Radioprotection by caffeine pre- and post-treatment in the bone marrow chromosomes of mice given whole-body gamma-irradiation.

The effect of caffeine given as pre- and post-treatment in mice exposed to whole-body gamma-irradiation (1.5 Gy 60Co gamma-rays) was studied. The pre-treatment was either acute or chronic. The acute dose (5 mg/kg and 15 mg/kg body weight) was in the form of an injection given intraperitoneally, 30 min before irradiation. The chronic administration was in the form of caffeine solution (4.208 x 10(-3) M and 7.72 x 10(-4) M) contained in the drinking water that mice had had ad libitum access to instead of plain drinking water for 5 weeks prior to radiation exposure. The acute pre-treatment with caffeine reduced the radiation-induced frequency of chromosomal aberrations discernibly, whereas the chronic pre-treatment afforded a much more significant degree of radioprotection. The caffeine post-treatment (5 mg/kg and 15 mg body weight) was given in the form of an intraperitoneal injection to the mice immediately following whole-body gamma-irradiation. It is noted that both post-treatment concentrations of caffeine also significantly reduced the frequency of chromosomal aberrations induced by gamma-rays. These data are briefly discussed in terms of possible mechanistic considerations.     

A comparison of the effects of acute versus chronic administration of phenoxybenzamine on pressor responses elicited by the selective alpha 1-adrenoceptor agonist cirazoline in the pithed rat preparation.

The effects of nifedipine on the pressor responses to cirazoline were examined in the pithed rat preparation that had received either acute or chronic phenoxybenzamine treatment. Phenoxybenzamine was administered, i.v., to conscious rats, either acutely at 0.01, 0.03, and 0.1 mg/kg, 60 min prior to the commencement of the experiments or chronically at 0.1, 0.3, and 1.0 mg/kg, once daily for 7 days. Nifedipine was administered i.a. (1.0 mg/kg) after the animals had been pithed. The acute or chronic administration of phenoxybenzamine alone displaced the dose-response curve to cirazoline to the right in a dose-dependent manner, while reducing the slope function and maximum response to the agonist. The combined effects of acute phenoxybenzamine and nifedipine produced an additive inhibitory effect on the pressor response elicited by cirazoline, which was most apparent following the removal of receptor reserve by acute phenoxybenzamine. The inhibitory effects of nifedipine and chronically administered phenoxybenzamine were additive at the lower administered doses of the alkylating agent but, in contrast with the effects of acute phenoxybenzamine, the enhanced inhibitory effects of nifedipine were reduced following the removal of receptor reserve. These results indicate that the chronic administration of phenoxybenzamine reduces the additive inhibitory effects of nifedipine and phenoxybenzamine that were observed following the acute administration of phenoxybenzamine.     

Short-term hardening effects on survival of acute and chronic cold exposure by Drosophila melanogaster larvae

We quantified the variation and plasticity in cold tolerance among four larval stages of four laboratory strains of Drosophila melanogaster in response to both acute (<2 h of cold exposure) and chronic (7 h of cold exposure) cold exposure. We observed significant differences in basal cold tolerance between the strains and among larval stages. Early larval instars were generally more tolerant of acute cold exposures than third-instar larvae. However, wandering larvae were more tolerant of chronic cold exposures than the other stages. Early stages also displayed a more pronounced rapid cold-hardening response than the later stages. Heat pre-treatment did not confer a significant increase in cold tolerance to any of the strains at any stage, pointing to different mechanisms being involved in resolving heat- and cold-elicited damage. However, when heat pre-treatment was combined with rapid cold-hardening as sequential pre-treatments, both positive (heat first) and negative (heat second) effects on cold tolerance were observed. We discuss possible mechanisms underlying cold-hardening and the effects of acute and chronic cold exposures.     

Induction of heat shock protein and prevention of caerulein-induced pancreatitis by water-immersion stress in rats

Water-immersion stress is known to be involved in the development of hemorrhagic pancreatitis in caerulein-induced pancreatitis, when the stress is given following caerulein injection. The effects of pre-treatment with water-immersion to caerulein-induced pancreatitis were investigated in this study.

• 1.1. A 60-kDa heat shock protein was induced by pre-treatment with water-immersion stress in the pancreas.
• 2.2. Intra-peritoneal injection of caerulein (40 μg/kg) induced acute pancreatitis in rats without pre-treatment with water-immersion. However, when the rats were pre-treated with water-immersion, acute pancreatitis was not developed and no change of serum amylase levels was observed by i.p. injection of caerulein.

     

Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures

G protein-coupled receptor (GPCR) signaling cascades may be key substrates for the antidepressant effects of chronic electroconvulsive seizures (ECS). To better understand changes in these signaling pathways, alterations in levels of mRNA's encoding regulators of G protein signaling (RGS) protein subtypes-2, -4, -7, -8 and -10 were evaluated in rat brain using northern blotting and in situ hybridization. In prefrontal cortex, RGS2 mRNA levels were increased several-fold 2 h following an acute ECS. Increases in RGS8 mRNA were of lesser magnitude (30%), and no changes were evident for the other RGS subtypes. At 24 h following a chronic ECS regimen, RGS4, -7, and -10 mRNA levels were reduced by 20-30%; only RGS10 was significantly reduced 24 h after acute ECS. Levels of RGS2 mRNA were unchanged 24 h following either acute or chronic ECS. In hippocampus, RGS2 mRNA levels were markedly increased 2 h following acute ECS. More modest increases were seen for RGS4 mRNA expression, whereas levels of the other RGS subtypes were unaltered. At 24 h following chronic ECS, RGS7, -8 and -10 mRNA levels were decreased in the granule cell layer, and RGS7 and -8 mRNA levels were decreased in the pyramidal cell layers. Only RGS8 and -10 mRNA levels were significantly reduced in hippocampus 24 h following an acute ECS. Paralleling neocortex, RGS2 mRNA content was unchanged in hippocampus 24 h following either acute or chronic ECS. In ventromedial hypothalamus, RGS4 mRNA content was increased 24 h following chronic ECS, whereas RGS7 mRNA levels were only increased 24 h following an acute ECS. The increased RGS4 mRNA levels in hypothalamus were significant by 2 h following an acute ECS. These studies demonstrate subtype-, time-, and region-specific regulation of RGS proteins by ECS, adaptations that may contribute to the antidepressant effects of this treatment.     

Ethanol but not acetaldehyde induced changes in brain taurine: a microdialysis study

Summary. Research has suggested that catalase plays a role in mediating ethanols psychopharmacological effects. Catalase is an enzyme that oxidizes ethanol to acetaldehyde. It has been reported that when catalase activity is reduced by 3-amino-1,2,4-triazole (AT), rats reduce their intake and preference for ethanol. The present study assessed the effects of AT on the brain amino acids levels following ethanol administration in Wistar rats. The study consisted of three parts. In the first part, we found no effects of acute and chronic intraperitoneally administered acetaldehyde on amino acids dialysate levels in nucleus accumbens. In the second part, AT was administered five hours prior to ethanol or its vehicle. Ethanol significantly affected the levels of taurine in rat pre-treated with AT. In the final part, ethanol was administered following the pre-treatment with AT but the dependent variable was the concentration of ethanol in the brain.     

Antagonism of the effects of pentobarbital in the chronic spinal dog by naltrexone

Some of the actions of pentobarbital in the chronic spinal dog were antagonized by naltrexone. Pentobarbital depressed the flexor reflex and the level of consciousness, and these actions of pentobarbital were partially antagonized by naltrexone. Naltrexone alone did not alter these functions. Pentobarbital also increased the latency of the skin twitch reflex, decreased pupillary diameter and depressed pulse and respiratory rates. The data are consistent with the hypothesis that some of the actions of pentobarbital may be mediated through functional systems involving the ? receptor.     

Meclofenamate blocks the pulmonary arterial vasopressor effects of leukotriene B4 in awake sheep

This study examined the hemodynamic effects of leukotriene B4 (LTB4) in chronically instrumented awake sheep, and the role of cyclooxygenase products in the sheep's response to LTB4. LTB4 (25 micrograms) was given as a bolus into the pulmonary artery. Six sheep were studied with LTB4, both before and after pretreatment with meclofenamate (5 mg/kg load, 3 mg/kg/hr maintenance infusion). LTB4 alone caused a rapid rise in pulmonary arterial pressure from 15 +/- 1 to 42 +/- 11 cm H2O. LTB4 had no effect on pulmonary arterial pressure following pretreatment with meclofenamate. LTB4 alone caused an increase in serum thromboxane B2 (TxB2) from 130 +/- 35 to 320 +/- 17 pg/ml 3 minutes after dosing but did not increase TxB2 following pre-treatment with meclofenamate. LTB4 caused a slight decrease in mean systemic arterial pressure and a transient fall in circulating white blood cells, both of which were unaffected by meclofenamate pre-treatment. The vasoactive effects of LTB4 in the pulmonary circulation appear to be mediated indirectly through the production of cyclooxygenase metabolites of arachidonic acid.     

Development of enhanced sensitivity to naloxone

The effects of naloxone were examined over a period of three and a half years in squirrel monkeys responding under a mult FR, FI schedule of food presentation. During the initial observation of naloxone's effects, monkeys were drug naive. At that time, doses of naloxone up to 3.0 mg/kg had very little effect on rates of responding under the multiple schedule. The effects of naloxone were then examined in combination with meperidine. Doses of naloxone between 0.3 and 3.0 mg/kg produced a dose-dependent antagonism of meperidine's effects. Monkeys were then exposed to ketocyclazocine and phencyclidine, alone and in combination with naloxone. When the naloxone dose-effect curve was redetermined subsequently, it had shifted to the left. Monkeys were then exposed to buprenorphine and diprenorphine, alone and in combination with naloxone. Redetermination of the naloxone dose-effect curve following this exposure revealed a further shift to the left. The effects of naloxone were then reexamined in combination with meperidine, and it was found that the leftward shift in the naloxone dose-effect curve was not accompanied by a decrease in the doses of naloxone which would reverse the effects of meperidine. Naloxone's effects were then examined in combination with either acute or chronic diazepam. The naloxone dose-effect curve determined during the chronic diazepam regimen was shifted to the right of that obtained prior to chronic diazepam.     

Combined chronic treatment with citalopram and lithium does not modify the regional neurochemistry of nitric oxide in rat brain.

A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentation strategy. Also inhibitors of nitric oxide synthase (NOS) have been used as an augmentation strategy, while inhibitors of NOS exhibit antidepressant-like properties in various animal models. Therefore, we hypothesized that modulation of NOS may be involved in the long-term effects of antidepressants and lithium, and studied the influence of acute and chronic administration of citalopram, alone or in combination with lithium, on NOS activity in hippocampus, cerebellum, and frontal cortex, by determination of L-citrulline being formed. We found that administration of acute or chronic citalopram (5 mg/kg and 20 mg/kg/24h, respectively) alone or in combination with subchronic lithium (60 mmol/kg chow pellet) did not influence the activity of NOS ex vivo in all regions compared to control. In contrast, high doses of lithium caused a significant decrease in NOS activity in vitro. We conclude that basal conditions are unsuitable for the study of antidepressant effects on NOS, and that the neurochemistry of nitric oxide remains unaltered following chronic citalopram or subchronic lithium under normal physiological conditions.     

Arteriolar nitric oxide concentration is decreased during hyperglycemia-induced betaII PKC activation

betaII protein kinase C (betaPKC) is activated during acute and chronic hyperglycemia and may alter endothelial cell function. We determined whether blockade of betaPKC protected in vivo endothelial formation of NO, as measured with NO-sensitive microelectrodes in the rat intestinal vasculature. NaCl hyperosmolarity, a specific endothelial stimulus to increase NO formation, caused approximately 20% arteriolar vasodilation and approximately 30% increase in NO concentration ([NO]). After topical 300 mg/dl hyperglycemia for 45 min, both responses were all but abolished. In comparison, pretreatment with LY-333531, a specific betaPKC inhibitor, maintained vasodilation and [NO] responses to NaCl hyperosmolarity after hyperglycemia. The betaPKC inhibitor alone had no significant effects on resting diameter or [NO] or their responses to NaCl hyperosmolarity. In separate rats, after topical hyperglycemia had suppressed dilation to ACh, LY-333531 restored approximately 70% of the dilatory response. These data demonstrated that activation of betaPKC during acute hyperglycemia depressed in vivo endothelial formation of NO at rest and during stimulation. This abnormality can be minimized by inhibition of betaPKC before hyperglycemia and can be substantially reversed by PKC inhibition after hyperglycemia-induced abnormalities have occurred.     

Analgesic effect of tianeptine in mice

The effects of tianeptine, a novel and unusual tricyclic antidepressant drug, on tail-flick and hot-plate tests, which are two thermal analgesia evaluating methods, have been investigated in mice. Tianeptine (5 and 10 mg/kg), para-chlorophenylalanine (pCPA) (100 mg/kg) and a combination of pCPA and tianeptine (10 mg/kg) or saline were injected to mice intraperitoneally. pCPA (100 mg/kg) was injected 24 h before tianeptine or saline treatment when it was combined with tinaeptine (10 mg/kg) or tested alone. The tail-flick latencies and hot-plate reaction times of the mice were measured between 15th and 180th minutes following injections. Tianeptine (10 mg/kg) exhibited a significant antinociceptive activity that could be measured by both tests as compared to groups which were treated with saline or pCPA alone between 15th and 180th min of the observation period. The lower dose of tianeptine (5 mg/kg) or pCPA (100 mg/kg) did not produce any significant changes on tail-flick latency or hot-plate reaction time of the mice. However, pretreatment with pCPA completely blocked the antinociceptive effect induced by tianeptine (10 mg/kg) in both tests used in the present study. Furthermore, tianeptine (10 mg/kg) did not cause any significant impairment effects on rotarod performance of the mice. Our results suggested that tianeptine has a prominent thermal antinociceptive activity in mice and that increased serotonergic activity may be responsible for the analgesic effect of tianeptine.     

Effects of digoxin on chemoreflex in patients with chronic heart failure.

The effects of digitalis on the baroreflexes in human chronic heart failure have been well studied. Similarly, since it has been recently shown that chemoregulation remains generally effective during cardiac failure, the goal of this study was to evaluate the effects of a chronic administration of digoxin on the chemoreflexes. Hemodynamic and blood gas parameters were assessed in 7 patients with chronic congestive heart failure before and after chronic administration for 10 days of digoxin therapy (0.25 mg daily). In both situations measurements were performed 1/ in baseline conditions at room air and, 2/ after inhalation of pure O2 for 30 min, in order to inhibit the activation of the chemoreflexes. At room air, acute O2 inhalation resulted in a significant decrease in heart rate and cardiac output. After digoxin therapy, comparatively to pre-treatment values, cardiac output, stroke volume and PaO2 were significantly higher while heart rate, systemic resistance and pulmonary wedge pressure were lower. Furthermore, acute O2 inhalation did not modify heart rate or any hemodynamic variables. These results suggest that after digoxin therapy chemoreflex was no more activated in these patients. This effect may be related to the sympatho-inhibitory and to the positive inotropic effects of digoxin: improving hemodynamic and blood gas parameters may result in the inactivation of the reflex.     

The effect of mescaline, 3, 4-dimethoxyphenethylamine and 2, 5-dimethoxy-4-methylamphetamine on rat plasma prolactin: evidence for serotonergic mediation.

Mescaline, 3,4-dimethoxyphenethylamine (DMPEA) or 2,5-dimethoxy-4-methylamphetamine (DOM) was administered to male Sprague-Dawley rats, alone or in combination with para-chlorophenylalanine (PCPA), an inhibitor of serotonin (5-HT) synthesis, or methysergide, a 5-HT receptor blocker. All three compounds increased plasma prolactin (PRL) levels. These increases were potentiated by PCPA and blocked by methysergide. Pretreatment with alpha-methylparatyrosine (AMPT), an inhibitor of catecholamine synthesis, resulted in an increase in plasma PRL equal to the additive effects of the independent administration of mescaline, DMPEA, or DOM plus the AMPT-induced response. The results suggest that mescaline, DMPEA and DOM may be exerting their effects on rat plasma PRL through direct stimulation of serotonin receptors. These results further demonstrate the ability of PCPA to rapidly induce supersensitivity of the 5-HT receptors which stimulate PRL secretion.     

Both acute and chronic buspirone treatments have different effects on regional 5-HT synthesis in Flinders Sensitive Line rats (a rat model of depression) than in control rats

The main objective of this investigation was to evaluate the effects of buspirone, a 5-HT_1A agonist with some partial agonist properties and also an antidepressant, on regional 5-HT synthesis in Flinders Sensitive Line (FSL) rats (“depressed”), and to compare the effects to the Flinders Resistant Line (FRL) control rats (not “depressed”). In addition results were compared to those previously reported in normal Sprague–Dawley (SPD) rats (normal control). Serotonin synthesis in both FSL and FRL rats was measured following acute and chronic treatments with buspirone. Both of these strains were derived from the SPD rats. No direct comparison was done between the FSL saline and FRL saline groups, or the FSL buspirone and FRL buspirone groups, because the objective of the studies was to evaluate effects of buspirone in these two strains. The results show that acute treatment with buspirone elevates 5-HT synthesis throughout the brain in the FRL rats. In the FSL rats, there were reductions in some brain regions (e.g., dorsal and median raphe, amygdala, anterior olfactory nucleus, substantia nigra reticulate), while in other regions, there were increases in the synthesis observed (e.g., frontal, parietal, visual and somatosensory cortices, ventral hippocampus). In 20 out of the 30 brain regions investigated in the FSL rats, there was no significant change in the synthesis following acute buspirone treatment. During the chronic treatment, buspirone produced a significant reduction of 5-HT synthesis in 15 out of 30 brain regions in the FRL rats. In the FSL rats, buspirone produced a significant elevation of the synthesis in 10 out of 30 brain regions. In both the FSL and FRL rats, buspirone produced rather different effects than those reported previously for SPD (normal) rats. The acute effect in the FSL rats was somewhat similar to the effect reported previously for the SPD rats, while in the FRL rats, the acute buspirone treatment produced an effect observed previously in treatments with 5-HT_1A antagonists suggesting an action of buspirone as partial agonist in FRL rats. The data suggest that with respect to 5-HT synthesis, FRL rats differ from SPD rats (a natural control; normal rats) and, as such, indicate that when the effects related to the serotonergic system (e.g., influence of serotonergic drugs) are studied in the FSL rats and compared to those in the FRL rats, any conclusions drawn may not reflect differences relative to a normal rat.     

Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C

Hepatitis B and hepatitis C viruses (HBV and HCV) are both noncytopathic and can cause acute and chronic infections of the liver. Although they share tropism for the same organ, development of chronic hepatitis is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV- and HCV-specific tetramer-positive CD8 cells during the acute phase of hepatitis B and C belong almost entirely to an effector-memory subset (CCR7(-) CD45RA(-)). Despite this phenotypic similarity, HBV- and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-gamma) production upon peptide stimulation. A comparable degree of functional efficiency is maintained after the resolution of hepatitis B. In contrast, HCV-specific CD8 cells in the acute phase of hepatitis C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-gamma production, irrespective of the final outcome of the disease. This defect is transient, because HCV-specific CD8 cells can progressively improve their function in patients with self-limited hepatitis C, while the CD8 function remains persistently depressed in subjects with a chronic evolution.     

Comparative hematopoietic toxicity of doxorubicin and 4'-epirubicin

4'-Epirubicin is an anthracycline analog of doxorubicin which has been shown to be similar to doxorubicin in its anti-tumor activity but significantly lower in its cardiotoxicity. Therefore, it has been proposed as a potential clinical substitute for doxorubicin. Using the hematopoietic colony-forming unit, spleen (CFU-S) assay technique, direct comparison was made of the hematopoietic toxicity of the two drugs in vivo in a mouse model, and 4'-epirubicin was found to be significantly (P less than 0.01) less toxic than doxorubicin. On a milligram per kilogram basis, the dose of 4'-epirubicin required to achieve a given level of hematopoietic progenitor cell kill was approximately 50% larger than that required for doxorubicin. Early CFU-S recovery following 4'-epirubicin exposure was also stronger than that achieved following doxorubicin, as was short-term peripheral white blood cell recovery. These findings confirm previous clinical suggestions that the acute toxicity of 4'-epirubicin toward hematopoietic progenitor cells might be less than that of doxorubicin. At the same time, however, when given in doses near their lethal limit, both drugs were shown to induce a chronic hematopoietic suppression. This was evident in the depressed long-term CFU-S levels following high doses of either drug, as well as in chronically depressed white blood cell levels following high-dose 4'-epirubicin.     

Endogenous opiate involvement in acute and chronic stress-induced changes in plasma LH concentrations in the male rat

The present study was carried out to examine the possible role of the endogenous opioid peptides ( EOP 's) on the pituitary luteinizing hormone (LH) response to both acute and chronic stress and to food deprivation. Thirty minutes after acute (2 min.) exposure to ether, plasma LH levels were elevated compared to controls; morphine (MOR) treatment prior to stress prevented this response. More prolonged etherization (15 minutes) significantly depressed circulating LH, whereas naltrexone ( NALT ), a specific opiate antagonist, reversed this decline. Immobilization for 8 hours resulted in a significant initial increase in LH release, followed by a decline toward baseline levels. Naltrexone treatment increased the magnitude of the acute LH rise, and attenuated the subsequent decrease in plasma LH. The effect of chronic stress on circulating LH was also examined. Plasma LH levels were depressed for 3 consecutive days following subcutaneous gauze pad implantation, whereas 3 daily NALT injections returned LH to control levels. Complete food deprivation for 5 days also resulted in a significant decline in circulating LH. Injection of NALT 3 times daily reversed this decline on days 2, 3 and 4 of treatment. These results support the hypothesis of a mediatory role for the EOP 's in the effect of both chronic stress and food deprivation on LH release in the rat.     

Semiparametric Contrasts of Cumulative Pre-Treatment Mortality in the Presence of Dependent Censoring

In clinical settings, the necessity of treatment is often measured in terms of the patient’s prognosis in the absence of treatment. Along these lines, it is often of interest to compare subgroups of patients (e.g., based on underlying diagnosis) with respect to pre-treatment survival. Such comparisons may be complicated by at least two important issues. First, mortality contrasts by subgroup may differ over follow-up time, as opposed to being constant, and may follow a form that is difficult to model parametrically. Moreover, in settings where the proportional hazards assumption fails, investigators tend to be more interested in cumulative (as opposed to instantaneous) effects on mortality. Second, pre-treatment death is censored by the receipt of treatment and in settings where treatment assignment depends on time-dependent factors that also affect mortality, such censoring is likely to be informative. We propose semiparametric methods for contrasting subgroup-specific cumulative mortality in the presence of dependent censoring. The proposed estimators are based on the cumulative hazard function, with pre-treatment mortality assumed to follow a stratified Cox model. No functional form is assumed for the nature of the non-proportionality. Asymptotic properties of the proposed estimators are derived, and simulation studies show that the proposed methods are applicable to practical sample sizes. The methods are then applied to contrast pre-transplant mortality for acute versus chronic End-Stage Liver Disease patients.     

Estrogens influence behavioral responses in a kainic acid model of neurotoxicity

The behavioral and neuroprotective effects of 17beta-estradiol (E2), on ovariectomized rats treated with a subconvulsive dose (7 mg/kg bw, ip) of kainic acid (KA), were examined. Estradiol was administered either acutely (150 mug/rat, ip) along with KA, 14 days post-ovariectomy, or chronically (sc capsules providing proestrus estrogen levels in serum) starting at ovariectomy. Exploratory behavior, as deduced by sniffing in the open field test, was reduced in KA-treated rats. Both hormonal schemes partially restored sniffing behavior in KA-lesioned subjects. Moreover, acute and chronic E2 administration in KA-treated rats resulted in increased vertical and horizontal activity of these animals in the open field test. Memory for object recognition was reduced following KA and was not restored by hormonal treatments. Acute, but not chronic, E2 coadministration with KA significantly impaired spatial performance in the water maze task, while KA alone had no effect. Both acute and chronic estradiol administration rescued hilar and CA1 neurons from KA-induced cell death. Chronic, but not acute, E2 increased neurofilament immunoreactivity in the mossy fibers of the dentate gyrus neurons, similarly to KA. Our results show that although estradiol administration in KA-treated rats has beneficial effects on cell survival, it has diverse effects on exploratory behavior, object, and spatial memory. Estradiol effects on KA-lesioned animals depended on the duration and timing of exposure to the hormone, implying different mechanisms of hormone actions.