Exposure of pregnant rats to uranium and restraint stress: effects on postnatal development and behavior of the offspring

The effects on postnatal development and behavior were assessed in the offspring of female rats concurrently exposed to uranium (U) and restraint stress. Adult female rats were administered uranyl acetate dihydrate (UAD) in the drinking water at doses of 0, 40 and 80 mg/(kg day) for 4 weeks before mating with untreated males, as well as during pregnancy and lactation. One-half of female rats in each group were concurrently subjected to restraint (2h/day). On gestation day 14, one-half of restrained and unrestrained rats were sacrificed in order to evaluate maternal toxicity and gestational parameters. Pups were evaluated for physical development, neuromotor maturation, and behavior. Uranium concentrations were also determined in various tissues of dams and fetuses. In all uranium-treated groups, the highest concentrations of this element were found in kidney and bone, being considerably higher than those in brain. Uranium levels in tissues of dam or fetuses were not significantly affected by restraint. No significant interactions between uranium and restraint could be observed in maternal toxicity. Moreover, no relevant effects of uranium, maternal restraint, or their combination were noted on developmental landmarks in the offspring. In the passive avoidance test, at 40 and 80 mg UAD/(kg day) restraint significantly modified passive avoidance acquisition (T1) and retention time (T2) 24h later. However, no significant differences were observed on the Morris water maze test. The results of the present study indicate that, in general terms, exposure of female rats to UAD before mating with untreated males, as well as during gestation and lactation, did not cause relevant dose-related adverse effects on postnatal development and behavior of the offspring. The influence of stress was very limited.     

Restraint stress does not enhance the uranium-induced developmental and behavioral effects in the offspring of uranium-exposed male rats

The influence of stress on postnatal development and behavior was assessed in the offspring of male rats exposed to uranium (U). Eight groups of adult animals received uranyl acetate dihydrate (UAD) in the drinking water at doses of 0, 10, 20 and 40 mg/kg/day during 3 months. One half of rats in each group were concurrently subjected to restraint stress during 2 h per day throughout the study. At the end of the experimental period, male rats were mated with untreated females (1:2). On gestation day 14, one half of pregnant rats were euthanized in order to evaluate maternal toxicity and gestational parameters. The remaining dams were allowed to deliver and wean their offspring. Pups were evaluated for physical development, neuromotor maturation, as well as for behavioral effects. Restraint significantly increased the gravid uterine weight at 40 mg/kg/day. However, no significant interactions between restraint and U could be established in the remaining parameters of maternal toxicity. In the offspring, no remarkable effects of U, restraint or their combination were noted on developmental landmarks, or in the passive avoidance and water maze test. It is concluded that at the current U doses, restraint stress did not enhance the few uranium-induced physical, neuromotor and behavioral changes in the offspring of UAD-exposed male rats.     

Combined action of uranium and stress in the rat. II. Effects on male reproduction

The effects of stress on the potential reproductive toxicity of long-term exposure to uranyl acetate dihydrate (UAD) were assessed in adult male rats. Six groups of animals were given UAD at 10, 20, and 40 mg/kg/day in the drinking water during 3 months. Animals in three of these groups were also subjected to restraint for 2 h/day during the same period. Control groups included restrained and unrestrained male rats not exposed to UAD. To evaluate the fertility, male rats were mated with untreated females for 2 weeks. Although body weight was not affected by uranium at any dose, there was a significant (not dose-related) decrease in the pregnancy rate. Moreover, spermatid number/testis was significantly decreased by uranium administration. Histopathological examination of the testes in rats killed after 3 months of treatment revealed few differences in the tubule and interstitial alterations (focal atrophy, binucleated cells) between control and uranium-exposed animals. The results of this investigation show that at the current UAD doses, restraint stress did not enhance the uranium-induced adverse effects on reproduction in male rats.     

Concurrent exposure to aluminum and stress during pregnancy in rats: Effects on postnatal development and behavior of the offspring

The present study was conducted to assess the potential combined influence of maternal restraint stress and aluminum (Al) exposure on postnatal development and behavior in the offspring of exposed rats. Female rats were concurrently exposed to 0 (control group), 50 or 100 mg/kg/day of Al administered as Al nitrate nonahydrate in drinking water with citric acid (355 or 710 mg/kg/day) for a period of 15 days prior to mating with untreated males. Aluminum exposure was maintained throughout the gestational, lactational and post-weaning periods. On days 6-20 of gestation, one-half of the pregnant animals in each group were restrained for 2 h/day. Food consumption and maternal body weight were decreased in the groups exposed to restraint only or combined with the highest Al dose. All of the animals were allowed to deliver and wean their offspring. The pups were evaluated for physical development and neuromotor maturation. Moreover, open-field activity, passive avoidance, and spatial learning in a water maze were also determined on postnatal days 30, 35 and 60, respectively. Body weight of pups treated with 100 mg/kg/day of Al was decreased relative to controls from postnatal day 12 through 21, sexual maturation was delayed in Al treated females and in males exposed to 100 mg/kg/day. Forelimb grip strength was reduced in males exposed to 100 mg/Al/kg/day and in females exposed to this Al dose plus prenatal restraint. Learning in a passive avoidance task indicated facilitated performance for Al treated rats at 100 mg/kg/day combined with prenatal restraint as evidenced by longer avoidance latencies, while learning in a water maze task showed a shorter latency to find the platform on acquisition day 2 for Al treated rats. However, no effects of Al on water maze performance were detected during the retention probe trial in which the only effect noted was an increase in the platform quadrant swim time for the prenatal restraint group. In general terms, the results of the present study did not show a notable influence of maternal restraint on the Al-induced postnatal developmental and behavioral effects in the offspring of prenatally Al-exposed rats.     

Rivastigmine reverses aluminum-induced behavioral changes in rats

Aluminum, a known neurotoxin, has long been implicated in the pathogenesis of Alzheimer's disease. Its exposure is associated with impairment in the cholinergic system in the brain. In this study we investigated the behavioral effects of aluminum in rats and the possible effect of rivastigmine, a cholinesterase inhibitor, on the aluminum-induced behavioral changes. Rats were exposed to aluminum chloride (100 mg/kg/day i.p.) for 60 days before the start of behavioral tests. Rivastigmine was given in doses of 0.5, 1, 1.5 and 2.5 mg/kg i.p. 60 min before the behavioral tests. Five tests were investigated; open field test, Morris water maze, radial arm maze, passive avoidance test and rota-rod test. Results showed that aluminum exposure was associated with significant reductions in spontaneous locomotor and exploratory activities in open field test and significant impairments in learning and memory in Morris water maze, radial arm maze and passive avoidance tests. The behavioral impairments caused by aluminum were significantly improved by rivastigmine. Neither aluminum alone nor co-treatment with rivastigmine caused any significant alteration of the animals' performance in rota-rod test. The improvements in activity, learning and memory caused by rivastigmine were found to be dose-dependent, and the maximal improvement was encountered with its large dose (2.5 mg/kg). From these results we can conclude that rivastigmine can reverse behavioral deficits caused by aluminum intoxication.     

Behavioral effects of adult rats concurrently exposed to high doses of oral manganese and restraint stress

The behavioral effects of concurrent exposure of high doses of manganese (Mn) and restraint stress were assessed in adult rats. Male Sprague-Dawley rats (250-300 g) received 0, 275 and 550 mg/kg/day of Mn in the drinking water for 19 weeks. Each group was divided into two subgroups. Animals in one subgroup were restrained for 2h/day. During the treatment period, food and water intake, and body weight were weekly recorded. At the end of the treatment period, activity levels were monitored in an open-field. Learning was evaluated by a water-maze task during five consecutive days. A trial probe was also conducted to assess the time spent in the platform quadrant. Body weight and food consumption were significantly reduced in the group receiving 550 mg/kg/day of Mn. A two-way analysis of variance (ANOVA) revealed an overall effect of Mn on the total distance traveled. Differences on spatial learning were observed in the acquisition period, in which rats given 550 mg/kg/day of Mn (alone or restrained) were impaired in comparison with the control and the restrained only groups. In the probe trial, there was an impaired retention in the group treated with Mn at 550 mg/kg/day. The results of this investigation in the open-field and water maze suggest that it would be plausible that restraint stress and a high exposure to Mn interact at common neurotransmitter levels but inducing opposite effects.     

Assessment of the pro-oxidant activity of uranium in kidney and testis of rats

The pro-oxidant activity of uranium (U) was assessed in kidney and testes of male rats, tissues in which toxic effects of this metal are well established. Eight groups of Sprague-Dawley rats received uranyl acetate dihydrate (UAD) in the drinking water at 0, 10, 20, and 40 mg/kgday for 3 months. Rats in four groups were concurrently subjected to restraint during 2 h/day throughout the study. Histopathological examination of the kidneys revealed an angiomatose transformation in U-treated animals. In kidney, thiobarbituric acid-reactive substances (TBARS) levels and oxidized glutathione (GSSG) activity were correlated with U exposure. The superoxide dismutase (SOD) activity was significantly enhanced in both kidney and testis. Oral UAD administration induced a decrease of glutathione reductase (GR) and reduced glutathione (GSH) in the male reproductive tract. The results of this study suggest that graded doses of U elicit depletion of the antioxidant defence system of the rat and induce oxidative stress in testes and kidneys. Although at the current U doses, restraint stress scarcely showed additional adverse effects, its potential influence should not be underrated.     

Pro-oxidant effects in the brain of rats concurrently exposed to uranium and stress

Metal toxicity may be associated with increased rates of reactive oxygen species (ROS) generation within the central nervous system (CNS). Although the kidney is the main target organ for uranium (U) toxicity, this metal can also accumulate in brain. In this study, we investigated the modifications on endogenous antioxidant capacity and oxidative damage in several areas of the brain of U-exposed rats. Eight groups of adult male rats received uranyl acetate dihydrate (UAD) in the drinking water at 0, 10, 20, and 40 mg/kg/day for 3 months. Animals in four groups were concurrently subjected to restraint stress during 2h/day throughout the study. At the end of the experimental period, cortex, hippocampus and cerebellum were removed and processed to examine the following stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as U concentrations. The results show that U significantly accumulated in hippocampus, cerebellum and cortex after 3 months of exposure. Moreover, UAD exposure promoted oxidative stress in these cerebral tissues. In cortex and cerebellum, TBARS levels were positively correlated with the U content, while in cerebellum GSSG and GSH levels were positively and negatively correlated, respectively, with U concentrations. In hippocampus, CAT and SOD activities were positively correlated with U concentration. The present results suggest that chronic oral exposure to UAD can cause progressive perturbations on physiological brain levels of oxidative stress markers. Although at the current UAD doses restraint scarcely showed additional adverse effects, its potential influence should not be underrated.     

Aluminum, restraint stress and aging: behavioral effects in rats after 1 and 2 years of aluminum exposure

Both aluminum (Al) and aging have been associated with neurobehavioral changes in mammals. In this study, the long-lasting neurobehavioral effects of prenatal restraint stress and oral Al exposure from conception to sacrifice were assessed in adult (1 year) and old (2 years) rats. Pregnant females were orally exposed to 0, 50, and 100 mg Al/kg/day. Each Al-exposed group was divided into two subgroups. One of this was subjected to restraint stress (2h/day on gestation days 6-20). The offspring of the treated females were maintained with the same Al treatment until sacrifice at 1 or 2 years of age. Activity in an open-field and learning in a water maze were evaluated. Although no significant differences were observed in motor activity, a biphasic effect of Al on learning could be observed. Thus, exposure to 100 mg Al/kg decreased performance of the task in both adult and old rats when compared to animals exposed to 50 mg Al/kg. An age-related effect on water maze performance, as well as an accumulation of Al in brain of rats exposed to 100 mg Al/kg at 2 years of age was found. Interestingly, while prenatal restraint stress did not modify behavioral parameters, Al accumulation was prevented by prenatal restraint.     

Influence of maternal restraint stress on the long-lasting effects induced by prenatal exposure to perfluorooctane sulfonate (PFOS) in mice

The behavioral effects of concurrent maternal exposure to restraint stress and perfluorooctane sulfonate (PFOS) were assessed in the offspring of mice at 3 months of age. Plug positive females were divided into two groups. Animals were given by gavage 0 and 6mg PFOS/kg/day on gestation days 12-18. One-half of the animals in each group were subjected to restraint stress (30min/session, three sessions per day) during the same period. At 3 months, mice were evaluated for general activity in an open-field, and for learning and memory in a water maze task. The group prenatally exposed to PFOS and restraint presented a reduced mobility in the open-field. In the water maze, an interaction between sex and restraint was observed. Delayed task learning was also detected in females prenatally exposed to PFOS and restraint. An overall effect of restraint was observed in mice on retention of the task, suggesting a better retention in restrained animals. On the other hand, corticosterone levels were lower in animals prenatally subjected to restraint stress. The current results suggest interactive effects between PFOS and maternal stress.     

The effect of tacrine (THA) on cycloheximide- and basal forebrain lesion-induced memory deficit in rats.

The effects of 9-amino-1,2,3,4-tetrahydroacridine (tacrine), an active acetylcholinesterase inhibitor, on cycloheximide- and basal forebrain (BF) lesion-induced memory deficit in the water maze and passive avoidance task were investigated. While cycloheximide (1.5 mg/kg, s.c.) produced amnesia in the passive avoidance task, chronic administration of tacrine (1, 3 and 10 mg/kg, once a day for 1 week) improved the amnesia. BF lesion produced amnesia in both the water maze and passive avoidance tasks. Chronic tacrine (0.1-3 mg/kg, passive avoidance task, or 0.3 mg/kg, water maze task, once a day for 1 week) improved BF lesion-induced amnesia in the passive avoidance and water maze tasks. These results suggest that tacrine may be useful for senile dementia.     

Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10 mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.     

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.     

Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating.

Serotonin(6) (5-HT(6)) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT(6) antagonists such as RO4368554 allows further characterization of the role of the 5-HT(6) receptor in these processes. Herein, we tested RO4368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, RO4368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. RO4368554 reversed the effects of scopolamine in novel object discrimination (active doses in mg/kg, i.p., 3, 10), social recognition (3, 10), social discrimination (1, 3, 10) and passive avoidance (10, 30 i.p. and 100 p.o.) tasks. In unimpaired rats, RO4368554 enhanced object discrimination (3, 10; 4-h forgetting interval) and autoshaping learning (3), but was inactive in a water maze task (doses tested: 1-10 mg/kg, i.p.). In tests sensitive to antipsychotics, RO4368554 did not reverse sensorimotor gating deficits induced by the psychostimulants dizocilpine and amphetamine (doses tested: 1-30 mg/kg, i.p.) or neonatal lesion of the ventral hippocampus (1-10 mg/kg, i.p.). In conclusion, RO4368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT(6) receptor antagonists involve modulation of cholinergic neurotransmission.     

Postnatal behavior in hatano high- and low-avoidance rats following prenatal exposure to low-dose methylazoxymethanol

The hypothesis that genetic factors influence behavioral effects was tested in rats exposed prenatally to methylazoxymethanol (MAM). We examined whether baseline behavior is an important factor influencing behavioral effects, and whether a behaviorally selected strain was useful for study of neurobehavioral teratology. Pregnant high- and low-avoidance animals (HAAs and LAAs) of the Hatano strain, selectively bred for high and low shuttlebox avoidance responses, respectively, were given an IP injection of a low dose of MAM (15 mg/kg) on day 14 of gestation. The offspring of these animals were subjected to behavioral tests for locomotor activity (running-wheel and open-field tests) and learning ability (Biel maze and shuttlebox avoidance tests). There were no significant effects of MAM on running-wheel activity or shuttlebox avoidance learning, whereas the number of errors in the Biel maze was increased in the MAM offspring of both strains. Interestingly, open-field activity of the MAM offspring was markedly decreased in LAAs but not in HAAs. Therefore, an additional experiment was performed to determine plasma levels of ACTH and corticosterone following open-field exposure. When compared to control offspring of the respective strains, plasma levels of ACTH and corticosterone were not altered by prenatal MAM treatment in LAAs. Instead, the MAM offspring in HAAs exhibited decreased ACTH levels in absence of behavioral alterations. These results demonstrated that prenatal exposure to low doses of MAM may alter postnatal behavior and endocrine response of the offspring, although to a differing degree in HAAs and LAAs. Our observations suggested that behaviorally selected strains are sensitive to neurobehavioral teratogens such as MAM.     

Stimulation of D1-receptors improves passive avoidance learning of female rats during ovary cycle

The involvement of D1-receptors in learning/memory processes during ovary cycle was assessed in the adult female rats. SKF-38393 (0,1 mg/kg, i.p.), D1-receptor agonist and SCH-23390 (0,1 mg/kg, i.p.), D1-receptor antagonist were injected chronically to adult female rats. Learning of these animals was assessed in different models: passive avoidance performance and Morris water maze. Chronic SKF-3839 administration to females resulted in the appearance of the passive avoidance performance in proestrous and estrous, as distinct from the control animals, but failed to change the dynamics of spatial learning in Morris water maze. Chronic SCH-23390 administration similarly impaired non-spatial and spatial learning in females during all phases of ovary cycle. The results of the study suggest modulating role of D1-receptors in learning/memory processes during ovary cycle in the adult female rats.     

Effect of CDP-choline on learning and memory processes in rodents.

The effects of cytidine (5') diphosphocholine (CDP-choline) on learning and memory were studied using conditioned reflex methods for passive avoidance and active avoidance with punishment reinforcement (step-through, step-down, shuttle box and maze), for active avoidance with alimentary reinforcement (staircase maze), and the Morris water maze. The majority of experiments involved comparative studies of the nootropic drugs meclofenoxate and/or piracetam. CDP-choline was administered orally, in some of the experiments also intraperitoneally, at doses of 10-500 mg/kg body weight once or twice daily for 5 or 7 days. In separate cases only single doses were administered. Trainings started one hour after the last dose of the drugs. Retention tests were given 3 h, 24 h, 7 days or 10 days after training. The results obtained with the different methods document CDP-choline's ability to improve learning and memory in rats and mice. No essential differences in the effects of CDP-choline were established upon oral and intraperitoneal administration of the drug. The learning- and memory-facilitating effects of CDP-choline were similar to those of meclofenoxate and piracetam. The results of the present study permit us to define CDP-choline as a substance capable of improving cognitive levels.     

Effects of 3,3′-iminodipropionitrile on acquisition and performance of spatial tasks in rats

3,3′-Iminodipropionitrile (IDPN) has been reported to disrupt learning and memory in rats (24). The present work addressed the effects of IDPN on tasks requiring the use of spatial information. Separate groups of male rats were dosed with IDPN (IP, in 1 ml/kg saline) for 3 consecutive days and tested in the following procedures: (a) step-through passive avoidance conditioning (0, 100, 150, and 200 mg/kg/day); (b) Morris water maze (MWM) acquisition and retention (0, 125, 150, 175, and 200 mg/kg/day); (c) radial arm maze (RAM) acquisition (0, 100, 200, and 400 mg/kg/day); (d) RAM steady-state performance (0, 200, and 400 mg/kg/day); (e) repeated acquisition in the RAM (0, and 200 mg/kg/day). The vestibular toxicity of IDPN resulted in alterations in spontaneous behavior or swimming deficits in 5 of 8 rats treated with 175 mg/kg/day and in all the animals dosed with 200 or 400 mg/kg/day. IDPN increased step-through PA latencies at 200 mg/kg/day but not at lower doses. In the MWM, no performance deficits were observed at the dose levels preserving the swimming ability of the animals. In both the acquisition and the steady-state RAM tasks, IDPN (400 mg/kg/day) induced an increase in both choice errors and perseverative errors. In the RAM repeated acquisition paradigm, IDPN (200 mg/kg/day) induced performance deficits that included a decreased rate of within-session reduction in errors. The present data show that IDPN disrupts performance of tasks requiring spatial learning and memory and indicate that these deficits can be in part caused by an acquisition deficit.     

An experimental study of the psychotropic effects of aspartic acid from the aspect of age

After acute injections to adult and 90-day old rats aspartic acid in doses of 100-500 mg/kg increased the locomotor and exploratory activity during the open-field test and in a dose of 100 mg/kg exerted the antidepressant effect during the forced swimming test. Following treatment for 10 days the amino acid in a dose of 10 mg/kg disrupted acquisition of passive avoidance reaction of young rats and in a dose of 100 mg/kg inhibited learning of active avoidance reaction in adult rats.     

PPARγ agonist pioglitazone improves scopolamine-induced memory impairment in mice

Objectives This study was conducted to evaluate the effects of exposure to pioglitazone, a peroxisome proliferator‐activated receptor agonist, on cognitive impairment induced by scopolamine, a muscarinic antagonist, in mice. Methods Pioglitazone (9 mg/kg, 18 mg/kg) was orally administered for 9 days at 30 min before intraperitoneal injection with scopolamine (0.8 mg/kg, i.p.). Cognitive function was evaluated by the passive avoidance test and the Morris water maze test on the 10th day after treatment. Changes in cholinergic system reactivity were also examined by measuring the acetylcholine, acetylcholinesterase and choline acetyltransferase in the hippocampus and cortex. Key findings Scopolamine injection induced impaired performance in the passive avoidance test and the water maze test and severe decrease of cholinergic system reactivity, as indicated by reduced acetylcholine levels, decreased choline acetyltransferase activity and increased acetylcholinesterase activity. Daily administration of pioglitazone significantly increased step‐through latency in passive avoidance test, and significantly decreased the escape latency, and increased the time spent in the platform quadrant in the Morris water maze test. Pioglitazone also protected against scopolamine‐induced cholinergic system deficit, including reduced acetylcholine levels, decreased choline acetyltransferase activity and increased acetylcholinesterase activity in the hippocampus or cortex. Conclusions Pioglitazone demonstrates a significant neuroprotective effect against scopolamine‐induced cholinergic system deficit and cognitive impairment.