High Fat Diet Exaggerate Metabolic and Reproductive PCOS Features by Promoting Oxidative Stress: An Improved EV Model in Rats.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent multifactorial endocrinopathy affecting women in the reproductive period, often associated with infertility and metabolic disorders. The use of animal models helps to better understand etiopathogenesis, enabling the examination of the effects of certain drugs in order to discover the best possible therapeutic approach. We tried to investigate the additional effect of estradiol-valerate (EV) and high-fat diet (HFD) in female rats to explore PCOS-related alterations with special focus on oxidative stress. Materials and Methods: Animals were divided into three groups: control group (CTRL, n = 6), estradiol-valerate group (EV, n = 6), and estradiol-valerate group on HFD (EV + HFD, n = 6). PCOS was induced by single subcutaneous injection of long-acting EV in a dose of 4 mg/per rat. We tried to improve the metabolic characteristics of the PCOS animal model by adding HFD, so the CTRL and EV group had a regular diet, while the EV + HFD group had HFD during the induction period of 60 days. Results: We observed alterations of anthropometric parameters and hormonal disturbances, along with estrus cycle impairment reassembly to obese-type PCOS phenotype. Moreover, glucose metabolism was impaired after addition of HFD to EV protocol, contrary to EV administered alone. Histological analysis confirmed more numerous cystic follicles after the combination of EV and HFD protocol. The alterations of oxidative stress markers could be related to and serve as the mechanistic base for development of PCOS-related endocrine, reproductive, and metabolic properties. Conclusions: The additive effect of EV and HFD was obvious in the majority of the parameters observed. Our study strongly demonstrated metabolic as well as reproductive properties of PCOS in rats.

The Potential of SGLT-2 Inhibitors in the Treatment of Polycystic Ovary Syndrome: The Current Status and Future Perspectives.

Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy during women's reproductive age. PCOS is a heterogeneous disorder featuring specific cardiometabolic properties. The association between the presence of metabolic disorders and PCOS supports the claim that the regulation of glycemic status is very important in these patients. There is a wide range of therapeutic options (including those treating diabetes mellitus type 2) with potential advantages available for the management of PCOS. Sodium-glucose cotransporter type 2 inhibitors (SGLT-2is) improve glucose metabolism, reduce fat tissue, lower blood pressure, reduce oxidative stress and inflammation, and protect the cardiovascular system. Currently, the use of SGLT-2is is not widespread in PCOS therapy, although these drugs represent a promising new therapeutic approach. Therefore, it is necessary to initiate further study in order to determine more effective therapies for PCOS and investigate the effect of SGLT-2is, both as a monotherapy and in combination with other drugs. It is necessary to understand the mechanisms underlying SGLT-2is in PCOS and their effects on long-term complications, especially since the gold standard treatment for PCOS, such as metformin and oral contraceptives, do not have long-term cardioprotective effects. The effects of SGLT-2is seem to involve cardiac protection, while diminishing endocrine and reproductive abnormalities in PCOS. In the current narrative review, we examine the most recent clinical evidence and discuss the potential applications of SGLT-2is for PCOS therapy.

In situ detection of the genotoxic potential as one of the lines of evidence in the weight-of-evidence approach-the Joint Danube Survey 4 Case Study.

Environmental studies which aim to assess the ecological impact of chemical and other types of pollution should employ a complex weight-of-evidence approach with multiple lines of evidence (LoEs). This study focused on in situ genotoxicological methods such as the comet and micronucleus assays and randomly amplified polymorphic DNA analysis as one of the multiple LoEs (LoE3) on the fish species Alburnus alburnus (bleak) as a bioindicator. The study was carried out within the Joint Danube Survey 4 (JDS4) at nine sites in the Danube River Basin in the Republic of Serbia. Out of nine sampling sites, two were situated at the Tisa, Sava, and Velika Morava rivers, and three sites were at the Danube River. The three additionally employed LoEs were: SumTUwater calculated based on the monitoring data in the database of the Serbian Environmental Protection Agency (SEPA) (LoE1); in vitro analyses of JDS4 water extracts employing genotoxicological methods (LoE2); assessment of the ecological status/potential by SEPA and indication of the ecological status for the sites performed within the JDS4 (LoE4). The analyzed biomarker responses in the bleak were integrated into the unique integrated biomarker response index which was used to rank the sites. The highest pollution pressure was recorded at JDS4 39 and JDS4 36, while the lowest was at JDS4 35. The impact of pollution was confirmed at three sites, JDS4 33, 40, and 41, by all four LoEs. At other sampling sites, a difference was observed regarding the pollution depending on the employed LoEs. This indicates the importance of implementing a comprehensive weight-of-evidence approach to ensure the impact of pollution is not overlooked when using only one LoE as is often the case in environmental studies.

Surface functional groups and degree of carbonization of selected chars from different processes and feedstock.

The knowledge of the structural and chemical properties of biochars is decisive for their application as technical products. For this reason, methods for the characterization of biochars that are generally applicable and allow quality control are highly desired. Several methods that have shown potential in other studies were used to investigate two activated carbons and seven biochars from different processes and feedstock. The chars were chosen to cover a wide range of chemical composition and structural properties as a hardness test for the analytical methods used in this study. Specific problems connected with the pretreatment of samples and drawbacks of some methods for some types of chars could be identified in an integrated consideration of the results from different methods. None of the spectroscopic methods was found to be suitable for the quality control of all types of chars. The most valuable results were obtained by chemical analysis that, however, required the complete determination of the main elements, including that of oxygen, and of inorganic components for adequate results. The combination of X-ray photoelectron spectroscopy (XPS) and FT-IR spectroscopy allows a rough characterization of surface functional groups, but cannot discriminate aliphatic and aromatic OH groups. FT-IR might be a suitable method for the quality control of biochars made at lower temperature. The results of Raman spectroscopy did not well correlate with the amount of sp2 hybridized carbon determined by XPS. A better correlation of XPS data was found with the electrical polarization determined by the method of spectral induced polarization that was used for the first time in conjunction with extensive analytical characterization.

The Expression of IL-1ß Correlates with the Expression of Galectin-3 in the Tissue at the Maternal-Fetal Interface during the Term and Preterm Labor.

The inflammatory processes that occur at the maternal−fetal interface are considered one of the factors that are responsible for preterm birth. The pro-inflammatory roles of the Gal-3-induced activation of NLRP3 inflammasome and the consecutive production of IL-1ß have been described in several acute and chronic inflammatory diseases, but the role of this inflammatory axis in parturition has not been studied. The aim of this study was to analyze the protein expression of Gal-3, NLRP3, and IL-1ß in the decidua, villi, and fetal membranes, and to analyze their mutual correlation and correlation with the clinical parameters of inflammation in preterm birth (PTB) and term birth (TB). The study included 40 women that underwent a preterm birth (gestational age of 25.0−36.6) and histological chorioamnionitis (PTB) and control subjects, 22 women that underwent a term birth (gestational age of 37.0−41.6) without histological chorioamnionitis (TB). An analysis of the tissue sections that were stained with anti- Gal-3, -NLRP3, and -IL-1ß antibodies was assessed by three independent investigators. The expression levels of Gal-3 and IL-1ß were significantly higher (p < 0.001) in the decidua, villi, and fetal membranes in the PTB group when they compared to those of the TB group, while there was no difference in the expression of NLRP3. A further analysis revealed that there was no correlation between the protein expression of NLRP3 and the expression of Gal-3 and IL-1ß, but there was a correlation between the expression of Gal-3 and IL-1ß in decidua (R = 0.401; p = 0.008), villi (R = 0.301; p = 0.042) and the fetal membranes (R = 0.428; p = 0.002) in both of the groups, PTB and TB. In addition, the expression of Gal-3 and IL-1ß in decidua and the fetal membranes was in correlation with the parameters of inflammation in the maternal and fetal blood (C-reactive protein, leukocyte number, and fibrinogen). The strong correlation between the expression of Gal-3 and IL-1ß in the placental and fetal tissues during labor indicates that Gal-3 may participate in the regulation of the inflammatory processes in the placenta, leading to increased production of IL-1ß, a cytokine that plays the main role in both term and preterm birth.

Corrigendum: Cell-Based Radiotracer Binding and Uptake Inhibition Assays: A Comparison of In Vitro Methods to Assess the Potency of Drugs That Target Monoamine Transporters.

[This corrects the article DOI: 10.3389/fphar.2020.00673.].

Mineral Composition of Herbaceous Species Seseli rigidum and Seseli pallasii: a Chemometric Approach.

Nutrients play an essential role in many metabolic processes whose deficiency or excess can be harmful to the plant itself and through the food chain to both animals and humans. Medicinal plants used in the food and pharmaceutical industries can be contaminated with increased concentrations of heavy metals. The plant species Seseli rigidum and Seseli pallasii from the Balkan Peninsula are used in traditional medicine and spices in the diet, so it was necessary to determine the mineral composition to ensure their safe application. In this work, the mineral composition was determined in medicinal species of the genus Seseli using inductively coupled plasma with optical emission spectrometry (ICP-OES). Two multivariate statistic methods -principal component analysis (PCA) and hierarchical cluster analysis (HCA) were applied to distinguish samples regarding their mineral composition. The mineral composition of both studied species is following the literature data. The results obtained using multivariate statistics methods agree and distinguish certain parts of the tested plants based on the highest content of micro, macro, or trace elements.

Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters.

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1-4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >>[H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.

Cell-Based Radiotracer Binding and Uptake Inhibition Assays: A Comparison of In Vitro Methods to Assess the Potency of Drugs That Target Monoamine Transporters.

High-affinity monoamine transporters are targets for prescribed medications and stimulant drugs of abuse. Therefore, assessing monoamine transporter activity for candidate medications and newly-emerging drugs of abuse provides essential information for industry, academia, and public health. Radiotracer binding and uptake inhibition are the gold standard assays for determining drug-transporter interaction profiles. The combined results from such assays yield a unique biochemical fingerprint for each compound. Over time, different assay methods have been developed to assess transporter activity, and the comparability of data across various assay platforms remains largely unclear. Here, we compare the effects of six well-established stimulants in two different cell-based uptake inhibition assays, one method using adherent cells and the other using suspended cells. Furthermore, we compare the data from transfected cell lines derived from different laboratories and data reported from rat synaptosomes. For transporter inhibitors, IC50 values obtained by the two experimental methods were comparable, but using different transfected cell lines yielded disparate results. For transporter substrates, differences between the two cell lines were less pronounced but the drugs displayed different inhibition potencies when evaluated by the two methods. Our study illustrates the inherent limitations when comparing transporter inhibition data from different laboratories and stresses the importance of including appropriate control experiments with reference compounds when investigating new drugs of interest.

Volatiles composition and antioxidant activity Inula oculus-christi L. from Serbia.

The chemical composition of the essential oil and the volatiles obtained by static headspace (HS) of Inula oculus-christi L. is presented. The GC-MS analysis of the hydrodistilled oil resulted in the identification of 90 components, representing 92.7% of the oil. The most abundant compounds were: caryophyllene oxide (9.8%), trans-longipinocarveol (9.2%), eucalyptol (7.3%) and intermedeol (6.2%). The major constituent of I. oculus-christi L. HS volatiles was eucalyptol (87.4%). The antioxidant activity was evaluated by four different methods: 2,2-diphenyl-1-picryl-hydrazylhydrate free radical assay (DPPH), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method, total reducing power (TRP), ferric reducing antioxidant power (FRAP), and cupric reducing antioxidant capacity (CUPRAC). Total phenolic content in (TPC) examined oil was 177.95 µg GAE/mg oil. Radical scavenging potential of the oil was promising RSC-DPPH was 57.4% and RSC-ABTS was 82.7%.[Formula: see text].

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.

Operculum shape variation in Theodoxus Montfort, 1810 (Gastropoda: Neritidae).

The operculum morphology of neritid snails of genus Theodoxus Montfort, 1810 yields important species-specific taxonomic characters. This study is the first attempt to describe morphological differences in snails based on operculum shapes using a geometric morphometric approach. We examined the variability of opercular shapes between sexes and among populations and species based on 91 opercula of adult specimens belonging to six populations of three species of Theodoxus from the central Balkan and the southern border of the Pannonian plain. There are no sex-related differences in operculum shape and size in the studied species. The presence of shape variations influenced by size (allometry) was confirmed for T. danubialis (C. Pfeiffer, 1828) indicating that allometry could be a component of the morphological variation of this species. At the intraspecific level, phenotypic plasticity of operculum shape was found in T. danubialis and T. fluviatilis (Linnaeus, 1758). Of particular interest is the lack of morphological variability in the rare and endangered T. transversalis (C. Pfeiffer, 1828). At the species level a clear morphological distinction of T. fluviatilis from T. danubialis and T. transversalis was detected, confirming that the operculum with a rib could be used as a species-specific morphological character. The main morphological differences between species are an outwardly-stretched opercular/apophysal rib and a shortened tip of the opercular plate in T. fluviatilis, compared to the same structures in T. danubialis and T. transversalis.

A comparison of the transport kinetics of glycine transporter 1 and glycine transporter 2.

Transporters of the solute carrier 6 (SLC6) family translocate their cognate substrate together with Na+ and Cl- Detailed kinetic models exist for the transporters of GABA (GAT1/SLC6A1) and the monoamines dopamine (DAT/SLC6A3) and serotonin (SERT/SLC6A4). Here, we posited that the transport cycle of individual SLC6 transporters reflects the physiological requirements they operate under. We tested this hypothesis by analyzing the transport cycle of glycine transporter 1 (GlyT1/SLC6A9) and glycine transporter 2 (GlyT2/SLC6A5). GlyT2 is the only SLC6 family member known to translocate glycine, Na+, and Cl- in a 1:3:1 stoichiometry. We analyzed partial reactions in real time by electrophysiological recordings. Contrary to monoamine transporters, both GlyTs were found to have a high transport capacity driven by rapid return of the empty transporter after release of Cl- on the intracellular side. Rapid cycling of both GlyTs was further supported by highly cooperative binding of cosubstrate ions and substrate such that their forward transport mode was maintained even under conditions of elevated intracellular Na+ or Cl- The most important differences in the transport cycle of GlyT1 and GlyT2 arose from the kinetics of charge movement and the resulting voltage-dependent rate-limiting reactions: the kinetics of GlyT1 were governed by transition of the substrate-bound transporter from outward- to inward-facing conformations, whereas the kinetics of GlyT2 were governed by Na+ binding (or a related conformational change). Kinetic modeling showed that the kinetics of GlyT1 are ideally suited for supplying the extracellular glycine levels required for NMDA receptor activation.

Synthesis of MnCo2O4 nanoparticles as modifiers for simultaneous determination of Pb(II) and Cd(II).

The porous spinel oxide nanoparticles, MnCo2O4, were synthesized by citrate gel combustion technique. Morphology, crystallinity and Co/Mn content of modified electrode was characterized and determined by Fourier transform infra-red spectroscopy (FT-IR), scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), X-ray diffraction pattern analysis (XRD), simultaneous thermogravimetry and differential thermal analysis (TG/DTA). Nanoparticles were used for modification of glassy carbon electrode (GCE) and new sensor was applied for simultaneous determination of Pb(II) and Cd(II) ions in water samples with the linear sweep anodic stripping voltammetry (LSASV).The factors such as pH, deposition potential and deposition time are optimized. Under optimal conditions the wide linear concentration range from 0.05 to 40 µmol/dm3was obtained for Pb(II), with limit of detection (LOD) of 8.06 nmol/dm3 and two linear concentration ranges were obtained for Cd(II), from 0.05 to 1.6 µmol/dm3 and from 1.6 to 40 µmol/dm3, with calculated LOD of 7.02 nmol/dm3. The selectivity of the new sensor was investigated in the presence of interfering ions. The sensor is stable and it gave reproducible results. The new sensor was succesfully applied on determination of heavy metals in natural waters.

Dispersive micro-solid phase extraction of 16 priority polycyclic aromatic hydrocarbons from water by using thermally treated clinoptilolite, and their quantification by GC-MS.

The authors report on a novel sorbent (thermally treated natural zeolite; clinoptilolite) for use in dispersive micro-solid phase extraction (D-µ-SPE) of polycyclic aromatic hydrocarbons (PAHs) from water samples. The method was applied to the D-µ-SPE of 16 priority PAHs which then were quantified by gas chromatography with mass spectrometric detection (GC-MS). The method was validated in terms of specificity and selectivity, linearity and linear range, accuracy, precision, uncertainty, limits of detection and quantification. Figures of merit include (a) linear analytical ranges between 2.08 and 208 ppb, and (b) detection limits in the range from 0.01 to 0.92 ppb. The method was successfully applied to the determination of PAHs in river waters. Graphical abstract Schematic representation of dispersive micro-solid phase extraction (D-µ-SPE) of trace levels of PAHs in water samples by using thermally treated clinoptilolite as sorbent prior to gas chromatography-mass spectrometry analysis (GC-MS).

A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and memory retrieval.

Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 µM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions.

Phytochemical analysis of Saponaria officinalis L. shoots and flowers essential oils.

Phytochemical analysis by GC and GC/MS of the essential oil samples obtained from fresh shoots and flowers of Saponaria officinalis L. allowed the identification of 96 components in total, comprising 94.7% and 86.0% of the total oils compositions, respectively. Regarding the shoots essential oil, the major of 87 identified volatile compounds were phytol (14.1%), tricosane-6,8-dione (13.4%), patchouli alcohol (7.9%) and tricosane (7.2%), whereas patchouli alcohol (20.0%), heneicosane (11.5%) and tricosane (8.4%) were dominant among the 66 volatiles in the flower oil. Nonterpenoid compounds had the highest contribution in S. officinalis shoots essential oil (53.7%), while in the flower oil, constituents were almost evenly distributed between the oxygenated sesquiterpenoid (41.2%) and nonterpenoid compounds (39.5%).

Essential oil composition of Erica spiculifolia Salisb - first report.

The essential oil isolated from Erica spiculifolia Salisb. by hydrodistillation was analysed by GC-MS. One hundred compounds representing 92.6% of total oil were identified. Among the detected compounds 38 were monoterpenoids (46.2%), 30 were sesquiterpenoids (31.7%), 2 diterpene (0.4%) and 30 compounds (14.3%) were with various non-terpenoid structures. Oxygenated monoerpenes were by far the main class (45.3%) with α-terpineol (7.5%) endo-borneol (7.2%), pinocarveol (5.9%) and thymol (3.7%) as the major compounds. The predominant components of sesquiterpenes were caryophyllene oxide (5.0%), caryophyllene (4.2%), τ -murrolol (3.5%), spathulenol (2.9) and α-cadinol (2.3%).

A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats.

Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT) are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123) with higher specificity for DAT in male rats in an attentional set-shifting task (ASST), that proves for cognitive flexibility and a 5-choice serial-reaction time task (5-CSRTT) assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R-Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity.