Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus.

Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.

Raphe AMPA receptors and nicotinic acetylcholine receptors mediate ketamine-induced serotonin release in the rat prefrontal cortex.

Several lines of evidence indicate that ketamine has a rapid antidepressant-like effect in rodents and humans, but underlying mechanisms are unclear. In the present study, we investigated the effect of ketamine on serotonin (5-HT) release in the rat prefrontal cortex by in vivo microdialysis. A subcutaneous administration of ketamine (5 and 25 mg/kg) significantly increased the prefrontal 5-HT level in a dose-dependent manner, which was attenuated by local injection of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists into the dorsal raphe nucleus (DRN). Direct stimulation of AMPARs in the DRN significantly increased prefrontal 5-HT level, while intra-DRN injection of ketamine (36.5 nmol) had no effect. Furthermore, intra-DRN injection of an α 4 ß 2-nicotinic acetylcholine receptor (nAChR) antagonist, dihydro-ß-erythroidine (10 nmol), significantly attenuated the subcutaneous ketamine-induced increase in prefrontal 5-HT levels. These results suggest that AMPARs and α 4 ß 2-nAChRs in the DRN play a key role in the ketamine-induced 5-HT release in the prefrontal cortex.

A physiologically based modeling strategy during preclinical CNS drug development.

Physiologically based pharmacokinetic (PBPK) modeling of the central nervous system (CNS) provides the opportunity to predict the relevant drug concentrations at the therapeutic target site during preclinical and clinical development. In order to successfully interpret model results, and to provide confidence in the subsequent human predictions, it is essential that an appropriate model structure is chosen at the preclinical stage which takes into account both physiological and drug-specific knowledge. However, the models published to date in the literature show significant variation in the approaches applied by different authors, which can lead to difficulties in the interpretation of model parameter estimates. We aimed to develop a coherent PBPK modeling approach in the rat, which would also be adaptable depending on the quantity and quality of in vivo data obtained during drug development. Based on a sensitivity analysis of the model parameters, and using three CNS drugs as case studies (atomoxetine, acetaminophen, and S 18986), we proposed a decision tree to aid in the appropriate parametrization and structure of the model according to the data available. We compared our parameter estimates to those originally published, and considered the impact of the respective approaches on the mechanistic interpretation of the parameter values. Since the measurement of brain extracellular fluid (ECF) concentrations using microdialysis is not routinely performed in the industrial environment, we also evaluated the bottom-up scaling of in vitro permeability data from the Caco-2 cell line to predict BBB passive permeability in the absence of measured ECF concentrations. Our strategy demonstrates the value of PBPK as a prediction tool throughout the development process of CNS-targeting drugs.

Effects of bentazone on lipid peroxidation and antioxidant systems in human erythrocytes in vitro.

Bentazone, a benzothiadiazole herbicide, is widely used for a variety of crops including cereals, maize, peas, rice and soy beans. The concern for human health is stil very high because bentazone is continuously monitored in environment and several studies to evaluate its potential carcinogenic effects when chronic and high doses were administered to animals. We aimed to investigate the possible effects of bentazone on lipid peroxidation, levels of glutathione and activities of antioxidant enzymes in human erythrocytes in vitro. For that, erythrocyte were incubated with bentazone in different concentrations (0-50 nM) at 37 °C for 1 hr. Bentazone showed significant increase in the levels of malondialdehyde (MDA) at the highest concentration in erythrocytes as an index of lipid peroxidation. Besides, alterations in the levels of reduced glutathione (GSH) and activities of glutathione peroxidase (GSH-Px) were observed while the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH-Rd) were unchanged. In conclusion, findings from this study indicate that in vitro toxicity of bentazone may be associated with oxidative stress and this work warrants further in vivo investigations.

Cyclothiazide: a subunit-specific inhibitor of GABAC receptors.

We tested the effects of cyclothiazide (CTZ), an agent used to block desensitization of AMPA-type glutamate receptors, on heterologously expressed GABA(C) receptors formed by homomeric rho subunits. CTZ inhibition of GABA(C) receptors was subunit specific; it produced a dose-dependent reduction of the GABA-elicited current on homomeric rho2 receptors with an IC(50) of about 12 microm, but had no significant effect on homomeric rho1 receptors. This differential sensitivity was attributable to a single amino acid located on the second transmembrane domain of the rho subunits. Mutating the residue at this position from serine to proline on the rho2 subunit eliminated CTZ sensitivity, whereas switching proline to serine on the rho1 subunit made the receptor CTZ sensitive. The inhibitory properties of CTZ were consistent with its action as a channel blocker on the receptors formed by rho2 subunits. The effect showed a small degree of voltage dependence, and was due mainly to a non-competitive mechanism that reduced the maximum response elicited by GABA. In addition, the prominent membrane current rebound when co-application of GABA and CTZ was terminated suggests that the binding site for CTZ on the GABA(C) receptor is distinct from that for GABA, and that CTZ acts as a non-competitive antagonist on the GABA(C) receptor. CTZ inhibited the open channel of the GABA(C) receptor with a time constant of about 0.4 s, but the kinetics were approximately 10-fold slower when GABA is absent. The ability of CTZ to interact with various types of neurotransmitter receptors indicates that the drug has multiple actions in the CNS.

Comparison of single vs. multiple administrations of the AMPA receptors modulator S 18986 in the object recognition task in rats.

The present study aimed at defining the best scheme of administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-positive modulator (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986) [once daily (o.d.) administration of 1 mg/kg for 3 days vs. three times daily (t.i.d.) administration of 0.3 mg/kg for 3 days] to get an optimal procognitive activity in the object recognition task in rats. Memory performance [Recognition Index (RI)] of rats was significantly improved 1 h (RI = 41%, P < 0.01) and 3 h (RI = 46%, P < 0.001) following oral administration of S 18986 (1 mg/kg, o.d.) when compared with animals receiving the vehicle (RI = 6%). When the interval between administration and testing was increased to 6 h and 9 h, no statistically significant improvement in memory performance was observed (RI = 42% for 6 h and RI = 18% for 9 h vs. 20% for the vehicle group). When S 18986 was administered at 0.3 mg/kg t.i.d., no statistically significant improvement in memory performance was observed (RI = 36%). These findings show a long-lasting efficacy of the AMPA receptor allosteric modulator in the object recognition task despite a short half-life in plasma and in brain (approximately 1 h). Accordingly, multiple administrations of S 18986 are not required to obtain a maximal efficacy in this paradigm, because a o.d. schedule of administration leads to a powerful procognitive activity.

Synthesis and characterisation of neem leaf extract, 2, 3-dehydrosalanol and quercetin dihydrate mediated silver nano particles for therapeutic applications.

The utility of green silver nanoparticles (AgNPs) in veterinary medicine is steadily increasing as they have many therapeutic applications against pathogens and arthropods of livestock. In this study, green AgNPs using neem (N-AgNPs), 2,3-dehydrosalanol (2,3-DHS-AgNPs) and quercetin dihydrate (QDH-AgNPs) were synthesised and characterised. Synthesised compounds were characterised by UV-Vis spectroscopy and the peak absorbance was recorded at 370 nm for neem extract. For N-AgNPs, 2,3-DHS-AgNPs and QDH-AgNPs, the maximum absorbance peaks were at 430, 230 and 220 nm, respectively. The FTIR analysis confirmed the synthesis of green AgNPs. The XRD pattern of N-AgNPs showed the peaks corresponding to whole spectra of 2 θ values ranging from 10-80. The relatively higher intensity of (111, 222) planes in face centred cubic crystalline structure supports the formation of synthesised AgNPs. In DLS analysis, the hydrodynamic diameter of neem leaf extract was found to be 259.8 nm, followed by 5.3, 6.7 and 261.8 nm for 2,3-DHS-AgNPs, N-AgNPs and QDH-AgNPs, respectively. Based on the transmission electron microscopy and scanning electron microscopy image analyses, confirmed the formation of N-AgNPs, 2,3-DHS-AgNPs and QDH-AgNPs. These eco-friendly phyto-AgNPs may be of use as an effective alternative to chemical control methods against the arthropods of livestock.

Cuticular uptake of xenobiotics into living plants. Part 2: influence of the xenobiotic dose on the uptake of bentazone, epoxiconazole and pyraclostrobin, applied in the presence of various surfactants, into Chenopodium album, Sinapis alba and Triticum aestivum leaves.

This study has determined the uptake of three pesticides, applied as commercial or model formulations in the presence of a wide range of surfactants, into the leaves of three plant species (bentazone into Chenopodium album L. and Sinapis alba L., epoxiconazole and pyraclostrobin into Triticum aestivum L.). The results have confirmed previous findings that the initial dose (nmol mm(-2)) of xenobiotic applied to plant foliage is a strong, positive determinant of uptake. This held true for all the pesticide formulations studied, although surfactant concentration was found to have an effect. The lower surfactant concentrations studied showed an inferior relationship between the amount of xenobiotic applied and uptake. High molecular mass surfactants also produced much lower uptake than expected from the dose uptake equations in specific situations.

Subacute and subchronic toxicity of Avalon(®) mixture (bentazone+dicamba) to rats.

Subacute and subchronic toxicity of the herbicide Avalon(®), a mixture of bentazone and dicamba, were tested on rats. Avalon(®) was administered at dose levels of 250, 500 and 1000mg/kg body weight/day for 28 and 90 days. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were monitored together with biochemistry parameters. The results showed that the mixture caused increases in the activities of ALT, AST and ALP, elevated concentrations of sodium, albumin and albumin/globulin ratio in males. In females, ALT activity, cholesterol and phosphate levels were increased. The changes generally were dose related and, in most cases, females exhibited lower susceptibility than males. The effects of a mixture are, in the most cases, different from the effects of the individual substances. The effects of bentazone were not prevalent which would be expected taking the composition of the mixture into account.

Antihypertensive effects of clonidine.

The antihypertensive effect of clonidine given either two or three times a day with a diuretic was compared in a double-blind crossover study in 18 hypertensive patients. In 11 patients given clonidine three times a day there was better control of blood pressure, although the differences in most instances were of the order of only a few millimeters Hg. There were no differences in the frequency or severity of side effects. Clonidine twice daily with a diuretic appears to be adequate for most patients.

The epileptogenic action of 6-aminomethyl-3-methyl,1-4H-1,2,6-benzothiadiazine-1,1-diazide hydrochloride (TAG): non-specific versus specific antitaurine pathogenesis.

Cortical superfusion with 6-aminomethyl-3-methyl, 1-4H-1,2,6-benzothiadiazine-1,1-diazide hydrocholoride (TAG) at a concentration which selectively blocks taurine (Tau) action fails to modify electroencephalographic (EEG) activity, cortical neuronal firing and caudate-induced inhibition of cortical neuronal activity. Higher concentrations of TAG increase neuronal firing rate and eventually induce EEG interictal spikes that can be suppressed by topical gamma-aminobutyric acid (GABA), but not by glycine or beta-alanine. Topical Tau consistently enhances the epileptiform activity. It is concluded that specific blockade of Tau does not affect any of the physiological function under observation and that the epileptogenic effect of TAG is due to its GABA antagonistic action.

Comparative clinical trial of bemetizide/triamterene and cyclopenthiazide/potassium chloride combinations in patients with mild to moderate hypertension.

A double-blind trial was carried out to compare the combination of 25 mg bemetizide plus 50 mg triamterene ('Hypertane') and 0.25 mg cyclopenthiazide plus 600 mg potassium chloride ('Navidrex' K) in the treatment of mild to moderate essential hypertension. Two well matched groups of patients were treated for periods of 6 weeks with one or other of the drugs under test. There were 2-week placebo run-in and run-out periods. Blood pressure and laboratory investigations were performed every 2 weeks during the trial period. Both treatments resulted in similar overall statistically significant reductions in blood pressure during the trial. With bemetizide/triamterene, mean lying blood pressure decreased by 11.1/11.2 mmHg and mean standing blood pressure by 15.9/10.3 mmHg; with cyclopenthiazide/potassium chloride the corresponding reductions were 14.9/12.1 mmHg and 9.1/11.7 mmHg. The fact that some of the observed overall reduction seen with both drugs was due to 'placebo effect' is discussed but the clinical importance of overall changes is stressed. There were no significant differences between changes in blood pressure with the two treatments. Biochemical changes were those expected with thiazide diuretics. However, the decrease in potassium and increases in urea and uric acid levels were less with bemetizide/triamterene than with cyclopenthiazide/potassium chloride. Clinical tolerance of both treatments was good.

Anti-HIV-1 activity of benzothiadiazine dioxide.

Antiviral assays carried out on the potent benzothiadiazine dioxide (BTD) human cytomegalovirus (HCMV) inhibitors have led us to find marginal but selective anti-HIV-1 activity. Specific pharmacological studies, such as time of addition experiments and assays on specific viral strains with mutations on its reverse transcriptase, have indicated that BTD compounds act as non-nucleoside reverse transcriptase inhibitors. Theoretical calculations showed a butterfly conformation for the active derivatives that are compatible with their mechanism of action. Therefore, BTD derivatives can be considered as potential lead compounds for the treatment of opportunistic HCMV infections in immunocompromised individuals such as AIDS patients.

The antagonistic action of 6-aminomethyl-3-methyl-4H,1,2, 4-benzothiadiazine-1,1-dioxide (TAG) on the prolactin-releasing action of taurine.

The action of the putative taurine antagonist 6-aminomethyl-3-methyl-4H-1, 2,4-benzothiadiazine-1,1 dioxide (TAG) was examined on the prolactin-releasing action of taurine. The study utilized unanesthetized male rats with indwelling jugular and cerebroventricular cannulas. The intracerebroventricular (I.C.V.) infusion of taurine (0.5 mumole) elicited an increase in prolactin (PRL) secretion elevating plasma levels significantly by 10 min. The I.C.V. infusion of TAG (0.01 mumole) did not alter baseline plasma PRL levels. When a combined I.C.V. infusion of taurine and TAG was given the PRL levels normally induced by taurine were significantly reduced. Neither taurine nor the antagonist TAG altered pituitary secretion of luteinizing hormone.

Effect of taurine on ethanol-induced sleep time in mice genetically bred for differences in ethanol sensitivity.

Long Sleep (LS) and Short Sleep (SS) mice were used in this study to investigate the interaction between ethanol and taurine. Sleep time (hypnosis) was selected as an index of ethanol-induced central nervous system depression. In order to achieve a similar degree of central nervous system depression with ethanol, SS and LS mice received 5.3 and 3.0 g/kg, IP, of ethanol, respectively. When taurine (7.5, 15 and 25 mumol/kg) was administered intracerebroventricularly (ICV) to LS and SS mice immediately after regaining the righting reflex following ethanol injection, a return to sleep time was produced. This effect of taurine was immediate in onset and occurred in a dose-dependent fashion. LS mice exhibited a greater effect from taurine administration than SS mice. In another experiment LS and SS mice were given ICV TAG, a taurine antagonist (6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide HCl), which significantly reduced the effect of taurine to produce a return to sleep time in the presence of ethanol. TAG did not affect ethanol-induced sleep time. In control experiments, in the absence of ethanol, neither taurine (25 mumol/kg, ICV) nor TAG (1 mumol/kg, ICV) caused a significant loss of the righting reflex (sleep time). When pentobarbital (50 mg/kg, IP) was injected instead of ethanol in the sleep time experiments, taurine (7.5, 15 and 25 mumol/kg, ICV) produced a return to sleep time in LS and SS mice that resembled the effect of taurine with ethanol in SS mice. These results indicate that taurine (ICV) can enhance the central depressant action of ethanol and pentobarbital and that the greatest effect of taurine occurred with LS mice in the presence of ethanol. It is possible that taurine may have some role in the central nervous system depressant properties of ethanol.

[Acute oral toxicity of bentazon, an herbicide developed in Czechoslovakia, in pheasants and rabbits and the clinical symptoms of poisoning]. / Akútna orálna toxicita ceskoslovenského vývojového herbicídu bentazón u bazantov a králikov a klinická symptomatológia otravy.

Adult rabbits of the New Zealand White breed and pheasants were used to determine the rate of acute oral toxicity (LD50), clinical symptomatology of poisoning of organisms loaded with lethal doses, and the recovery of intoxicated individuals from the toxic effects of bentazon, Czechoslovak developmental herbicide (Research Institute of Chemical Technology, Bratislava), administered at sublethal doses within the framework of obligatory toxicological testing of this herbicide. The determined acute oral toxicity (LD50) was 1139 mg/kg in rabbits and 2918 mg/kg of live weight in pheasants. The table shows LD50 of the tested herbicide for various animal species. The LD50 values of bentazon produced abroad (Germany) are also shown for comparison in this table. If the LD50 values of both herbicides are compared, Czechoslovak developmental bentazon appears safer. The administration of lethal doses (1110 and 1170 mg/kg in rabbits, 2750 and 3100 mg/kg of live weight in pheasants) resulted in clinical symptoms of poisoning detected predominantly in the respiratory system. Shallow accelerated breathing and dyspnoea, CNS suppression, pronounced increase in body temperature, rapid onset and high intensity of rigor mortis were observed. Animals which died as a result of asphyxia induced by the sublethal doses (1000 mg/kg in rabbits and 2200 mg/kg in pheasants) were observed after 2-4 days. Difficult accelerated breathing and increased body temperature disappeared after 1-2 days while the remaining symptoms after 2-3 days. The loss of appetite persisted for 2-4 days.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effect of bentazone, an herbicide produced in Czechoslovakia, on the invasiveness of intestinal nematodes in sheep]. / Vplyv herbicídu bentazón ceskoslovenskej proveniencie na invadovanost oviec gastroenteronematódami.

Possible anthelmintic effects of the Czechoslovak herbicide bentazone (Research Institute of Chemical Technology, Bratislava) on gastrointestinal tract strongylates of common occurrence were investigated in sheep of the Slovak Merino breed (housed on deep bedding and put out to grass daily) during the autumn and spring seasons. Our orientation to the investigation of anthelmintic effects of the mentioned herbicide resulted from the fact that its possible intervention in the energy metabolism of helminths could not be excluded, as it was indirectly indicated by our toxicological studies under the conditions of acute and subacute intoxication. Bentazone was administered at a dose of 250 mg/kg live weight in autumn and 500 mg/kg live weight in the spring season. It was administered per os as a single dose in sunflower oil. A control coprological examination on day 10 following the administration of the herbicide in question indicates the lower invasiveness of sheep in comparison with findings prior to its application (Tab. I) in both experiments (autumn, spring). No marked dose-dependent differences of bentazone efficiency were recorded.

[Long-term efficacy and side effect profile of a low-dose bemetizid-triamterene combination in patients with essential hypertension]. / Langzeitwirksamkeit und Nebenwirkungsprofil einer niedrigdosierten Bemetizid-Triamteren-Kombination bei Patienten mit essentieller Hypertonie.

As only few data are available on the antihypertensive effectiveness and pattern of adverse reactions to low-dose diuretic treatment, a multicenter study was designed in which 77 patients with essential hypertension (WHO grades I to II) were followed up for one year with a view to answering the above questions. In patients who, at the end of a two weeks' placebo period had diastolic pressure values of more than 90 mmHg treatment was initiated with one daily tablet of a new preparation containing 10 mg bemetizide and 20 mg triamterene, for eight weeks. If, at the end of this interval, the target pressure values of less than 90 mmHg had not been attained, the dose was doubled. Blood pressure measurements (in sitting position) were repeated fortnightly, serum electrolytes, metabolic parameters and urinary triamterene fluorescence determined every four weeks. 56 of the 77 patients stayed on 10/20 mg bemetizide-triamterene for twelve months running. In 13 cases the dose had to be raised. Eight patients dropped out of the study. Average blood pressure values of 56 patients decreased from 169/103 mmHg (at the end of the placebo period) to 145/83 mm Hg after 52 weeks. Diastolic pressure reductions averaged 18 mmHg in 27 patients below the age of 49, 19 mmHg in 22 patients aged between 50 and 65, and 22 mmHg in seven patients older than 65 years. At the end of the 52 weeks' therapy, total serum cholesterol, HDL and LDL cholesterol, triglycerides, glucose and uric acid were unchanged in comparison to the placebo period in the entire group.(ABSTRACT TRUNCATED AT 250 WORDS)

Epileptiform response of CA1 neurones to convulsant stimulation by cyclothiazide, kainic acid and pentylenetetrazol in anaesthetized rats.

We have previously reported that cyclothiazide (CTZ) evokes epileptiform activities in hippocampal neurons and induces seizure behavior. Here we further studied in vivo the sensitivity of the hippocampal CA1 neurons in response to CTZ in epileptogenesis in comparison with two other classic convulsants of kainic acid (KA) and pentylenetetrazol (PTZ). CTZ administered intracerebral ventricle (i.c.v.) induced epileptiform activities from an initial of multiple evoked population spikes, progressed to spontaneous spikes and finally to highly synchronized burst activities in hippocampal CA1 neurons. PTZ, when given by subcutaneously, but not by intracerebral ventricle injection, evoked similar progressive epileptiform activities. In contrast, KA given by i.c.v. induced a quick development of epileptiform burst activities and then shortly switched to continuous high frequency firing as acute status epilepticus (ASE). Pharmacologically, alprazolam, a high-potency benzodiazepine ligand, inhibited CTZ and PTZ, but not KA, induced epileptiform burst activities while GYKI 53784, an AMPA receptor antagonist, suppressed CTZ and KA but not PTZ evoked epileptiform activities. In conclusion, CTZ and PTZ induced epileptiform activities are most likely to share a similar progressive pattern in hippocampus with GABAergic mechanism dominant in epileptogenesis, while CTZ model involves additional glutamate receptor activation. KA induced seizure in hippocampus is different to that of both CTA and PTZ. The results from this study indicate that hippocampal neurons respond to various convulsant stimulation differently which may reflect the complicated causes of the seizure in clinics.

S 18986 reverses spatial working memory impairments in aged mice: comparison with memantine.

RATIONALE: Normal or pathological ageing is characterized by working-memory dysfunction paired with a marked reduction in several neurotransmitters activity. The development of therapeutic strategy centered on the glutamatergic system known to bear a critical role in cognitive functions, is therefore of major importance in the treatment of mild forms of AD or age-related memory dysfunctions. OBJECTIVES: In Experiment 1, we investigated the effects of ageing on spatial working memory measured by sequential alternation (SA). Thus, the decay of alternation rates over a series of trials separated by varying intertrial temporal intervals (ITI, from 5 sec to 180 sec) was studied in mice of different age groups. In Experiment 2, we investigated the memory-enhancing potential of S 18986--a modulator of AMPA receptors--on age-related SA impairments, in comparison with memantine--an antagonist of NMDA receptors--. RESULTS: In Experiment 1, aged mice responded at chance with shorter ITI's and exhibited greater levels of interference in the SA task as compared to young adult mice. In Experiment 2, (1) S 18986 at 0.03 and 0.1 mg/kg reversed the memory deficit in aged mice but did not modify performance in young adult mice; (2) memantine at 10 mg/kg also increased SA rates in aged mice but did not improve performance in young adult mice. CONCLUSION: The SA task is a useful tool to reveal age-induced time-dependent working memory impairments. As compared to memantine, S 18986--a compound targeting AMPA receptors--contributes a valuable therapy in the treatment of age-related cognitive dysfunctions or mild forms of AD.