The neurokinin 1 receptor antagonist, ezlopitant, reduces appetitive responding for sucrose and ethanol

Abstract Background: The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7,8]. The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown. Methodology/Principal Findings: We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption. Conclusions/Significance: The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Long-evans rats acquire operant self-administration of 20% ethanol without sucrose fading

A major obstacle in the development of new medications for the treatment of alcohol use disorders (AUDs) has been the lack of preclinical, oral ethanol consumption paradigms that elicit high consumption. We have previously shown that rats exposed to 20% ethanol intermittently in a two-bottle choice paradigm will consume two times more ethanol than those given continuous access without the use of water deprivation or sucrose fading (5-6 g/kg every 24 h vs 2-3 g/kg every 24 h, respectively). In this study, we have adapted the model to an operant self-administration paradigm. Long-Evans rats were given access to 20% ethanol in overnight sessions on one of two schedules: (1) intermittent (Monday, Wednesday, and Friday) or (2) daily (Monday through Friday). With the progression of the overnight sessions, both groups showed a steady escalation in drinking (3-6 g/kg every 14 h) without the use of a sucrose-fading procedure. Following the acquisition phase, the 20% ethanol groups consumed significantly more ethanol than did animals trained to consume 10% ethanol with a sucrose fade (1.5 vs 0.7 g/kg every 30 min) and reached significantly higher blood ethanol concentrations. In addition, training history (20% ethanol vs 10% ethanol with sucrose fade) had a significant effect on the subsequent self-administration of higher concentrations of ethanol. Administration of the pharmacological stressor yohimbine following extinction caused a significant reinstatement of ethanol-seeking behavior. Both 20% ethanol models show promise and are amenable to the study of maintenance, motivation, and reinstatement. Furthermore, training animals to lever press for ethanol without the use of sucrose fading removes a potential confound from self-administration studies. © 2010 Nature Publishing Group All rights reserved.

Improved sugar cane juice clarification by understanding calcium oxide-phosphate-sucrose systems

It is accepted that the efficiency of sugar cane clarification is closely linked with sugar juice composition (including suspended or insoluble impurities), the inorganic phosphate content, the liming condition and type, and the interactions between the juice components. These interactions are not well understood, particularly those between calcium, phosphate, and sucrose in sugar cane juice. Studies have been conducted on calcium oxide (CaO)/phosphate/sucrose systems in both synthetic and factory juices to provide further information on the defecation process (i.e., simple liming to effect impurity removal) and to identify an effective clarification process that would result in reduced scaling of sugar factory evaporators, pans, and centrifugals. Results have shown that a two-stage process involving the addition of lime saccharate to a set juice pH followed by the addition of sodium hydroxide to a final juice pH or a similar two-stage process where the order of addition of the alkalis is reversed prior to clarification reduces the impurity loading of the clarified juice compared to that of the clarified juice obtained by the conventional defecation process. The treatment process showed reductions in CaO (27% to 50%) and MgO (up to 20%) in clarified juices with no apparent loss in juice clarity or increase in residence time of the mud particles compared to those in the conventional process. There was also a reduction in the SiO2 content. However, the disadvantage of this process is the significant increase in the Na2O content.

Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long–Evans rats by the α-2 adrenoreceptor antagonist yohimbine

Rationale Developing models to efficiently explore the mechanisms by which stress can mediate reinstatement of drug-seeking behavior is crucial to the development of new pharmacotherapies for alcohol use disorders. Objectives We examined the effects of multiple reinstatement sessions using the pharmacological stressor, yohimbine, in ethanol- and sucrose-seeking rats in order to develop a more efficient model of stress-induced reinstatement. Methods Long–Evans rats were trained to self-administer 10% ethanol with a sucrose-fading procedure, 20% ethanol without a sucrose-fading procedure, or 5% sucrose in 30-min operant self-administration sessions, followed by extinction training. After reaching extinction criteria, the animals were tested once per week with yohimbine vehicle and yohimbine (2 mg/kg), respectively, 30 min prior to the reinstatement sessions or blood collection. Levels of reinstatement and plasma corticosterone (CORT) were determined each week for four consecutive weeks. Results Yohimbine induced reinstatement of ethanol- and sucrose-seeking in each of the 4 weeks. Interestingly, the magnitude of the reinstatement decreased for the 10% ethanol group after the first reinstatement session but remained stable for the 20% ethanol group trained without sucrose. Plasma CORT levels in response to injection of both vehicle and yohimbine were significantly higher in the ethanol-trained animals compared to sucrose controls. Conclusions The stable reinstatement in the 20% ethanol group supports the use of this training procedure in studies using within-subject designs with multiple yohimbine reinstatement test sessions. Additionally, these results indicate that the hormonal response to stressors can be altered following extinction from self-administration of relatively modest amounts of ethanol.

Degradation of hydroxycinnamic acid mixtures in aqueous sucrose solutions by the Fenton process

The degradation efficiencies and behaviors of caffeic acid (CaA), p-coumaric acid (pCoA) and ferulic acid (FeA) in aqueous sucrose solutions containing the mixture of these hydroxycinnamic acids (HCAs) mixtures were studied by the Fenton oxidation process. Central composite design and multi-response surface methodology were used to evaluate and optimize the interactive effects of process parameters. Four quadratic polynomial models were developed for the degradation of each individual acid in the mixture and the total HCAs degraded. Sucrose was the most influential parameter that significantly affected the total amount of HCA degraded. Under the conditions studied there was < 0.01% loss of sucrose in all reactions. The optimal values of the process parameters for a 200 mg/L HCA mixture in water (pH 4.73, 25.15 °C) and sucrose solution (13 mass%, pH 5.39, 35.98 °C) were 77% and 57% respectively. Regression analysis showed goodness of fit between the experimental results and the predicted values. The degradation behavior of CaA differed from those of pCoA and FeA, where further CaA degradation is observed at increasing sucrose and decreasing solution pH. The differences (established using UV/Vis and ATR-FTIR spectroscopy) were because, unlike the other acids, CaA formed a complex with Fe(III) or with Fe(III) hydrogen-bonded to sucrose, and coprecipitated with lepidocrocite, an iron oxyhydroxide.

Direct photocatalytic conversion of aldehydes to esters using supported gold nanoparticles under visible light irradiation at room temperature

Visible light can drive esteri fi cation from aldehydes and alcohols using supported gold nanoparticles (Au/Al 2 O 3 ) as photo- catalysts at ambient temperatures. The gold nanoparticles (AuNPs) absorb visible light due to the localized surface plasmon resonance (LSPR) e ff ect, and the conduction electrons of the AuNPs gain the energy of the incident light. The energetic electrons, which concentrate at the NP surface, facilitate the activation of a range of aldehyde and alcohol substrates. The photocatalytic e ffi ciencies strongly depend on the Au loading, particle sizes of the AuNPs, irradiance, and wavelength of the light irradiation. Finally, a plausible reaction mechanism was proposed, and the Au/Al 2 O 3 catalysts can be reused several times without signi fi cantly losing activity. The knowledge acquired in this study may inspire further studies in new e ffi cient recyclable photocatalysts and a wide range of organic synthesis driven by sunlight.

Catalytic transformation of aliphatic alcohols to corresponding esters in O2 under neutral conditions using visible-light irradiation

Selective oxidation of aliphatic alcohols under mild and base-free conditions is a challenging process for organic synthesis. Herein, we report a one-pot process for the direct oxidative esterification of aliphatic alcohols that is significantly enhanced by visible-light irradiation at ambient temperatures. The new methodology uses heterogenerous photocatalysts of gold–palladium alloy nanoparticles on a phosphate-modified hydrotalcite support and molecular oxygen as a benign oxidant. The alloy photocatalysts can absorb incident light, and the light-excited metal electrons on the surface of metal nanoparticles can activate the adsorbed reactant molecules. Tuning the light intensity and wavelength of the irradiation can remarkably change the reaction activity. Shorter wavelength light (<550 nm) drives the reaction more efficiently than light of longer wavelength (e.g., 620 nm), especially at low temperatures. The phosphate-exchanged hydrotalcite support provides sufficient basicity (and buffer) for the catalytic reactions; thus, the addition of base is not required. The photocatalysts are efficient and readily recyclable. The findings reveal the first example of using “green” oxidants and light energy to drive direct oxidative esterification of aliphatic alcohols under base-free, mild conditions.

Prolonged consumption of sucrose in a binge-like manner, alters the morphology of medium spiny neurons in the nucleus accumbens shell

The modern diet has become highly sweetened, resulting in unprecedented levels of sugar consumption, particularly among adolescents. While chronic long-term sugar intake is known to contribute to the development of metabolic disorders including obesity and type II diabetes, little is known regarding the direct consequences of long-term, binge-like sugar consumption on the brain. Because sugar can cause the release of dopamine in the nucleus accumbens (NAc) similarly to drugs of abuse, we investigated changes in the morphology of neurons in this brain region following short- (4 weeks) and long-term (12 weeks) binge-like sucrose consumption using an intermittent two-bottle choice paradigm. We used Golgi-Cox staining to impregnate medium spiny neurons (MSNs) from the NAc core and shell of short- and long-term sucrose consuming rats and compared these to age-matched water controls. We show that prolonged binge-like sucrose consumption significantly decreased the total dendritic length of NAc shell MSNs compared to age-matched control rats. We also found that the restructuring of these neurons resulted primarily from reduced distal dendritic complexity. Conversely, we observed increased spine densities at the distal branch orders of NAc shell MSNs from long-term sucrose consuming rats. Combined, these results highlight the neuronal effects of prolonged binge-like intake of sucrose on NAc shell MSN morphology.

Cryoreservation of alginate-fibrin beads involving bone marrow derived mesenchymal stromal cells by vitrification

Application of cell-–biomaterial systems in regenerative medicine can be facilitated by their successful low temperature preservation. Vitrification, which avoids ice crystal formation by amorphous solidification, is an emerging approach to cryopreservation. Developing vitrification strategy, effective cryopreservation of alginate–fibrin beads with porcine mesenchymal stromal cells has been achieved in this study. The cell–biomaterial constructs were pre-cultured for 20 days before cryopreservation, allowing for cell proliferation and construct stabilization. Ethylene glycol (EG) was employed as the basic cryoprotectant for two equilibration solutions. Successful cryopreservation of the constructs was achieved using vitrification solution composed of penetrating (EG MW 62 Da) and non-penetrating (sucrose MW 342 Da) cryoprotectants. Stepwise procedure of introduction to and removal of cryoprotectants was brief; direct plunging into liquid nitrogen was applied. Cell viability, evaluated by combining live/death staining and confocal laser microscopy, was similar for both control and vitrified cells in the beads. No detectable damage of microstructure of cryopreserved beads was found as shown by scanning electron microscopy. Both osteogenically induced control and vitrified cells in the constructs were equally capable of mineral production and deposition. There was no statistically significant difference in metabolic activity and proliferation between both groups during the entire culture period. Our study leads to the conclusion that the developed cryopreservation protocol allowed to maintain the integrity of the beads while preserving the ability of the pig bone marrow derived mesenchymal stromal cells to proliferate and subsequently differentiate; demonstrating that vitrification is a promising approach for cryopreser-vation of “ready-to-use” cell–biomaterial constructs.