Tongue-on-a-Chip: Parallel Recording of Sweet and Bitter Receptor Responses to Sequential Injections of Pure and Mixed Sweeteners.

A microfluidic tongue-on-a-chip platform has been evaluated relative to the known sensory properties of various sweeteners. Analogous metrics of typical sensory features reported by human panels such as sweet taste thresholds, onset, and lingering, as well as bitter off-flavor and blocking interactions were deduced from the taste receptor activation curves and then compared. To this end, a flow cell containing a receptor cell array bearing the sweet and six bitter taste receptors was transiently exposed to pure and mixed sweetener samples. The sample concentration gradient across time was separately characterized by the injection of fluorescein dye. Subsequently, cellular calcium responses to different doses of advantame, aspartame, saccharine, and sucrose were overlaid with the concentration gradient. Parameters describing the response kinetics compared to the gradient were quantified. Advantame at 15 µM recorded a significantly faster sweetness onset of 5 ± 2 s and a longer lingering time of 39 s relative to sucrose at 100 mM with an onset of 13 ± 2 s and a lingering time of 6 s. Saccharine was shown to activate the bitter receptors TAS2R8, TAS2R31, and TAS2R43, confirming its known off-flavor, whereas addition of cyclamate reduced or blocked this saccharine bitter response. The potential of using this tongue-on-a-chip to bridge the gap with in vitro assays and taste panels is discussed.

Potential exacerbation of polycystic ovary syndrome by saccharin sodium Via taste receptors in a letrozole rat model.

The most common cause of anovulatory infertility is polycystic ovarian syndrome (PCOS), which is closely associated with obesity and metabolic syndrome. Artificial sweetener, notably saccharin sodium (SS), has been utilized in management of obesity in PCOS. However, accumulating evidence points towards SS deleterious effects on ovarian physiology, potentially through activation of ovarian sweet and bitter taste receptors, culminating in a phenotype reminiscent of PCOS. This research embarked on exploration of SS influence on ovarian functions within a PCOS paradigm. Rats were categorized into six groups: Control, Letrozole-model, two SS groups at 2 dose levels, and two groups receiving 2 doses of SS with Letrozole. The study underscored SS capability to potentiate PCOS-related anomalies. Elevated cystic profile with outer thin granulosa cells, were discernible. This owed to increased apoptotic markers as cleaved CASP-3, mirrored by high BAX and low BCL-2, with enhanced p38-MAPK/ERK1/2 pathway. This manifestation was accompanied by activation of taste receptors and disruption of steroidogenic factors; StAR, CYP11A1, and 17ß-HSD. Thus, SS showed an escalation in testosterone, progesterone, estrogen, and LH/FSH ratio, insinuating a perturbation in endocrine regulation. It is found that there is an impact of taste receptor downstream signaling on ovarian steroidogenesis and apoptosis instigating pathophysiological milieu of PCOS.

Mice Condition Cephalic-Phase Insulin Release to Flavors Associated with Postoral Actions of Concentrated Glucose.

Rats can condition cephalic-phase insulin responses (CPIRs) to specific sounds or times of the day that predict food availability. The present study asked whether mice can condition a CPIR to the flavor of sapid solutions that produce postoral glucose stimulation. To this end, we subjected C57BL/6 mice to one of six experimental protocols. We varied both the duration of the five training sessions (i.e., 23 h or 1 h) and the nature of the training solution. In Experiment 1, consumption of a 0.61% saccharin solution was paired with IG co-infusion of a 16% glucose solution. In Experiments 2-6, the mice consumed a training solution containing a mixture of 0.61% saccharin + 16% glucose, 32% sucrose, 32% maltodextrin, flavored 32% maltodextrin, or 16% maltodextrin. We subsequently asked whether consumption of any of these fluids conditioned a CPIR to a test solution that produced a similar flavor, but which did not elicit a CPIR in naïve mice. The mice did condition a CPIR, but only to the solutions containing 32% maltodextrin. We attribute this conditioning to postoral actions of the concentrated maltodextrin solutions.

Glucose appetition in C57BL/6J mice: Influence of nonnutritive sweetener experience, food deprivation state and sex differences.

In addition to its sweet taste, glucose has potent and rapid postoral actions (appetition) that enhance its reward value. This has been demonstrated by the experience-induced preference for glucose over initially preferred nonnutritive sweetener solutions in 24-h choice tests. However, some sweetener solutions (e.g., 0.8% sucralose) have inhibitory postoral actions that may exaggerate glucose appetition whereas others (e.g., 0.1% sucralose + 0.1% saccharin, S+S) do not. Experiment 1 revealed that food-restricted (FR) male C57BL/6J mice displayed similar rapid glucose appetition effects (stimulation of glucose licking within minutes) and conditioned flavor preferences following 1-h experience with flavored 0.8% sucralose or 0.1% S+S and 8% glucose solutions. Thus, the inhibitory effects of 0.8% sucralose observed in 24-h tests were not apparent in 1-h tests. Experiment 2 evaluated the effects of food deprivation state and sweetener concentration on glucose appetition in female mice. Unlike FR mice tested with 0.1% S+S and 8% glucose, ad libitum (AL) fed mice displayed no stimulation of 8% glucose licking in the 1-h tests. A second ad libitum group (AL) tested with 0.2% S+S and 16% glucose solutions displayed stimulation of 16% glucose licking by the third 1-h test. Both AL groups, like the FR group, developed a preference for the glucose-paired flavor over the S+S paired flavor. Thus, food restriction promotes increased glucose licking but is not required for a conditioned preference. The FR male mice (Exp. 1) and FR female mice (Exp. 2) showed similar appetition responses (licking stimulation and flavor preference) to 8% glucose.

The Effects of Fingolimod (FTY720) on Leukocyte Subset Circulation cannot be Behaviourally Conditioned in Rats.

Suppression of immune functions can be elicited by behavioural conditioning using drugs such as cyclosporin A or rapamycin. Nevertheless, little is known about the underlying mechanisms and generalisability of this phenomenon. Against this background, the present study investigated whether the pharmacological properties of fingolimod (FTY720), an immunosuppressive drug widely applied to treat multiple sclerosis, can be conditioned in rats by means of taste-immune associative learning. For this purpose, a conditioned taste avoidance paradigm was used, pairing the presentation of a novel sweet drinking solution (saccharin or sucrose) as conditioned stimulus (CS) with therapeutically effective doses of FTY720 as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time point revealed that conditioning with FTY720 induced a mild conditioned taste avoidance only when saccharin was employed as CS. However, on an immunological level, neither re-exposure with saccharin nor sucrose altered blood immune cell subsets or splenic cytokine production. Despite the fact that intraperitonally administered FTY720 could be detected in brain regions known to mediate neuro-immune interactions, the present findings show that the physiological action of FTY720 is not inducible by mere taste-immune associative learning. Whether conditioning generalises across all small-molecule drugs with immunosuppressive properties still needs to be investigated with modified paradigms probably using distinct sensory CS. Moreover, these findings emphasize the need to further investigate the underlying mechanisms of conditioned immunomodulation to assess the generalisability and usability of associative learning protocols as supportive therapies in clinical contexts.

Locus Ceruleus Dynamics Are Suppressed during Licking and Enhanced Postlicking Independent of Taste Novelty.

Attending to salient sensory attributes of food, such as tastes that are new, displeasing, or unexpected, allows the procurement of nutrients without food poisoning. Exposure to new tastes is known to increase norepinephrine (NE) release in taste processing forebrain areas, yet the central source for this release is unknown. Locus ceruleus norepinephrine neurons (LC-NE) emerge as a candidate in signaling salient information about taste, as other salient sensory stimuli (e.g., visual, auditory, somatosensation) are known to activate LC neurons. To determine if LC neurons are sensitive to features of taste novelty, we used fiber photometry to record LC-NE activity in water-restricted mice that voluntarily licked either novel or familiar substances of differential palatability (saccharine, citric acid). We observed that LC-NE activity was suppressed during lick bursts and transiently activated upon the termination of licking and that these dynamics were independent of the familiarity of the substance consumed. We next recorded LC dynamics during brief and unexpected consumption of tastants and found no increase in LC-NE activity, despite their responsiveness to visual and auditory stimuli, revealing selectivity in LC's responses to salient sensory information. Our findings suggest that LC activity during licking is not influenced by taste novelty, implicating a possible role for non-LC noradrenergic nuclei in signaling critical information about taste.

Design, synthesis, and docking study of saccharin N-triazolyl glycoconjugates.

To achieve better-repurposed motifs, saccharin has been merged with biocompatible sugar molecules via a 1,2,3-triazole linker, and ten novel 1,2,3-triazole-appended saccharin glycoconjugates were developed in good yield by utilizing modular CuAAC click as regioselective triazole forming tool. The docking study indicated that the resulting hybrid molecules have an overall substantial interaction with the CAXII macromolecule. Moreover, the galactose triazolyl saccharin analogue 3h has a binding energy of -8.5 kcal/mol with 5 H-bonds, and xylosyl 1,2,3-triazolyl saccharin analogue 3d has a binding energy of -8.2 kcal/mol with 6 H-bond interactions and have exhibited the highest binding interaction with the macromolecule system.

Acesulfame and other artificial sweeteners in a wastewater treatment plant in Alberta, Canada: Occurrence, degradation, and emission.

Acesulfame (ACE), sucralose (SUC), cyclamate (CYC), and saccharin (SAC) are widely used artificial sweeteners that undergo negligible metabolism in the human body, and thus ubiquitously exist in wastewater treatment plants (WWTPs). Due to their persistence in WWTPs, ACE and SUC are found in natural waters globally. Wastewater samples were collected from the primary influent, primary effluent, secondary effluent, and final effluent of a WWTP in Alberta, Canada between August 2022 and February 2023, and the artificial sweeteners concentrations were measured by LC-MS/MS. Using wastewater-based epidemiology, the daily per capita consumption of ACE in the studied wastewater treatment plant catchment was estimated to be the highest in the world. Similar to other studies, the removal efficiency in WWTP was high for SAC and CYC, but low or even negative for SUC. However, ACE removal remained surprisingly high (>96%), even in the cold Canadian winter months. This result may indicate a further adaptation of microorganisms capable of biodegrading ACE in WWTP. The estimated per capita discharge into the environment of ACE, CYC, and SAC is low in Alberta due to the prevalent utilization of secondary treatment throughout the province, but is 17.4-18.8 times higher in Canada, since only 70.3% of total discharged wastewater in Canada undergoes secondary treatment.

Exploring the Impact of Saccharin on Neovascular Age-Related Macular Degeneration: A Comprehensive Study in Patients and Mice.

Purpose: We aimed to determine the impact of artificial sweeteners (AS), especially saccharin, on the progression and treatment efficacy of patients with neovascular age-related macular degeneration (nAMD) under anti-vascular endothelial growth factor (anti-VEGF-A) treatment. Methods: In a cross-sectional study involving 46 patients with nAMD undergoing intravitreal anti-VEGF therapy, 6 AS metabolites were detected in peripheral blood using liquid chromatography - tandem mass spectrometry (LC-MS/MS). Disease features were statistically tested against these metabolite levels. Additionally, a murine choroidal neovascularization (CNV) model, induced by laser, was used to evaluate the effects of orally administered saccharin, assessing both imaging outcomes and gene expression patterns. Polymerase chain reaction (PCR) methods were used to evaluate functional expression of sweet taste receptors in a retinal pigment epithelium (RPE) cell line. Results: Saccharin levels in blood were significantly higher in patients with well-controlled CNV activity (P = 0.004) and those without subretinal hyper-reflective material (P = 0.015). In the murine model, saccharin-treated mice exhibited fewer leaking laser scars, lesser occurrence of bleeding, smaller fibrotic areas (P < 0.05), and a 40% decrease in mononuclear phagocyte accumulation (P = 0.06). Gene analysis indicated downregulation of inflammatory and VEGFR-1 response genes in the treated animals. Human RPE cells expressed taste receptor type 1 member 3 (TAS1R3) mRNA and reacted to saccharin stimulation with changes in mRNA expression. Conclusions: Saccharin appears to play a protective role in patients with nAMD undergoing intravitreal anti-VEGF treatment, aiding in better pathological lesion control and scar reduction. The murine study supports this observation, proposing saccharin's potential in mitigating pathological VEGFR-1-induced immune responses potentially via the RPE sensing saccharin in the blood stream.

COMPARISON OF GUT MICROBIOTA IN ALCOHOLIC AND METABOLIC-DYSFUNCION ASSOCIATED STEATOTIC LIVER DISEASE IN ANIMAL MODELS.

BACKGROUND: Alcoholic liver disease (ALD) and metabolic-dysfunction associated steatotic liver disease (MASLD) are common, and gut microbiota (GM) is involved with both. Here we compared GM composition in animal models of MASLD and ALD to assess whether there are specific patterns for each disease. METHODS: MASLD model- adult male Sprague Dawley rats, randomized into two groups: MASLD-control (n=10) fed a standard diet; MASLD-group (n=10) fed a high-fat-choline-deficient diet for 16 weeks. ALD model- adult male Wistar rats randomized: ALD-control (n=8) fed a standard diet and water+0.05% saccharin, ALD groups fed with sunflower seed and 10% ethanol+0.05% saccharin for 4 or 8 weeks (ALC4, n=8; ALC8, n=8). ALC4/8 on the last day received alcoholic binge (5g/kg of ethanol). Afterwards, animals were euthanized, and feces were collected for GM analysis. RESULTS: Both experimental models induced typical histopathological features of the diseases. Alpha diversity was lower in MASLD compared with ALD (p<0.001), and structural pattern was different between them (P<0.001). Bacteroidetes (55.7%), Firmicutes (40.6%), and Proteobacteria (1.4%) were the most prevalent phyla in all samples, although differentially abundant among groups. ALC8 had a greater abundance of the phyla Cyanobacteria (5.3%) and Verrucomicrobiota (3.2%) in relation to the others. Differential abundance analysis identified Lactobacillaceae_unclassified, Lachnospiraceae_NK4A136_group, and Turicibacter associated with ALC4 and the Clostridia_UCG_014_ge and Gastranaerophilales_ge genera to ALC8. CONCLUSION: In this study, we demonstrated that the structural pattern of the GM differs significantly between MASLD and ALD models. Studies are needed to characterize the microbiota and metabolome in both clinical conditions to find new therapeutic strategies. BACKGROUND: •Changes in the composition of the intestinal microbiota are related to the development of alcoholic liver disease and metabolic-dysfunction associated steatotic liver disease. BACKGROUND: •The diversity of the intestinal microbiota was lower in animals with MASLD compared to ALD. BACKGROUND: •The structural pattern of the intestinal microbiota was significantly different among the experimental groups. BACKGROUND: •Studies are needed to characterize the composition of the intestinal microbiota and metabolome to find new therapeutic strategies.

Obesogenic potentials of environmental artificial sweeteners with disturbances on both lipid metabolism and neural responses.

Artificial sweeteners (ASs) entered the environments after application and emissions. Recent studies showed that some ASs had obesogenic risks. However, it remained unclear whether such risks are common and how they provoke such effects. Presently, the effects of 8 widely used ASs on lipid accumulation were measured in Caenorhabditis elegans. Potential mechanisms were explored with feeding and locomotion behavior, lipid metabolism and neural regulation. Results showed that acesulfame (ACE), aspartame (ASP), saccharin sodium (SOD), sucralose (SUC) and cyclamate (CYC) stimulated lipid accumulation at µg/L levels, showing obesogenic potentials. Behavior investigation showed that ACE, ASP, SOD, SUC and CYC biased more feeding in the energy intake aspect against the locomotion in the energy consumption one. Neotame (NEO), saccharin (SAC) and alitame (ALT) reduced the lipid accumulation without significant obesogenic potentials in the present study. However, all 8 ASs commonly disturbed enzymes (e.g., acetyl-CoA carboxylase) in lipogenesis and those (e.g., carnitine palmitoyl transferase) in lipolysis. In addition, ASs disturbed PPARγ (via expressions of nhr-49), TGF-ß/DAF-7 (daf-7) and SREBP (sbp-1) pathways. Moreover, they also interfered neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh), with influences in Gsα (e.g., via expressions of gsα-1, ser-7), glutamate (e.g., mgl-1), and cGMP-dependent signaling pathways (e.g., egl-4). In summary, environmental ASs commonly disturbed neural regulation connecting behavior and lipid metabolism, and 5 out of 8 showed clear obesogenic potentials. ENVIRONMENTAL IMPLICATION: Artificial sweeteners (ASs) are become emerging pollutants after wide application and continuous emission. Recent studies showed that some environmental ASs had obesogenic risks. The present study employed Caenorhabditis elegans to explore the influences of 8 commonly used ASs on lipid metabolisms and also the underlying mechanisms. Five out of 8 ASs stimulated lipid accumulation at µg/L levels, and they biased energy intake against energy consumption. The other three ASs reduced the lipid accumulation. ASs commonly disturbed lipogenesis and lipolysis via PPARγ, TGF-ß and SREBP pathways, and also influenced neurotransmitters with Gsα, glutamate and cGMP-dependent signaling pathways.

Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence.

RATIONALE: Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning. OBJECTIVES: This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound. METHODS: CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure. RESULTS: Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was largely absent in CIE-exposed rats. Re-conditioning after vapor exposure facilitated increased CTA magnitude to a similar degree in AIR- and CIE-exposed males. In contrast, CTA magnitude was unchanged by re-conditioning in females. CONCLUSIONS: These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.

Activation of multiple neuromodulatory systems in alert rats acquiring conditioned taste aversion revealed by positron emission tomography.

Conditioned taste aversion (CTA) is an essential ability for animals to consume food safely and is regulated by neuromodulatory systems including the dopamine, noradrenaline, serotonin, and acetylcholine systems. However, because few studies focused on a comprehensive understanding of whole-brain activities, how these neuromodulators contribute to the process of CTA remains an open issue. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can visualize activated regions within the whole brain simultaneously and noninvasively. This study aimed to understand the mechanisms of CTA, especially focusing on the retrieval process after CTA acquisition by FDG-PET imaging. CTA was established in rats who received an intraoral application of saccharin solution (IOAS) on the first day (Day 1), a LiCl i.p. injection after an IOAS on Day 2, and an IOAS on Day 3 (CTA group). The subtraction images of Day 3 of the SHAM group, which received a 0.9 % NaCl (saline) injection instead of a LiCl on Day 2, from those of Day 3 of the CTA group revealed increases in FDG signals in multiple brain regions including the substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and nucleus basalis magnocellularis, in addition to the hippocampus and nociception-related regions, including the parabrachial nucleus and solitary nucleus. On the other hand, the visceral pain induced by the LiCl injection increased FDG signals in the primary and secondary somatosensory and insular cortices in addition to the parabrachial nucleus and solitary nucleus. These results suggest that the retrieval process of CTA induces brain regions producing neuromodulators and pain-related brainstem.

Effect of low-and non-calorie sweeteners on the gut microbiota: A review of clinical trials and cross-sectional studies.

Use of non-nutritive sweeteners (NNSs) has increased worldwide in recent decades. However, evidence from preclinical studies shows that sweetener consumption may induce glucose intolerance through changes in the gut microbiota, which raises public health concerns. As studies conducted on humans are lacking, the aim of this review was to gather and summarize the current evidence on the effects of NNSs on human gut microbiota. Only clinical trials and cross-sectional studies were included in the review. Regarding NNSs (i.e, saccharin, sucralose, aspartame, and stevia), only two of five clinical trials showed significant changes in gut microbiota composition after the intervention protocol. These studies concluded that saccharin and sucralose impair glycemic tolerance. In three of the four cross-sectional studies an association between NNSs and the microbial composition was observed. All three clinical trials on polyols (i.e, xylitol) showed prebiotic effects on gut microbiota, but these studies had multiple limitations (publication date, dosage, duration) that jeopardize their validity. The microbial response to NNSs consumption could be strongly mediated by the gut microbial composition at baseline. Further studies in which the potential personalized microbial response to NNSs consumption is acknowledged, and that include longer intervention protocols, larger cohorts, and more realistic sweetener dosage are needed to broaden these findings.

Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats.

Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats.

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30-45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3ß (GSK3ß), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3ß signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

A test of the role of stimulus-response and stimulus-outcome associations in the effects of intermittent-access training.

Increased reinforcer motivation in rats has been repeatedly demonstrated following intermittent-access (IntA) training, where the reinforcer is only available for brief periods during a session, compared to continuous-access (ContA) training where the reinforcer is available throughout the session. The present study investigated whether different associations learned during training on the two procedures contributes to the effect. Two experiments tested the importance of the stimulus-response (S-R) and stimulus-outcome (S-O) associations between the IntA availability cues and the training response and reinforcer, respectively. In Exp. 1, separate groups of rats were trained to lever press for saccharin on the IntA or ContA procedures. Increased motivation for saccharin was observed in the IntA group on a later progressive ratio test where nosepoking was the operant (but not when lever pressing was the operant). The outcome of the nosepoke test suggests that a potential S-R association formed during IntA training was not critical for the effect. In Exp. 2, increased saccharin motivation (on nosepoke tests) after IntA training (with lever pressing) was observed regardless of the presence or absence of IntA availability cues, indicating that the S-O association formed during training is not critical for the effect either. Overall, these results suggest that the elemental associations learned on IntA procedures may not be what drives increased motivation observed after IntA training.

Taste Neophobia, Latent Inhibition of Taste Aversion and Object Recognition Memory in Adolescent Rats / Neofobia Gustativa, Inhibición Latente de la Aversión Gustativa y Memoria de Reconocimiento de Objetos en Ratas Adolescentes

Background: Adolescence in mammals is a period marked by increased novelty-seeking and enhanced responsiveness to the stressful properties of novel stimuli. Despite the need to taste potentially toxic novel foods during the adolescent growth spurt, there has been little study of taste neophobia and its attenuation. Method: Four experiments were carried out to compare taste neophobia and related memory processes in male and female adolescent (PND28) and adult (PND70) Wistar rats. Experiments 1 and 2 evaluated attenuation of taste neophobia to cider vinegar (3%) and sodium saccharin (0.1%) solutions were evaluated. Additionally, to test the role of memory in neophobia during adolescence, latent inhibition of taste aversion and object recognition memory were assessed in Experiment 3 and Experiment 4, respectively. Results: Adolescent and adult rats exhibited taste neophobia to the saccharin solution but adolescent rats required more exposure trials than adults to recognize the vinegar solution as safe. Both groups exhibited similar latent inhibition of taste aversion and object recognition memory. No sex effect was significant. Conclusions: Contrary to the accepted view associating adolescence with reduced neophobia, adolescent rats exhibited taste neophobia which even increased when sour tastes were encountered.(AU)

Antecedentes: La adolescencia está marcada por búsqueda de la novedad y acentuada sensibilidad a las propiedades estresantes de los estímulos novedosos. A pesar de la necesidad de probar nuevos alimentos potencialmente tóxicos durante el periodo de crecimiento adolescente, la neofobia gustativa y su atenuación durante este periodo apenas ha sido estudiada. Método: Se evaluaron la neofobia gustativa y los procesos de memoria relacionados en ratas Wistar macho y hembra adolescentes (PND28) y adultas (PND70). En los Experimentos 1 y 2 Se exploró la atenuación de la neofobia gustativa a soluciones de vinagre de sidra (3%) y sacarina sódica (0,1%), respectivamente. En los experimentos 3 y 4, se evaluó también la inhibición latente de aversiones gustativas y la memoria de reconocimiento de objetos. Resultados: Adolescentes y adultos mostraron neofobia gustativa a la sacarina, pero las ratas adolescentes requirieron más exposiciones a la solución de vinagre para reconocerla como segura. No hubo diferencias entre los grupos en los Experimentos 3 and 4. No se hallaron efectos significativos del sexo. Conclusiones: A pesar de la ampliamente aceptada asociación entre adolescencia y reducida neofobia, las ratas adolescentes muestran neofobia al sabor que resulta incluso incrementada cuando se trata de sabores ácidos.(AU)

Relationship between nasal mucociliary clearance and disease severity in children with allergic rhinitis: A comparative cross-sectional study

OBJECTIVES: Mucociliary clearance (MCC) is impaired due to chronic inflammation in allergic rhinitis. Our aim was to evaluate MCC in children with allergic rhinitis, to determine its relationship with disease severity and evaluate MCC change after nasal irrigation. MATERIALS AND METHODS: Saccharin test was performed in 51 patients with allergic rhinitis and in 50 controls. Nasal irrigation was performed to the patients and saccharin test was repeated at the 10th minute. Total nasal symptom score (TNSS) and visual analogue scale (VAS) results were recorded. Patients were divided into mild/moderate-severe groups according to TNSS, VAS, and ARIA guidelines. Nasal MCC time (NMCCT) of the patients and the controls and NMCCT before and after nasal irrigation of the patients were compared. Correlations between NMCCT and TNSS/VAS were evaluated. NMCCTs of the mild and moderate-severe groups were compared. The cut-off values were calculated to discriminate the patient group. RESULTS: The mean NMCCT of the patient group was higher than the controls. Mean NMCCTs were different between before and after irrigation. NMCCT was higher in uncontrolled/moderate-severe groups than in controlled/mild groups. NMCCT correlated positively with VAS and TNSS. The sensitivity and specificity of NMCCT > 535 s were found to be 86.27% and 94%, respectively. CONCLUSIONS: In children with allergic rhinitis, the prolongation of MCC may be identified with the easily applicable saccharin test, the deterioration in MCC increases as disease severity increases. Nasal irrigation is important in children with allergic rhinitis to improve MCC

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Effects of oral isotretinoin therapy on the nasal cavities / Efeitos nasais da terapia com isotretinoína oral

Abstract Introduction Isotretinoin (13 cis-retinoic acid) is the most effective treatment for acne vulgaris and is the only treatment option that can provide either remission or a permanent cure. Objective The aim of this study was to use both subjective and objective methods to assess the nasal complaints of patients with severe acne who received oral isotretinoin therapy. Methods Fifty-four subjects were enrolled in the study. All the subjects were assessed with subjective (NOSE and VAS questionnaires) and objective (rhinomanometry and saccharine) tests to determine the severity of their nasal complaints. Results The mean severity scores (min: 0; max: 100) for nasal dryness/crusting and epistaxis were 0.47 ± 1.48 (0-5); 0.35 ± 1.30 (0-5) at admission, 3.57 ± 4.45 (0-10); 2.26 ± 4.71 (0-20) at the first month, and 4.28 ± 6 (0-20); 2.26 ± 4.71 (0-20) at the third month of the treatment respectively. Total nasal resistance of 0.195 ± 0.079 (0.12-0.56) Pa/cm3/s at admission, 0.21 ± 0.084 (0.12-0.54) Pa/cm3/s at the first month, and 0.216 ± 0.081 (0.14-0.54) Pa/cm3/s at the third month. Conclusion Oral isotretinoin therapy can cause the complaint of nasal obstruction. In addition, nasal complaints, such as dryness/crusting and epistaxis, significantly increase in patients during the therapy schedule.

Resumo Introdução A isotretinoína (ácido-13 cis-retinóico) é o tratamento por via oral mais eficaz para acne vulgar e é a única opção de tratamento que pode produzir remissão ou cura permanente. Objetivo Usar métodos subjetivos e objetivos para avaliar as queixas nasais de pacientes com acne grave que receberam terapia com isotretinoína oral. Método Foram incluídos no estudo 54 indivíduos. Todos os indivíduos foram avaliados por meio de testes subjetivos (questionários NOSE e escala EVA) e objetivos (rinomanometria e teste de sacarina) para determinar a gravidade de suas queixas nasais. Resultados Os escores médios de gravidade (min: 0; max: 100) para ressecamento/crostas e epistaxe nasal foram de 0,47 ± 1,48 (0-5); 0,35 ± 1,30 (0-5) no início, 3,57 ± 4,45 (0-10); 2,26 ± 4,71 (0-20) no primeiro mês e 4,28 ± 6 (0-20); 2,26 ± 4,71 (0-20) no terceiro mês do tratamento, respectivamente. A resistência nasal total foi de 0,195 ± 0,079 (0,12 a 0,56) Pa/cm3/s no início, 0,21 ± 0,084 (0,12 a 0,54) Pa/cm3/s no primeiro mês e 0,216 ± 0,081 (0,14 a 0,54) Pa/cm3/s no terceiro mês. Conclusão A terapia com isotretinoína por via oral pode resultar em queixa de obstrução nasal. Além disso, queixas nasais, tais como ressecamento/formação de crostas e epistaxe, aumentam significativamente nos pacientes durante o esquema terapêutico.