RESUMEN
This study aimed to elucidate the effects of sucrose (SUC) consumption on neurodevelopmental processes through behavioral changes in rodents and determine whether these effects could be because of sweet taste, energy supply, or both. Mice were divided into five groups based on the time of SUC or sucralose (SUR, a noncaloric sweetener) administration: for 6 days from gestation day (GTD) 7, to birth from GTD13 and for 15 days from postnatal day (PND) 21, PND38, and PND56. SUC and SUR administration did not impact body weight. However, food intake in the PND56 group and water intake in the GTD13 and PND56 groups were increased by SUC and SUR administration. Amphetamine (0.5, 1, 2, and 3â mg/kg), a dopamine reuptake inhibitor, administration to assess alterations in the dopaminergic system induced increases in distance traveled after SUC administration in the GTD13 and PND21 groups compared with that in the control (vehicle administration) group. In contrast, the SUR group showed a decrease in the distance traveled in the PND56 group. Although there were no differences in locomotor activity and foraging behavior, SUC preference increased in the SUC group regarding the GTD13 and PND38 groups. The correlations between SUC preference and foraging behavior and between SUC preference and amphetamine response varied in both groups according to the developmental stage. Excessive SUC consumption might affect neural function at different developmental stages, as it could affect brain function through complex mechanisms involving sweet taste and energy supply and influence the dopaminergic system.
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Sacarosa , Animales , Sacarosa/administración & dosificación , Sacarosa/análogos & derivados , Femenino , Ratones , Embarazo , Masculino , Anfetamina/farmacología , Conducta Animal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Actividad Motora/efectos de los fármacos , Edulcorantes/administración & dosificación , Peso Corporal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Ingestión de Líquidos/efectos de los fármacosRESUMEN
The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviours that can be modelled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that Kv7/KCNQ channels may contribute to the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drugs is not known. Here, we tested the ability of retigabine (ezogabine), a Kv7 channel opener, to regulate instrumental behaviour in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a conditioned place preference (CPP) assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine pretreatment attenuated the SA of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared with sucrose-SA, cocaine-SA was associated with reductions in the expression of the Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward-specific reduction in SA behaviour and support the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
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Carbamatos , Cocaína , Fenilendiaminas , Ratas Sprague-Dawley , Autoadministración , Sacarosa , Animales , Fenilendiaminas/farmacología , Fenilendiaminas/administración & dosificación , Carbamatos/farmacología , Carbamatos/administración & dosificación , Cocaína/farmacología , Cocaína/administración & dosificación , Masculino , Ratas , Sacarosa/administración & dosificación , Sacarosa/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Canales de Potasio KCNQ/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Inhibidores de Captación de Dopamina/administración & dosificaciónRESUMEN
PURPOSE: We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo. METHODS: Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. RESULTS: The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. CONCLUSIONS: Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.
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Barrera Hematoencefálica , Propofol , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Propofol/farmacocinética , Propofol/administración & dosificación , Propofol/farmacología , Ratones , Masculino , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Anestésicos Intravenosos/farmacocinética , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/farmacología , Xilazina/farmacología , Ketamina/farmacología , Ketamina/administración & dosificación , Ketamina/farmacocinética , Sacarosa/administración & dosificación , Ratones Endogámicos C57BL , Permeabilidad/efectos de los fármacosRESUMEN
INTRODUCTION: Oral sucrose is repeatedly administered to neonates in the neonatal intensive care unit (NICU) to treat pain from commonly performed procedures; however, there is limited evidence on its long-term cumulative effect on neurodevelopment. We examined the association between total sucrose volumes administered to preterm neonates for pain mitigation in the NICU and their neurodevelopment at 18 months of corrected age (CA). METHODS: A prospective longitudinal single-arm observational study that enrolled hospitalised preterm neonates <32 weeks of gestational age at birth and <10 days of life was conducted in four level III NICUs in Canada. Neonates received 0.1 mL of 24% sucrose 2 min prior to all commonly performed painful procedures during their NICU stay. Neurodevelopment was assessed at 18 months of CA using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Multiple neonatal and maternal factors known to affect development were adjusted for in the generalised linear model analysis. RESULTS: 172 preterm neonates were enrolled and 118 were included in the analysis at 18 months of CA. The total mean sucrose volume administered/neonate/NICU stay was 5.96 (±5.6) mL, and the mean Bayley-III composite scores were: cognitive 91 (±17), language 86 (±18) and motor 88 (±18). There was no association between Bayley-III scores and the total sucrose volume: cognitive (p=0.57), language (p=0.42) and motor (p=0.70). CONCLUSION: Cumulative sucrose exposure for repeated procedural pain in preterm neonates was neither associated with a delay in neurodevelopment nor neuroprotective effects at 18 months of CA. If sucrose is used, we suggest the minimally effective dose combined with other non-pharmacological interventions with demonstrated effectiveness such as skin-to-skin contact, non-nutritive sucking, facilitated tucking and swaddling. TRIAL REGISTRATION NUMBER: NCT02725814.
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Recien Nacido Prematuro , Unidades de Cuidado Intensivo Neonatal , Dolor Asociado a Procedimientos Médicos , Sacarosa , Humanos , Sacarosa/administración & dosificación , Estudios Prospectivos , Recién Nacido , Femenino , Masculino , Recien Nacido Prematuro/crecimiento & desarrollo , Estudios Longitudinales , Lactante , Dolor Asociado a Procedimientos Médicos/prevención & control , Dolor Asociado a Procedimientos Médicos/etiología , Desarrollo Infantil/efectos de los fármacos , Desarrollo Infantil/fisiología , Canadá , Administración OralRESUMEN
Background: Diabetic foot ulcers and venous leg ulcers may not always heal in a timely manner despite proper wound care. Treatments that improve the healing rate of these ulcers would improve clinical outcomes for patients and may result in downstream cost savings for the health care system. We conducted a health technology assessment of sucrose octasulfate-impregnated dressings for adults with difficult-to-heal noninfected diabetic foot ulcers and difficult-to-heal noninfected venous leg ulcers, which included an evaluation of effectiveness, safety, cost-effectiveness, the budget impact of publicly funding sucrose octasulfate-impregnated dressings, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool for randomized trials (RoB 2) and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and analyzed the budget impact of publicly funding sucrose octasulfate-impregnated dressings for adults with difficult-to-heal noninfected diabetic foot ulcers and difficult-to-heal noninfected venous leg ulcers in Ontario. We did not conduct a primary economic evaluation because there is existing evidence to approximate the cost-effectiveness of sucrose octasulfate-impregnated dressings in Ontario. We leveraged 4 previous health technology assessments to explore the perspectives and experiences of patients with diabetic foot ulcers and venous leg ulcers, as well as the perspectives and experiences of their care partners. Results: We included 3 randomized controlled trials and 2 subsequent publications of these randomized controlled trials in the clinical evidence review. Compared with dressings that do not contain sucrose octasulfate, sucrose octasulfate-impregnated dressings result in faster wound closure in patients with difficult-to-heal noninfected neuroischemic diabetic foot ulcers (GRADE: Moderate) and reduce ulcer size and improve health-related quality of life in the domains of pain/discomfort and anxiety/depression for patients with difficult-to-heal noninfected venous leg ulcers (GRADE: Moderate). The use of sucrose octasulfate-impregnated dressings with noninfected wounds is considered safe (GRADE: Moderate).The economic evidence showed that, compared with dressings that do not contain sucrose octasulfate, sucrose octasulfate-impregnated dressings are highly likely to be cost-effective for both difficult-to-heal noninfected diabetic foot ulcers and difficult-to-heal noninfected venous leg ulcers and would lead to cost savings due to faster and increased complete wound healing. The annual budget impact of publicly funding sucrose octasulfate-impregnated dressings in Ontario over the next 5 years would range from cost savings of $0.93 million in year 1 to $0.62 million in year 5 for adults with difficult-to-heal noninfected diabetic foot ulcers, and cost savings of $0.8 million in year 1 to $0.53 million in year 5 for adults with difficult-to-heal noninfected venous leg ulcers. Overall, we estimate that publicly funding sucrose octasulfate-impregnated dressings in Ontario for adults with difficult-to-heal noninfected diabetic foot ulcers and difficult-to-heal noninfected venous leg ulcers would lead to total cost savings of $3.91 million and $3.38 million, respectively, over the next 5 years.Patients with diabetic foot ulcers and venous leg ulcers discussed the effects of living with these wounds, as well as their treatment journey. They spoke about the burden of their condition and its negative impact on their daily lives, including mobility, employment, social activities, and mental health. Patients also spoke about the variety of treatment options available and the financial barriers to accessing these treatments. Conclusions: Sucrose octasulfate-impregnated dressings are safe and improve the healing of difficult-to-heal noninfected neuroischemic diabetic foot ulcers and difficult-to-heal noninfected venous leg ulcers compared with dressings that do not contain sucrose octasulfate. We estimate that publicly funding sucrose octasulfate-impregnated dressings in Ontario would result in cost savings for both difficult-to-heal noninfected diabetic foot ulcers and difficult-to-heal noninfected venous leg ulcers. Evidence from patient engagement suggests that people with diabetic foot ulcers or venous leg ulcers face negative impacts on their quality of life, especially related to mobility. Patients spoke about their challenges, including long and difficult care journeys, as well as trying different treatment options to heal their ulcers and avoid amputation. It is not clear if the participants had direct experience with sucrose octasulfate-impregnated dressings, so we could not draw specific conclusions about these dressings from the preferences and values evidence.
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Análisis Costo-Beneficio , Pie Diabético , Evaluación de la Tecnología Biomédica , Cicatrización de Heridas , Humanos , Pie Diabético/terapia , Sacarosa/análogos & derivados , Sacarosa/administración & dosificación , Úlcera Varicosa/terapia , Vendajes/economía , Adulto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Neokestose is considered to have a prebiotic function. However, the physiological activity of neokestose remains unknown. Neokestose has a blastose, a sucrose analog, in its structure. We previously demonstrated that oral administration of blastose to diabetic rats suppressed the increase in plasma glucose (PG) concentration after sucrose administration. Therefore, neokestose might have a similar effect. In this study, we investigated the effects of neokestose on PG concentrations and the mechanism of its action. We first administered neokestose orally to streptozotocin-induced diabetic rats and observed that the expected consequent increase in PG concentration was significantly suppressed. Next, we examined the inhibitory effect of neokestose on glycosidase activity, but observed only a slight inhibitory effect. Therefore, we hypothesized that neokestose might be hydrolyzed by gastric acid to produce blastose. We performed an acid hydrolysis of neokestose using artificial gastric juice. After acid hydrolysis, peaks corresponding to neokestose and its decomposition products including blastose were observed. Therefore, we suggest that neokestose and blastose, a decomposition product, synergistically inhibit glycosidase activity. These findings support the potential use of neokestose as a useful functional oligosaccharide that can help manage plasma glucose concentrations in patients with diabetes mellitus.
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Glucemia , Diabetes Mellitus Experimental , Sacarosa , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Glucemia/metabolismo , Administración Oral , Ratas , Masculino , Sacarosa/análogos & derivados , Sacarosa/administración & dosificación , Estreptozocina , Glicósido Hidrolasas/metabolismo , Hidrólisis , Oligosacáridos/farmacología , Oligosacáridos/administración & dosificaciónRESUMEN
Molecular mechanisms associated to improvement of metabolic syndrome (MetS) during exercise are not fully elucidated. MetS was induced in 250 g male Wistar rats by 30% sucrose in drinking water. Control rats receiving tap water were controls, both groups received solid standard diet. After 14 weeks, an endurance exercised group, and a sedentary were formed for 8 weeks. The soleus and extensor digitorum longus (EDL) muscles were dissected to determine contractile performance, expression of myosin heavy chain isoforms, PGC1α, AMPKα2, NFATC1, MEF2a, SIX1, EYA1, FOXO1, key metabolic enzymes activities. Exercise mildly improved MetS features. MetS didn't alter the contractile performance of the muscles. Exercise didn't altered expression of PGC1α, NFATC1, SIX1 and EYA1 on MetS EDL whereas NFATC1 increased in soleus. Only citrate synthase was affected by MetS on the EDL and this was partially reverted by exercise. Soleus α-ketoglutarate dehydrogenase activity was increased by exercise but MetS rendered the muscle resistant to this effect. MetS affects mostly the EDL muscle, and endurance exercise only partially reverts this. Soleus muscle seems more resilient to MetS. We highlight the importance of studying both muscles during MetS, and their metabolic remodeling on the development and treatment of MetS by exercise.
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Metabolismo Energético , Síndrome Metabólico , Condicionamiento Físico Animal , Ratas Wistar , Animales , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Ratas , Músculo Esquelético/metabolismo , Sacarosa/metabolismo , Sacarosa/administración & dosificación , Fibras Musculares Esqueléticas/metabolismo , Contracción Muscular , FenotipoRESUMEN
D-Allulose has blood glucose suppression effects in both animal and clinical studies. The mechanism mediating glucose suppression in animals is controlled by several actions including the inhibition of sucrase. To investigate the dose-response effects of D-allulose with a sucrose beverage on glucose tolerance and insulin levels using Thai volunteers. This was a prospective, randomized, double-blinded, crossover study. Subjects had five oral sucrose tolerance tests (OSTT) with escalating doses of D-allulose (0, 2.5, 5, 7.5 or 10 g) with a 50 g sucrose beverage in a random order once a week for five consecutive weeks. The five drinks were consumed in a random order; the order being blinded for both subjects and investigators. Blood samples were drawn immediately before consumption and at 30, 60, 90 and 120 min after consumption of the study product for measurement of plasma glucose and insulin levels. Thirty healthy subjects (11 men and 19 women) completed the study. The peak postprandial glucose (PePPG) and insulin levels (PePPI) were lower when D-allulose was added in a dose-dependent manner. The lowest plasma glucose and insulin levels occurred at 120 min after OSTT in all five products and they were raised when D-allulose was added in a dose-dependent manner. D-Allulose has a suppression response on glucose and insulin shown by the decrease in postprandial plasma glucose and insulin levels following the addition of D-allulose to sucrose in a dose-dependent manner. The more D-allulose added, the less marked the glucose and insulin response occurred.
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Glucemia , Estudios Cruzados , Insulina , Periodo Posprandial , Sacarosa , Humanos , Masculino , Insulina/sangre , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Glucemia/análisis , Adulto , Método Doble Ciego , Femenino , Adulto Joven , Tailandia , Sacarosa/administración & dosificación , Sacarosa/farmacología , Fructosa/administración & dosificación , Fructosa/farmacología , Prueba de Tolerancia a la Glucosa , Relación Dosis-Respuesta a Droga , Estudios Prospectivos , Bebidas , Voluntarios Sanos , Bebidas Azucaradas , Pueblos del Sudeste AsiáticoRESUMEN
Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.
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Disbiosis , Emulsionantes , Microbioma Gastrointestinal , Enfermedades Metabólicas , Animales , Disbiosis/inducido químicamente , Disbiosis/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Masculino , Enfermedades Metabólicas/inducido químicamente , Enfermedades Metabólicas/microbiología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiología , Ratones Endogámicos C57BL , Carboximetilcelulosa de Sodio , Sacarosa/efectos adversos , Sacarosa/administración & dosificación , Sacarosa/metabolismo , Resistencia a la Insulina , LecitinasRESUMEN
BACKGROUND: Small infants experience a myriad of stimuli while in the Neonatal Intensive Care Unit (NICU), with many being painful or stressful experiences, although medically necessary. PURPOSE: To determine what is known about nonpharmacological developmental care interventions used in the NICU to mitigate procedural pain of infants born under 32 weeks gestation. SEARCH/STRATEGY: Five electronic databases were searched: Medline, CINAHL, Scopus, Embase and the Cochrane Library. The inclusion criteria were as follows: experimental and nonexperimental studies from all publication years with infants born at less than 32 weeks gestational age; peer-reviewed research articles studying nonpharmacological interventions such as skin-to-skin care, facilitated tucking, nonnutritive sucking, hand hugs, and swaddling; and English language articles. Our search yielded 1435 articles. After the elimination of 736 duplicates, a further 570 were deemed irrelevant based on their abstract/titles. Then, 124 full-text articles were analyzed with our inclusion and exclusion criteria. FINDINGS: Twenty-seven studies were reviewed. Sucrose, facilitated tucking, pacifier, skin-to-skin care, and human milk appeared to lessen pain experienced during heel sticks, suctioning, nasogastric tube insertions, and echocardiograms. All nonpharmacological interventions failed to prove efficacious to adequately manage pain during retinopathy of prematurity (ROP) examinations. IMPLICATIONS FOR PRACTICE: Evidence review demonstrates that healthcare practitioners should use nonpharmacological measures to help prevent pain from day-to-day procedures in the NICU including heel sticks, nasogastric tube insertions, suctioning, echocardiograms, and subcutaneous injections. IMPLICATIONS FOR RESEARCH: Future research is necessary to better understand and measure how pain is manifested by very small premature infants. Specific research on mitigating the pain of examinations for retinopathy of prematurity is also needed.
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Unidades de Cuidado Intensivo Neonatal , Manejo del Dolor , Dolor Asociado a Procedimientos Médicos , Humanos , Recién Nacido , Dolor Asociado a Procedimientos Médicos/prevención & control , Manejo del Dolor/métodos , Recien Nacido Prematuro , Método Madre-Canguro/métodos , Contención del Recién Nacido/métodos , Chupetes , Leche Humana , Sacarosa/uso terapéutico , Sacarosa/administración & dosificaciónRESUMEN
The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner.
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Dieta Alta en Grasa , Inflamación , Medicina Kampo , Obesidad , Receptores de Oxitocina , Animales , Femenino , Masculino , Ratones , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Preferencias Alimentarias/efectos de los fármacos , Inflamación/metabolismo , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Oxitocina/farmacología , Sacarosa/administración & dosificación , Japón , Receptores de Oxitocina/agonistasRESUMEN
Hyperglycemia and high adiposity are risk factors for pain in diabetes. To clarify these links with pain, the effects of a glucose load on sensory detection, pain sensitivity, conditioned pain modulation (primary aims), and autonomic and endothelial functions (secondary aims) were examined in 64 pain-free participants: 22 with normal adiposity (determined by dual-energy X-ray absorptiometry), 29 with high adiposity, and 13 with combined high adiposity and elevated glycated hemoglobin (HbA1c; including prediabetes and type 2 diabetes). Participants ingested either 37.5 g glucose or 200 mg sucralose (taste-matched) in the first session and crossed over to the other substance in the second session 1 month later. At baseline, painful temple cooling (the conditioning stimulus) inhibited pressure- and heat-pain in the ipsilateral arm (the test stimuli) immediately after cooling ceased (partial η2's > .32). Glucose ingestion weakened pressure-pain inhibition irrespective of HbA1c levels (partial η2 = .11). However, a larger reduction in pressure-pain inhibition after ingesting glucose was associated with a higher waist/hip ratio (r = .31), suggesting a role of central obesity. Heat-pain inhibition was absent at baseline in unmedicated participants with elevated HbA1c, and these participants reported more occlusion-induced pain after ingesting glucose (partial η2's > .17). Glucose ingestion interfered with parasympathetic activity in all participants (partial η2 = .11) but did not affect endothelial function (measured by reactive hyperemia) or alter other sensations (eg, feet vibration detection). The disruptive effect of hyperglycemia on conditioned pain modulation increases in line with central obesity, which might facilitate pain in diabetes. PERSPECTIVE: Ingesting 37.5 g glucose (approximately 350 mL soft drink) interfered with pain modulation in pain-free adults with normal adiposity or with combined high adiposity and HbA1c levels. The interference was stronger alongside increasing central obesity, suggesting that controlling blood glucose and body fat mass might help preserve pain modulation.
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Estudios Cruzados , Hiperglucemia , Obesidad Abdominal , Humanos , Masculino , Femenino , Hiperglucemia/fisiopatología , Adulto , Obesidad Abdominal/fisiopatología , Obesidad Abdominal/complicaciones , Método Simple Ciego , Persona de Mediana Edad , Glucosa/metabolismo , Umbral del Dolor/fisiología , Hemoglobina Glucada/metabolismo , Dolor/fisiopatología , Dolor/etiología , Sacarosa/administración & dosificación , Sacarosa/farmacología , Sacarosa/análogos & derivados , Adulto Joven , Percepción del Dolor/fisiología , Condicionamiento Psicológico/fisiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatologíaRESUMEN
INTRODUCTION: High sugar intake is associated with many chronic diseases. However, non-caloric sweeteners (NCSs) might fail to successfully replace sucrose due to the mismatch between their rewarding sweet taste and lack of caloric content. The natural NCS erythritol has been proposed as a sugar substitute due to its satiating properties despite being non-caloric. We aimed to compare brain responses to erythritol vs. sucrose and the artificial NCS sucralose in a priori taste, homeostatic, and reward brain regions of interest (ROIs). METHODS: We performed a within-subject, single-blind, counterbalanced fMRI study in 30 healthy men (mean ± SEM age:24.3 ± 0.8 years, BMI:22.3 ± 0.3 kg/m2). Before scanning, we individually matched the concentrations of both NCSs to the perceived sweetness intensity of a 10% sucrose solution. During scanning, participants received 1 mL sips of the individually titrated equisweet solutions of sucrose, erythritol, and sucralose, as well as water. After each sip, they rated subjective sweetness liking. RESULTS: Liking ratings were significantly higher for sucrose and sucralose vs. erythritol (both pHolm = 0.0037); water ratings were neutral. General Linear Model (GLM) analyses of brain blood oxygen level-depended (BOLD) responses at qFDR<0.05 showed no differences between any of the sweeteners in a priori ROIs, but distinct differences were found between the individual sweeteners and water. These results were confirmed by Bayesian GLM and machine learning-based models. However, several brain response patterns mediating the differences in liking ratings between the sweeteners were found in whole-brain multivariate mediation analyses. Both subjective and neural responses showed large inter-subject variability. CONCLUSION: We found lower liking ratings in response to oral administration of erythritol vs. sucrose and sucralose, but no differences in neural responses between any of the sweeteners in a priori ROIs. However, differences in liking ratings between erythritol vs. sucrose or sucralose are mediated by multiple whole-brain response patterns.
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Encéfalo , Eritritol , Preferencias Alimentarias , Imagen por Resonancia Magnética , Sacarosa , Edulcorantes , Humanos , Eritritol/farmacología , Eritritol/análogos & derivados , Eritritol/administración & dosificación , Masculino , Adulto Joven , Adulto , Sacarosa/análogos & derivados , Sacarosa/administración & dosificación , Sacarosa/farmacología , Preferencias Alimentarias/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Método Simple Ciego , Edulcorantes/administración & dosificación , Edulcorantes/farmacología , Gusto/efectos de los fármacos , Administración Oral , Percepción del Gusto/efectos de los fármacos , RecompensaRESUMEN
Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are coexpressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.
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Dopamina , Núcleo Accumbens , Receptores de Polipéptido Amiloide de Islotes Pancreáticos , Área Tegmental Ventral , Animales , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Masculino , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/metabolismo , Ratas Sprague-Dawley , Grasas de la Dieta/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Agonistas de los Receptores de Amilina/farmacología , Ratas , Sacarosa/administración & dosificación , Sacarosa/farmacologíaRESUMEN
Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [3H]raclopride on dopamine D2/3 receptors, [3H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [3H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [3H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [3H]UCB-J and [3H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.
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Sacarosa , Porcinos Enanos , Animales , Porcinos , Sacarosa/administración & dosificación , Masculino , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores de Cannabinoides/metabolismo , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Receptores de Dopamina D2/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Femenino , Receptores de Dopamina D3/metabolismoRESUMEN
The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and Cre- (control) mice were tested for alcohol consumption in two drinking paradigms: limited access "Drinking in the Dark" and intermittent access. Quinine was added to the drinking bottles in the DID experiment to test aversion-resistant, "compulsive" drinking. Nicotine and sucrose drinking were also assessed so comparisons could be made with other rewarding substances. Cholinergic MOR deletion did not influence consumption or preference for ethanol (EtOH) in either drinking task. Differences were observed in aversion-resistance in males with Cre + mice tolerating lower concentrations of quinine than Cre-. In contrast to EtOH, preference for nicotine was reduced following cholinergic MOR deletion while sucrose consumption and preference was increased in Cre+ (vs. Cre-) females. Locomotor activity was also greater in females following the deletion. These results suggest that cholinergic MORs participate in preference for rewarding substances. Further, while they are not required for consumption of alcohol alone, cholinergic MORs may influence the tendency to drink despite negative consequences.
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Consumo de Bebidas Alcohólicas , Ratones Noqueados , Quinina , Receptores Opioides mu , Recompensa , Animales , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Masculino , Femenino , Ratones , Quinina/farmacología , Quinina/administración & dosificación , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/psicología , Nicotina/farmacología , Etanol/farmacología , Etanol/administración & dosificación , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/fisiología , Neuronas Colinérgicas/metabolismo , Autoadministración , Sacarosa/administración & dosificación , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Interneuronas/efectos de los fármacos , Interneuronas/fisiología , Interneuronas/metabolismoRESUMEN
A growing body of evidence suggests that elevated sucrose intake may contribute to the development of neurological disorders. Recognizing that regular exercise has the potential to reduce the occurrence of neuromuscular disorders, the present research investigated the impact of exercise on the redox status of the hypothalamus in mitigating the adverse effects associated with high sucrose intake. Forty Wistar albino rats were subjected to a high sucrose diet, with some groups engaging in exercise for a duration of 3 months. The exercise regimen was found to sustain the redox balance in the hypothalamus. In summary, the consumption of a high sucrose diet resulted in the disturbance of the histological morphology of the hypothalamus, accompanied by an increased percentage of caspase-3 positive cells. Additionally, the high sucrose diet disrupted the oxidant/antioxidant ratio in favor of oxidants, leading to elevated levels of AOPPs and AGEP. Conversely, exercise was effective in restoring most of these values to levels approximating the control group, indicating a potential protective effect of regular exercise against the detrimental impacts of high sucrose dietary consumption on the hypothalamus. Graphical abstract.
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Hipotálamo , Condicionamiento Físico Animal , Ratas Wistar , Animales , Hipotálamo/metabolismo , Condicionamiento Físico Animal/fisiología , Ratas , Masculino , Estrés Oxidativo , Caspasa 3/metabolismo , Oxidación-Reducción , Sacarosa en la Dieta/efectos adversos , Sacarosa en la Dieta/administración & dosificación , Antioxidantes/metabolismo , Sacarosa/efectos adversos , Sacarosa/administración & dosificaciónRESUMEN
Although the phenomenon of memory formation and recall associated with the use of psychotropic drugs has been extensively studied, mechanisms underlying memories for natural reward have not been clarified. Herein, we test the hypothesis that glutamatergic receptors in the dentate gyrus play a role in memories associated with sucrose. We used pellet self-administration protocol to generate memories in two-port nose-poke discrimination task using male Wistar rats. During non-rewarded probe trial, the conditioned animals readily discriminated the active port versus inactive port and showed massive increase in mRNA expression of AMPA receptor subunit genes (gria2, gria3) as well as c-Fos protein in the DG. Access to sweet pellet further enhanced c-Fos expression in the DG. However, animals pre-treated with AMPA receptor antagonist CNQX (intra-DG), on exposure to operant chamber (no pellet), showed decreased discrimination as well as c-Fos expression. We suggest that AMPA receptors in DG mediate recall and consolidation of memories associated with sucrose consumption. CNQX pre-treated animals, if presented with sweet pellet on nose poke, exhibited high discrimination index coupled with increased c-Fos expression. In these CNQX treated rats, the DI was again decreased following administration of NMDA receptor antagonist AP5. We suggest that, although AMPA receptors are blocked, the access to sweet pellet may induce surge of glutamate in the DG, which in turn may reinstate memories via activation of erstwhile silent synapses in NMDA dependant manner.
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Giro Dentado , Receptores AMPA , Receptores de N-Metil-D-Aspartato , Sacarosa , Animales , Masculino , Ratas , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Aprendizaje Discriminativo/efectos de los fármacos , Aprendizaje Discriminativo/fisiología , Discriminación en Psicología/efectos de los fármacos , Discriminación en Psicología/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Memoria/fisiología , Memoria/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Wistar , Receptores AMPA/metabolismo , Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , ARN Mensajero/metabolismo , Autoadministración , Sacarosa/administración & dosificaciónRESUMEN
Consumption of sucrose-sweetened drinks (SSDs) during pregnancy and breastfeeding can lead to various health and metabolism issues, but the potential impact on neurodevelopment and long-term effects remains unclear. This study aims to examine how maternal consumption of SSDs during gestation and lactation influences anxiety and depression-related behavior in adult offspring. Adult female CD-1 mice were randomly assigned to a control group (CG) or a sucrose group (SG) 2 weeks before gestation. The SG had 2 h of access to an SSD (15% w/w, 0.6 kcal/ml) for 2 weeks before mating, during pregnancy, and throughout lactation, totaling 8 weeks. Adult offspring were then evaluated for depressive-related behaviors and anxiety-related behaviors. Our findings reveal that perigestational consumption of SSDs does not lead to offspring presenting behaviors related to depression, but it does increase swimming behavior. However, maternal consumption of SSDs could impact the fighting response due to a diminished motivational component. In contrast, perigestational consumption of SSDs has apparent effects on anxiety-related behavior. Furthermore, female offspring appeared to be particularly vulnerable, exhibiting a higher anxiety index compared with controls. These findings indicate that females could be more vulnerable to the effects of maternal consumption of SSDs, being more susceptible to the presence of anxiety-related behaviors.
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Ansiedad , Depresión , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Ratones , Embarazo , Depresión/etiología , Masculino , Modelos Animales de Enfermedad , Bebidas Azucaradas , Sacarosa/administración & dosificación , Caracteres Sexuales , Natación/psicología , Conducta Animal/efectos de los fármacosRESUMEN
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.