamine (50, 100 ng/site, ih) and intraperitoneal(ip) injection of histidine (100, 200 mg/kg) markedly improved the spatial memory deficits induced by MK-801. On the other hand, the ameliorating effect of histidine (100 mg/kg, ip) was completely antagonized by α-fluoromethylhistidine (α-FMH, 5μg/site, ih), a potent and selective histidine decarboxylase (HDC) inhibitor, and H1-antagonist pyrilamine (1μg/site, ih), but not by H2-antagonist cimetidine, even at a high dose (2.5μg/site, ih).CONCLUSION: The hippocampal histamine plays an important role in the ameliorating effect on MK-801-induced spatial memory deficits, and its action is mediated through postsynaptic H1-receptor.     

On the role of the dorsal noradrenergic bundle in learning and habituation to novelty

In Experiment 1, the performance of vehicle control rats and rats with 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DB) was examined in acquisition and extinction of bar pressing and in spontaneous and food-reinforced alternation in a T-shape maze. Plasma corticosterone levels in basal conditions, after chronic food restriction, after transportation to a novel environment, and after sessions of either rewarded or nonrewarded bar pressing were assayed. DB lesions produced a significant decrease of spontaneous alternation and a significant but small resistance to extinction, without reliably altering either corticosterone responses or instrumental spatial alternation. In Experiment 2, bar-press extinction and instrumental alternation were reexamined in new groups of control rats and rats with DB lesions without any blood collection procedures. The DB lesions did not reliably alter either behaviors on any measures. Taken together, these data indicate no consistent effects of forebrain noradrenaline depletion on either extinction or spatial memory or pituitary-adrenocortical function. However, the impairment of spontaneous alternation found in a previous study was confirmed. These findings are discussed in terms of the proposed roles of the dorsal noradrenergic bundle in learning and habituation to novelty.     

St John's wort (Hypericum perforatum) diminishes cognitive impairment caused by the chronic restraint stress in rats.

In this study we tested the hypothesis that St John's wort (Hypericum perforatum) may counteract stress-induced memory impairment. Object recognition test and Morris water maze were used to determine whether administration of H. perforatum (350 mg kg(-1) for 21 days), standardized to 0.3% hypericin content, protects against non-spatial and/or spatial memory impairments due to chronic restraint stress (2h daily for 21 days). A group of rats administered the exogenous corticosterone at the dose of 5 mg kg(-1) daily for 21 days, yielding its similar plasma levels as these observed in stress was run in parallel. In the first experiment all rats were tested for recognition memory in the object recognition test. On the following day, the animals were tested in open field and elevated "plus" maze to control for the contribution of respectively, motor and emotional effects of our treatments to the memory tests. In the second experiment, new group of stressed animals was tested for spatial memory in the water maze. We observed that H. perforatum prevented the deleterious effects of both chronic restraint stress and long-term corticosterone on learning and memory as measured in both, the object recognition and the water maze tests. The herb not only prevented stress- and corticosterone-induced memory impairments, but it significantly improved recognition memory (p<0.01) in comparison to control. These results suggest that H. perforatum has a potential to prevent stress memory disorders.     

Intraseptal injection of the 5-HT<Subscript>1A</Subscript>/5-HT<Subscript>7</Subscript> agonist 8-OH-DPAT and working memory in rats

Rationale In rats, 5-HT_1A receptors are present in the septal region, e.g. on cholinergic neurons of the medial septum, where they might be a substrate for cognitively relevant interactions between cholinergic and serotonergic systems.Objective The present experiment assessed the effects of the stimulation of septal 5-HT_1A receptors on spatial working memory.Methods Stimulation of septal 5-HT_1A receptors was carried out by infusions targetting the medial septum of the 5-HT_1A/5-HT₇ receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT; 0.5 or 4 µg). Spatial memory was assessed in a water maze using a protocol placing emphasis on spatial working memory. The location of the hidden platform was changed every day and performance was assessed on two consecutive trials each day.Results In comparison to vehicle injections, the intraseptal infusion of 4 µg 8-OH-DPAT impaired performance significantly: rats treated with 8-OH-DPAT exhibited increased distances to reach the hidden platform on both trials 1 and 2. Rats infused with 0.5 µg showed similar changes that failed to be significant. Such effects were not observed when the platform was visible.Conclusions These results extend those of a previous experiment which showed that intraseptal injections of 8-OH-DPAT impaired spatial reference memory. Based on the characteristics of the observed deficits, it is suggested that the 8-OH-DPAT-induced impairment, rather than being only the result of a true alteration of working memory, might reflect a more global cognitive deficiency in which alteration of general memory capacities may be biased by disrupted search strategies/exploration and/or dysfunctions of attention.H. Jeltsch and F. Bertrand contributed equally to the work.     

Acute and chronic effects of corticosterone on 5-HT1A receptor-mediated autoinhibition in the rat dorsal raphe nucleus

Corticosteroid modulation of 5-HT(1A) receptor function may contribute to the aetiology of affective disorders. To examine this modulation, the effects of acute and chronic corticosterone administration on 5-HT(1A) autoreceptor function were investigated using in vitro electrophysiology in the rat dorsal raphe nucleus (DRN). The magnitude and time course of the inhibitory response to a submaximal dose of 5-HT was not affected by acute application of either corticosterone (30-200 nM) or dexamethasone (100 nM) in vitro, when tested either in slices from control rats or rats adrenalectomised two weeks prior to recording. For chronic treatment, rats were supplied with drinking water containing corticosterone (50 microg/ml) or ethanol vehicle (0.5%) for 25-31 days. The autoinhibitory response to 5-HT was significantly attenuated in the corticosterone-treated group; vehicle EC(50)=48+/-8 microM vs. corticosterone EC(50)=121+/-20 microM. Furthermore a subpopulation of 5-HT neurones from corticosterone-treated animals exhibited marked insensitivity to 5-HT. In situ hybridisation histochemistry showed that corticosterone did not affect the expression of mRNA encoding the 5-HT(1A) receptor or either the type 1 and type 3 subunits of the G-protein linked inwardly rectifying K+ (GIRK) channel. However, GIRK2 subunit mRNA expression was significantly reduced. Thus, 5-HT(1A) autoreceptor function in the DRN is attenuated following chronic, but not acute, exposure to elevated corticosterone levels, and this effect may involve changes to the receptor-effector coupling mechanism.     

Blocking effects of intra-hippocampal naltrexone microinjections on glucocorticoid-induced impairment of spatial memory retrieval in rats

Previous studies have indicated that stress levels of glucocorticoid hormones induce impairment of long-term memory retrieval. In a recent study, we have found that peripheral injections of naloxone blocked stress or glucocorticoid-induced deficit in memory retrieval, but the anatomical sites of such an interaction were not known. The present study examined whether the opioid receptors in the hippocampus interact with glucocorticoid effects on memory retrieval in a water maze (WM). Young rats carrying bilateral cannulae aimed at the hippocampus were trained in a WM task with six trials per day for six consecutive days. Retention of the spatial training was assessed 24h after the last training session with a 60-s probe trial. Corticosterone (1mg/kg) was injected 30 min before retention testing with or without prior bilateral intra-hippocampal injections of naltrexone (5, 10 or 20 microg/mul per site) as a classical opioid antagonist. The results show that corticosterone-induced impairment of memory retrieval was blocked by intra-hippocampal infusions of naltrexone in a dose-dependent manner. Moreover, even a higher dose of corticosterone (3 mg/kg) was ineffective in impairing memory retrieval in the animals that received 20 microg of naltrexone. These findings provide evidence for the view that glucocorticoids interact with the hippocampal opioid receptors in influencing long-term memory retrieval.     

No evidence for a physiological coupling between melatonin and glucocorticoids

Much has been speculated about the existence of a physiological coupling between melatonin and glucocorticoid secretion and about a possible anti-stress action of melatonin. We examined the relationship between melatonin and glucocorticoid secretion under close-to-physiological conditions, when the plasma concentration of either melatonin or glucocorticoids was elevated acutely or chronically in both rats and humans. Tryptophan administration caused a massive rise of plasma melatonin, but had no effect on corticosterone levels in rats or on cortisol levels in humans. The acute and long-lasting exposure of rats to uncontrollable stress resulted in a significant rise of adrenal corticosterone secretion, but had no effect on circulating melatonin levels. Orchectomy caused an initial increase in circulating corticosterone (when melatonin was unaffected) and a delayed rise in circulating melatonin (when corticosterone levels were normalized). In humans, no correlation was found between the nocturnal urinary excretion of melatonin and cortisol, either among healthy subjects, or among patients suffering from panic disorder (with an increased urinary excretion of cortisol) or among insomnia patients (with a high incidence of low melatonin secretion). Furthermore, no evidence was found for a suppressive action of melatonin on dexamethasone-mediated thymus regression in rats and on dexamethasone-mediated suppression of lymphocyte proliferation in vitro. Taken together, the results of this study provide no evidence for the existence of mutual influences between melatonin and glucocorticoid secretion, nor do they support the proposed attenuation of glucocorticoid-mediated effects on target cells or tissues by melatonin under physiological conditions. Received: 25 July 1996/Final version: 21 May 1997     

Dissociable effects of isolation rearing and environmental enrichment on exploration,spatial learning and HPA activity in adult rats

Male Lister hooded rats were reared from weaning either singly or in groups of three in either barren or enriched cages (n=9 each) to study effects of isolation rearing and environmental enrichment on open-field activity, object exploration, activity in the Light/Dark box (L/D box), spatial learning and memory in the Morris water maze, and hypothalamic-pituitary-adrenal (HPA) activity in response to restraint stress. Regardless of inanimate background, isolation rearing mainly enhanced activity under several conditions of environmental novelty. By contrast, environmental enrichment, regardless of social background, primarily accelerated habituation to novelty and improved spatial learning and memory. None of the treatments significantly altered basal and response levels of plasma ACTH and corticosterone. Furthermore, rats reared singly in barren cages showed persistent activity in the L/D box, indicating an interaction between isolation-induced hyperactivity and reduced habituation due to barren caging. These results show that isolation rearing and environmental enrichment affect behaviour selectively, while at the same time revealing biologically relevant interactions between social and inanimate stimulation. It is concluded that systematic variation of social and inanimate stimulation can help distinguish between effects that generalise across variation in environmental background and effects that are idiosyncratic to a specific environmental background.     

Effects of nicotine on plasma corticosterone and brain amines in stressed and unstressed rats.

The administration of nicotine (0.4 mg/kh) to unstressed rats caused a rise in plasma corticosterone which persisted for 60 minutes and a fall in hippocampal 5-hydroxytryptamine (5-HT) at 45 minutes followed by a rise at 60 minutes. In rats which were stressed by being placed on an elevated platform, nicotine caused a reduction in hippocampal 5-HT at 45 and 75 minutes but did notaffect the plasma corticosterone concentration. Rats studied 16 hours after the last injection of a course of treatment with metypone had much reduced levels of plasma corticosterone and hippocampal 5-HT. Under the present conditions metyrapone also much diminished the effects of nicotine on plasma corticosterone levels in unstressed rats but had little effect on the response to stress.     

Impairments in water maze learning of aged rats that received dextromethorphan repeatedly during adolescent period

Rationale Dextromethorphan (DM), an over-the-counter cough suppressant, has been recently used as a drug of abuse by teenage groups in some countries, such as the United States, Canada, and Korea. We previously showed that repeated administration of DM, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors, impairs spatial learning performance in adolescent rats. Objectives In the present study, long-term adverse effects of repetitive DM use at adolescence were examined in rats. Methods Male and female Sprague–Dawley rat pups received either intraperitoneal DM (40 mg/kg) or saline daily during postnatal days 28–37, and were then subjected to the Morris water maze task at the age of 18 months. Expression levels of NMDAR1, functional subunit of NMDA receptors, in the prefrontal cortex and the hippocampus were examined by Western blot analysis. Changes in plasma corticosterone levels responding to stress were determined by radioimmunoassay. Results DM-experienced male rats exhibited deficits in the probe trial, and female rats in the initial learning and the reversal training, in water maze performance. Expression levels of NMDAR1 in the brain regions were significantly increased in DM-experienced rats, compared to control rats. Stress-induced increases in plasma corticosterone levels were blunted both in male and female DM rats. Conclusions The results suggest that repeated administration of DM at high doses during adolescent period may induce permanent deficits in cognitive function and that increased expression of NMDAR1 in the prefrontal cortex and the hippocampus may take a role in DM-induced memory deficits.