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Dysregulated appetite is common in autism spectrum disorder (ASD) and it includes excessive interest in tasty foods. Overconsumption of palatable fluids has been found in the valproic acid-induced ASD rat. Though ASD has a strong genetic component, the link between ASD-related genes and appetite for palatable foods remains elusive. We focused on the CNTNAP2 gene whose deletion in mice recapitulates human ASD symptoms. We investigated whether Cntnap2-/- male mice consume greater amounts of palatable 10% sucrose, 0.1% saccharin, and 4.1% intralipid solutions offered in episodic meals either in a no-choice paradigm or a two-bottle choice test. We examined how sucrose intake affects c-Fos immunoreactivity in feeding-related brain areas. Finally, we determined doses at which intraperitoneal oxytocin decreases sucrose intake in mutants. In the single-bottle tests, Cntnap2-/- mice drank more sucrose, saccharin, and intralipid compared to WTs. Given a choice between two tastants, Cntnap2-/- mice had a higher preference for sucrose than intralipid. While the standard 1 mg/kg oxytocin dose reduced sucrose intake in WTs, a low oxytocin dose (0.1 mg/kg) decreased sucrose intake in Cntnap2-/- mice. Sucrose intake induced a more robust c-Fos response in wild-type (WT) than Cntnap2-/- mice in the reward and hypothalamic sites and it increased the percentage of Fos-immunoreactivity oxytocin neurons in WTs, but not in mutants. We conclude that Cntnap2-/- mice overconsume palatable solutions, especially sucrose, beyond levels seen in WTs. This excessive consumption is associated with blunted c-Fos immunoreactivity in feeding-related brain sites, and it can be reversed by low-dose oxytocin., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Alcohol use disorder (AUD) is a highly prevalent public health problem. The ghrelin system has been identified as a potential target for therapeutic intervention for AUD. Previous work showed that systemic administration of the growth hormone secretagogue receptor (GHSR) antagonist DLys reduced alcohol intake and preference in male mice. Yet, it is unclear whether central or peripheral GHSRs mediated these effects. We hypothesized that alcohol consumption is driven by central GHSRs and addressed this hypothesis by testing the effects of central administration of DLys. Male C57BL/6J mice consumed alcohol in a two-bottle choice procedure (10% ethanol versus water). DLys (2 nmol) was administered intracerebroventricularly for 7 days to examine alcohol intake and preference. DLys decreased alcohol intake and preference but had no effect on food intake. The effects on alcohol intake and preference persisted after several administrations, indicating lack of tolerance to DLys' effects. These results suggest that central administration of DLys is sufficient to reduce alcohol drinking and that DLys remains effective after several administrations when given intracerebroventricularly. Moreover, this work suggests that the effects of intracerebroventricularly administered DLys are specific to alcohol and do not generalize to other calorie-driven behaviors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Royalties - Tyndale House Publishers (NAA). Speakers Bureau Consultation Fees - American Program Bureau (NAA)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest All authors certify no conflict of interest. This research has been funded by the Research Foundation - Flanders (FWO) [grant number G0D2420N, 2020]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Although the brain can discriminate between various sweet substances, the underlying neural mechanisms of this complex behavior remain elusive. This study examines the role of the anterior paraventricular nucleus of the thalamus (aPVT) in governing sweet preference in mice. We fed the mice six different diets with equal sweetness for six weeks: control diet (CD), high sucrose diet (HSD), high stevioside diet (HSSD), high xylitol diet (HXD), high glycyrrhizin diet (HGD), and high mogroside diet (HMD). The mice exhibited a marked preference specifically for the HSD and HSSD. Following consumption of these diets, c-Fos expression levels in the aPVT were significantly higher in these two groups compared to the others. Utilizing fiber photometry calcium imaging, we observed rapid activation of aPVT neurons in response to sucrose and stevioside intake, but not to xylitol or water. Our findings suggest that aPVT activity aligns with sweet preference in mice, and notably, stevioside is the sole plant-based sweetener that elicits an aPVT response comparable to that of sucrose., Competing Interests: Disclosure statement The authors declare no competing financial interests., (Copyright © 2024. Published by Elsevier B.V.)

The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity. Therefore, this study examined the effect of TCDD on depression-like behaviors. Female mice were fed standard chow or a high-fat diet (HFD) for 11 weeks, and their weight was recorded. Subsequently, they were tested for baseline sucrose preference and splash test grooming. Then, TCDD (0.1 µg/kg/day) or vehicle was administered orally for 28 days, and mice were examined for their sucrose preference and performances in the splash test, forced swim test (FST), and Morris water maze (MWM) task. TCDD significantly decreased sucrose preference, increased FST immobility time, and decreased groom time in chow-fed mice. HFD itself significantly reduced sucrose preference. However, TCDD significantly increased FST immobility time and decreased groom time in HFD-fed mice. A small decrease in bodyweight was observed only at the fourth week of daily TCDD administration in chow-fed mice, and no significant effects of TCDD on bodyweights were observed in HFD-fed mice. TCDD did not have a significant effect on spatial learning in the MWM. Thus, this study demonstrated that TCDD induces a depression-like state, and the effects were not due to gross lethal toxicity. This study further suggests that more studies should examine a possible role for AhR and AhR-active environmental pollutants in precipitating or worsening MDD., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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/m 2 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., Competing Interests: HO and KM were employed by Tsumura & Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Maejima, Yokota, Yamachi, Misaka, Ono, Oizumi, Mizuno, Hidema, Nishimori, Aoyama, de Wet and Shimomura.)

Objectives: Inbred mouse strains differ in the pharmacology mediating sugar and fat intake and conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice are differentially sensitive to dopamine (DA) D1, opioid and muscarinic receptor antagonism of sucrose, saccharin or fat intake, and to DA, opioid, muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonism of acquisition of sucrose-CFP. DA D1, opioid and NMDA receptor antagonists differentially alter fat (Intralipid)-CFP in BALB/c and SWR mice. The present study examined whether naltrexone, SCH23390 or MK-801 altered acquisition and expression of Intralipid-CFP in C57BL/6 mice. Methods: In acquisition, groups of male food-restricted C57BL/6 mice received vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 μg/kg) before 10 training sessions in which mice alternately consumed two novel-flavored 5% (CS+) and 0.5% (CS-) Intralipid solutions. Six two-bottle CS choice tests followed with both flavors mixed in 0.5% Intralipid without injections. In expression, C57BL/6 mice underwent the 10 training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 μg/kg). Results: Fat-CFP acquisition in C57BL/6 mice was significantly though marginally reduced following naltrexone, SCH23390 and MK-801. Fat-CFP expression was similarly reduced by naltrexone, SCH23390 and MK-801 in C57BL/6 mice. Discussion: C57BL/6 mice were more sensitive to DA D1, opioid and NMDA antagonists in the expression of fat-CFP relative to sugar-CFP, but were less sensitive to DA D1 and NMDA antagonists in the acquisition of fat-CFP relative to sugar-CFP.

Stress during pregnancy is not only detrimental to a woman's own physical and mental health, but can also cause changes in the intrauterine environment and even have an impact on later growth and development, this study was designed to understand the changes of gut microbiota in the maternal and offspring caused by prenatal chronic stress, and to explore the regulatory effect of LBP on gut microbiota, and then to improve the emotional damage caused by prenatal chronic stress in the offspring. A rat model of prenatal chronic stress was made and used LBP to intervene by gavage. Fresh feces of offspring were collected, the concentration of microbial metabolites were tested by ELISA. Illumina MiSeqPE300 sequencing technology was used to determine the sequence of 16S rRNA V3-V4 of microorganisms. On the PND 42, the emotional function of offspring were tested by open-field test (OFT), sucrose preference test (SPT) and tail of suspend test (TST). Results indicated that stress factors increased the plasma corticosterone level of rats during pregnancy and they appeared depressive behaviors. The body weight of offspring during prenatal chronic stress was lower than the control group, and the plasma corticosterone level was increased. Prenatal chronic stress had a significant impact on emotional performance of the offspring on OFT, SPT and TST. Alpha diversity of gut microbiota and microbiota composition in offspring of prenatal chronic stress was attenuated and some relationships existed between these parameters. LBP treatment reduced offspring's plasma corticosterone level and improved their body weight, changed the emotional function, increased the diversity of gut microbiota. Collectively, these findings disclose that prenatal chronic stress not only causes emotional injury on the offspring, but also changes the gut microbiota of the mother and offspring; LBP may regulate the intestinal flora of the mother, then reducing the influence of stress factors on the emotional injury of offspring., (Copyright © 2021. Published by Elsevier Masson SAS.)

In addition to the taste receptors corresponding to the six basic taste qualities-sweet, salty, sour, bitter, umami, and fatty-another type of taste receptor, calcium-sensing receptor (CaSR), is found in taste-bud cells. CaSR is called the ' kokumi ' receptor because its agonists increase sweet, salty and umami tastes to induce ' koku ', a Japanese word meaning the enhancement of flavor characters such as thickness, mouthfulness, and continuity. Koku is an important factor for enhancing food palatability. However, it is not well known whether other kokumi -receptors and substances exist. Here, we show that ornithine (L-ornithine but not D-ornithine) at low concentrations that do not elicit a taste of its own, enhances preferences to sweet, salty, umami, and fat taste solutions in mice. Increased preference to monosodium glutamate (MSG) was the most dominant effect. Antagonists of G-protein-coupled receptor family C group 6 subtype A (GPRC6A) abolished the additive effect of ornithine on MSG solutions. The additive effects of ornithine on taste stimuli are thought to occur in the oral cavity, and are not considered post-oral events because ornithine's effects were confirmed in a brief-exposure test. Moreover, the additive effects of ornithine and the action of the antagonist were verified in electrophysiological taste nerve responses. Immunohistochemical analysis implied that GPRC6A was expressed in subsets of type II and type III taste cells of mouse circumvallate papillae. These results are in good agreement with those reported for taste modulation involving CaSR and its agonists. The present study suggests that ornithine is a kokumi substance and GPRC6A is a newly identified kokumi receptor.

Although dopamine plays a prominent role in mediating cocaine's abuse-related effects, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2Rs) have been characterized, less is known about dopamine D1-like receptors (D1Rs). The present experiments examined the effects of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status influenced the behavioral effects of D1R-acting drugs. The high-efficacy D1R agonist SKF 81297, low-efficacy D1R agonist SKF 38393, and D1R antagonist SCH 23390 were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine-choice dose-effect curve was determined daily. To assess selectivity of behavioral effects on cocaine choice, effects of doses that did not disrupt responding (indicated by a ≥35% decrease in total reinforcers delivered) were analyzed. Neither SKF 81297 nor SCH 23390 affected cocaine choice in dominant or subordinate monkeys. However, the low-efficacy agonist SKF 38393 selectively decreased cocaine choice; this effect was larger and only reached statistical significance in subordinate monkeys. Increasing the time between D1-acting drug administration and the cocaine choice session did not affect these results. The results indicate that, like D2R-acting drugs, the behavioral effects of D1R-acting drugs on cocaine choice can vary according to intrinsic efficacy and social status. Moreover, they demonstrate that D1R-acting drugs affect behavior under a narrower range of conditions than D2R-acting drugs. SIGNIFICANCE STATEMENT: Cocaine use disorder represents an insidious public health concern with no Food and Drug Administration-approved medications. Although dopamine receptors have been strongly implicated in mediating the abuse-related effects of cocaine, the roles of dopamine receptor subtypes are incompletely understood. The present study in nonhuman primates found that cocaine choice was decreased only by a low-efficacy D1R agonist, and that this effect depended on the social status of the monkey., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Ethnopharmacological Relevance: Xiaoyaosan (XYS), a representative and classic prescription in traditional Chinese medicines (TCMs), has been used for thousands of years for treating depression. The anti-depression effect of XYS has been demonstrated both clinically and experimentally. However, it is still unclear that whether XYS could regulate the abnormalities of gut microbiota and metabolites of cecum induced by depression, and in which way. This study aimed to explore the underlying mechanism of the anti-depressant effects of XYS from the perspective of cecal microbiota and metabolites., Materials and Methods: Chronic unpredictable mild stress (CUMS)-induced depression-like rats were used as the depression animal model. Various classic behavioral tests were performed to assess the anti-depressant effects of XYS. Additionally, the composition, the richness, and the diversity of the cecum microbiota were assessed by 16S rRNA gene sequencing technology. Besides, the metabolic profiling of cecum samples was analyzed by 1 H-NMR metabolomics. Multivariate data analysis was then applied to screen the differential metabolites and to characterize the changes in cecum metabolites. Moreover, a correlation analysis between differential metabolites and crucial microbiota was conducted., Results: XYS significantly improved depressive behaviors and the abnormal diversity of cecum microbiota induced by CUMS. At the phylum level, XYS could significantly increase the abundance of Firmicutes while decrease the abundance of Actinobacteria in depressed rats. XYS significantly regulated the abundances of 9 out of 13 potential microbial biomarkers at the genus level. Cecal metabolomics showed that XYS could also regulate the abnormal levels of alanine, proline, lactate, and valine of depression rats., Conclusions: This study revealed, for the first time, from the perspectives of microbiota and cecum metabolites, the anti-depression mechanisms of XYS. This study is of significance for not only comprehensively understanding the anti-depression effects and mechanisms of XYS, but also for providing a research approach for revealing the underlying mechanisms of action of TCMs, i.e. to apply a combination of 16S rRNA gene sequencing and metabolomics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

ALTERTASTE is a prospective study to evaluate changes in taste/flavor perception and food preferences in patients treated with adjuvant or neoadjuvant chemotherapy for breast or colorectal cancer. The study adopts a longitudinal approach. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and their psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors. Furthermore, the trial aims to develop an easy and reliable procedure to test smell, taste and food behavior alterations to allow a routine measure with patients. Clinical trial registration: NCT04495387 (ClinicalTrials.gov).

Rationale: Past research suggests that people with opioid dependence show increased consumption of sweet food, but it is unclear if this is influenced by altered taste preference and/or taste perception., Objectives: We tested whether people prescribed opioid substitution therapy (OST) exhibited a shift in preference towards sweeter flavours, and altered perception of sweetness, and explored whether these measures of taste preference/perception were associated with measures of opioid use., Methods: Three groups of participants (people prescribed OST, n=36; people with past opioid dependence, but now abstinent from all opioids, n=18; and controls with no history of substance dependence other than nicotine, n=29) provided ratings of "sweetness", "liking", and "desire" of 4 solutions with varying concentrations of sucrose., Results: We did not find significant differences between groups in the effect of sucrose concentration on "sweetness", "liking", or "desire" ratings. However, among those prescribed OST, frequency of recent illicit opioid use was associated with reduced perception of "sweetness" of low sucrose concentrations. Higher methadone dose was associated with a shift towards liking sweeter concentrations. Among those with past opioid dependence, longer duration of abstinence from opioids was associated with a shift towards liking sweeter concentrations., Conclusions: Among people currently dependent on opioids, reduced sensitivity to low levels of sweetness and increased preference for sweeter flavours may be associated with increased dependence on opioids. Among those who have ceased opioid use, the association between preference for sweeter flavours and duration of abstinence is a novel finding that deserves further investigation.

Background: A low-protein diet can induce compensatory intake of excess energy. This must be better evaluated to anticipate the obesogenic risk that may result from the dietary recommendations for reducing animal protein consumption., Objectives: We aimed to further characterize the behavioral and physiological responses to a reduction in dietary protein and to identify the determinants of protein appetite., Methods: Thirty-two male Wistar rats [4 wk old, (mean ± SEM) 135 ± 32 g body weight] were fed a low-protein (LP; 6% energy value) or normal-protein (NP; 20%) diet for 8 wk. Food intake and body mass were measured during the entire intervention. During self-selection sessions after 4 wk of experimental diets, we evaluated rat food preference between LP, NP, or high-protein (HP; 55%) pellets. At the end of the experiment, we assessed their hedonic response [ultrasonic vocalizations (USVs)] and c-Fos neuronal activation in the olfactory tubercle and nucleus accumbens (NAcc) associated with an LP or HP meal., Results: Rats fed an LP diet had greater food intake (24%), body weight (5%), and visceral adiposity (30%) than NP rats. All LP rats and half of the NP rats showed a nearly exclusive preference for HP pellets during self-selection sessions, whereas the other half of the NP rats showed no preference. This suggests that the appetite for proteins is driven not only by a low protein status but also by individual traits in NP rats. LP or HP meal induced similar USV emission and similar neuronal activation in the NAcc in feed-deprived LP and NP rats, showing no specific response linked to protein appetite., Conclusions: Protein appetite in rats is driven by low protein status or individual preferences in rats receiving adequate protein amounts. This must be considered and further analyzed, in the context of current recommendations for protein intake reduction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Food neophobia is a behavior observed in rodents involving reduced consumption of a novel food or drink. In the absence of negative post-ingestive consequences, consumption increases with exposure (attenuation of neophobia), which is seen as an associative safe memory. Olfaction and gustation are sensory modalities essential for the development of a food preference. However, little is known about the neural mechanisms underlying neophobia to a food-related odor stimulus. In the present study, we examined the effect of pharmacological inactivation of the ventral hippocampus (vHPC) on neophobia to orally consumed solutions in rats using muscimol, a gamma aminobutyric acid type A receptor agonist. Two different types of solutions, almond odor (benzaldehyde) and sweet taste (saccharin), were prepared. In the results, microinjections of muscimol into the bilateral vHPC before the first odor and taste exposures did not alter the neophobic reactions of the rats to each stimulus. However, in the second odor, but not taste, exposure, the muscimol-injected rats showed higher consumption in comparison to that observed in the control rats, suggesting that the vHPC inactivation facilitates the attenuation of odor neophobia. On the other hand, intra-vHPC muscimol microinjections after the first odor and taste exposures did not facilitate consumption at the second exposures. These results indicate that neural activations within vHPC during orally consuming a novel odor, but not taste, solution play an inhibitory role in the subsequent attenuation of neophobia., (Copyright © 2020. Published by Elsevier B.V.)

Ethnopharmacology Relevance: The water extract of Panax ginseng (GT) and Polygala tenuifolia (YT), the main constituents of the commonly used kai-xin-san formula of traditional Chinese medicine, represents SY. It possesses strong neuroprotective effects. Using behavioural tests, we have previously established that the SY formulation exerts superior antidepressant activity than that of GT or YT., Aim: To elucidate the impact of SY treatment on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours and the prospective mechanism related to hippocampal neurogenesis and the BDNF signaling pathway., Methods: We exposed Sprague-Dawley rats (male; 180-200 g) to CUMS for 35 days. The rats in the experimental treatment groups were daily treated with either fluoxetine (10 mg kg -1 d -1 ) or SY (67.5, 135, or 270 mg kg -1 d -1 ) orally until the behavioural tests (tail suspension test [TST], novelty-suppressed feeding test [NSFT], sucrose preference test [SPT], and forced swim test [FST]) were completed. We assessed the modifications in the hippocampal neurogenesis and the BDNF signaling pathway post-treatment with CUMS and SY. Additionally, K252a, a tyrosine protein kinase inhibitor, was utilized to evaluate the antidepressant mechanisms of SY., Result: s: The results of SPT, NSFT, FST, and TST in CUMS-exposed rats confirmed the antidepressant actions of SY. Additionally, SY treatment induced the BDNF signaling pathway and reversed the hippocampal neurogenesis caused by CUMS. Moreover, we found that the TrkB antagonist K252a blocked SY effects on behavioural improvement, inhibited the incremental effects of SY on hippocampal neurogenesis, and eliminated the impact of SY on BDNF-TrkB signaling activation. Thus, the impact of SY treatment on BDNF signaling molecules (pAkt, pERK1/2, and pCREB) were significantly inhibited by K252a., Conclusions: This study showed that SY acted as an antidepressant in rats exhibiting CUMS-induced depressive-like behaviours, and was facilitated by promoting hippocampal neurogenesis and the BDNF signaling pathway activation. Thus, SY could act as a potential novel supplement or adjuvant to prevent or treat clinical depressive disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cannabinoids have an important role in regulating feeding behaviors via cannabinoid receptors in mammals. Cannabinoids also exhibit potential therapeutic functions in Drosophila melanogaster, or fruit fly that lacks cannabinoid receptors. However, it remains unclear whether cannabinoids affect food consumption and metabolism in a cannabinoid receptors-independent manner in flies. In this study, we systematically investigated pharmacological functions of various cannabinoids in modulating food preference and consumption in flies. We show that flies display preferences for consuming cannabinoids, independent of two important sensory regulators Poxn and Orco. Interestingly, phyto- and endo- cannabinoids exhibit an inhibitory effect on food intake. Unexpectedly, the non-selective CB1 receptor antagonist AM251 attenuates the suppression of food intake by endocannabinoids. Moreover, the endocannabinoid anandamide (AEA) and its metabolite inhibit food intake and promote resistance to starvation, possibly through reduced lipid metabolism. Thus, this study has provided insights into a pharmacological role of cannabinoids in feeding behaviors using an adult Drosophila model.

Phosphodiesterase 2 is one of the phosphodiesterase (PDEs) family members that regulate cyclic nucleotide (namely cAMP and cGMP) concentrations. The present study determined whether PDE2 inhibition could rescue post-traumatic stress disorder (PTSD)-like symptoms. Mice were subjected to single prolonged stress (SPS) and treated with selective PDE2 inhibitor Bay 60-7550 (0.3, 1, or 3 mg/kg, i.p.). The behavioral tests such as forced swimming, sucrose preference test, open field, elevated plus maze, and contextual fear paradigm were conducted to determine the effects of Bay 60-7550 on SPS-induced depression- and anxiety-like behavior and fear memory deficits. The results suggested that Bay 60-7550 reversed SPS-induced depression- and anxiety-like behavior and fear memory deficits. Moreover, Bay 60-7550 prevented SPS-induced changes in the adrenal gland index, synaptic proteins synaptophysin and PSD95 expression, PKA, PKG, pCREB, and BDNF levels in the hippocampus and amygdala. These effects were completely prevented by PKG inhibitor KT5823. While PKA inhibitor H89 also prevented Bay 60-7550-induced pCREB and BDNF expression, but only partially prevented the effects on PSD95 expression in the hippocampus. These findings suggest that Bay 60-7550 protects mice against PTSD-like stress induced traumatic injury by activation of cGMP- or cAMP-related neuroprotective molecules, such as synaptic proteins, pCREB and BDNF., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Preclinical studies into drug vs. nondrug choice have emerged to better model and investigate the neurobehavioral mechanisms underlying drug preference. Current literature has suggested that drugs of abuse have inherently low value, thus promoting food preference. Herein, we examined remifentanil vs. food choice to test both the relative value hypothesis and the 'direct effects' (pharmacological effects of drugs on alternative reinforcers) hypothesis of opioid preference., Methods: Adult male rats were trained under two choice procedures (controlled vs. uncontrolled reinforcer frequency) for remifentanil vs. food choice. Furthermore, a series of procedural manipulations known to affect drug reinforcement were tested under both choice procedures. Using remifentanil self-administration data, pharmacokinetic profiles were calculated and analyzed to determine if opioid intake was related to opioid preference., Results: Both choice procedures produced dose-dependent preference. Moreover, procedural manipulations produced comparable changes in remifentanil preference under both choice procedures. In addition, calculated pharmacokinetic data revealed that preference was dissociable from intake under the controlled reinforcer frequency choice procedure., Conclusions: When compared to the 'direct effects' hypothesis, remifentanil preference was better predicted by the relative value hypothesis, formalized in generalized matching. Use of a controlled reinforcer frequency schedule successfully removed the drug preference-intake confound found in most drug-choice procedures. Importantly, drug preference under the controlled reinforcer frequency schedule remained sensitive to procedural manipulations known to affect drug reinforcement. Thus, given that differential drug intake itself affects neurobiological measurements, future use of controlled reinforcer frequency schedules may help to better isolate the neurobehavioral mechanisms that mediate opioid preference., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Main Conclusion: Cotton genotypes displayed similar volatile organic compound (VOC) profiles, but major differences in terpenoid aldehyde (TA) content. The differences in VOC production were minor among genotypes, but these differences are crucial for boll weevil attraction. Weevils did not display any preference in feeding behaviour towards cotton genotypes, suggesting physiological adaptation to cope with cotton chemical defence mechanisms. Plant cultivar selection for resistance to herbivore pests is an effective, environmentally safe and inexpensive method to implement in integrated pest management programmes. In this study, we evaluated seven cotton genotypes with respect to the production of volatile organic compounds (VOCs) and non-volatile compounds [terpenoid aldehydes (TAs)], and the attraction and feeding preference of adult boll weevils. Chemical analyses of VOCs from BRS-293, BRS-Rubi, CNPA TB-15, CNPA TB-85, CNPA TB-90, Delta Opal, and Empire Glandless showed that there were few qualitative and quantitative differences across the range of genotypes. In contrast, major differences in TA content were observed, with CNPA TB-15 and CNPA TB-85 producing higher levels of TAs compared to the other genotypes. Our results showed that boll weevil attraction to cotton genotypes varied, suggesting that the ratios and quantities of emitted cotton VOCs are important for host location. However, boll weevil feeding behaviour was neither positively nor negatively influenced by the terpenoid content (non-volatile compounds) of cotton genotypes. The results in this study suggest that boll weevils have adapted physiologically to cope with cotton chemical defence mechanisms.

Mammalian taste buds are comprised of specialized neuroepithelial cells that act as sensors for molecules that provide nutrition (e.g., carbohydrates, amino acids, and salts) and those that are potentially harmful (e.g., certain plant compounds and strong acids). Type II and III taste bud cells (TBCs) detect molecules described by humans as "sweet," "bitter," "umami," and "sour." TBCs that detect metallic ions, described by humans as "salty," are undefined. Historically, type I glial-like TBCs have been thought to play a supportive role in the taste bud, but little research has been done to explore their role in taste transduction. Some evidence implies that type I cells may detect sodium (Na + ) via an amiloride-sensitive mechanism, suggesting they play a role in Na + taste transduction. We used an optogenetic approach to study type I TBCs by driving the expression of the light-sensitive channelrhodopsin-2 (ChR2) in type I GAD65 + TBCs of male and female mice. Optogenetic stimulation of GAD65 + TBCs increased chorda tympani nerve activity and activated gustatory neurons in the rostral nucleus tractus solitarius. "N neurons," whose NaCl responses were blocked by the amiloride analog benzamil, responded robustly to light stimulation of GAD65 + TBCs on the anterior tongue. Two-bottle preference tests were conducted under Na + -replete and Na + -deplete conditions to assess the behavioral impact of optogenetic stimulation of GAD65 + TBCs. Under Na + -deplete conditions GAD65-ChR2-EYFP mice displayed a robust preference for H 2 O illuminated with 470 nm light versus nonilluminated H 2 O, suggesting that type I glial-like TBCs are sufficient for driving a behavior that resembles Na + appetite. SIGNIFICANCE STATEMENT This is the first investigation on the role of type I GAD65 + taste bud cells (TBCs) in taste-mediated physiology and behavior via optogenetics. It details the first definitive evidence that selective optogenetic stimulation of glial-like GAD65 + TBCs evokes neural activity and modulates behavior. Optogenetic stimulation of GAD65 + TBCs on the anterior tongue had the strongest effect on gustatory neurons that responded best to NaCl stimulation through a benzamil-sensitive mechanism. Na + -depleted mice showed robust preferences to "light taste" (H 2 O illuminated with 470 nm light vs nonilluminated H 2 O), suggesting that the activation of GAD65 + cells may generate a salt-taste sensation in the brain. Together, our results shed new light on the role of GAD65 + TBCs in gustatory transduction and taste-mediated behavior., (Copyright © 2020 the authors.)

Ethnopharmacological Relevance: Danzhi Xiaoyao Powder (DZXY) is a classical prescription, that has been extensively used in traditional Chinese medicine (TMC) to treat depression for many years. However, the mechanism of DZXY is still unclear., Aim of the Study: The aim was to investigate the mechanism of the antidepressant effect of DZXY on a rat model of chronic unpredictable mild stress (CUMS)., Materials and Methods: Forty male SD (Sprague-Dawley) rats with similar open field test (OFT) results were randomLy divided into a control group (n = 10) and an experimental group (n = 30). A depression model was established in the experimental group using the CUMS method. After the CUMS model was established successfully, the rats were randomLy divided into a depression model group and a DZXY group. The DZXY group was fed DZXY, while the depression model group and control group were given an equal amount of 0.5% sodium carboxymethyl cellulose suspension. Intragastric administration was performed once daily for 14 consecutive days. Animal weight, the sugar preference test, the open field test and the forced swimming test were used to evaluate the modeling effect and the antidepressant effect of DZXY. After the experiment, the plasma of rats was collected and the changes in plasma metabolites were analyzed by UPLC/Q-TOF-MS. The UPLC/Q-TOF-MS spectra data were evaluated by pattern recognition analysis to determine the changes in endogenous metabolites in the rat plasma samples., Results: The results of the behavioral investigation showed that the rat model of depression was successfully replicated and that DZXY had an antidepressant effect. Using the UPLC-MS/MS metabolomics platform, partial least squares (PLS) and orthogonal partial least squares (OPLS), metabolic profile models (R2 and Q2 ≥ 0.5) of rat plasma were successfully constructed. The model could distinguish among the control group, the depression model group and the DZXY group. Finally, 38 differential metabolites were identified in the plasma. According to KEGG (http://www.kegg.jp) pathway analysis, amino acid metabolism, lipid metabolism, purine metabolism, the prolactin signaling pathway and bile secretion were enriched and represented the main metabolic pathways influenced in the plasma., Conclusions: This study successfully established a CUMS depression model. A total of 38 differential metabolites associated with depression were identified in the plasma of rats, 24 of which were modulated by DZXY. These results suggest that DZXY can improve excitability and play an antidepressant role by regulating phenylalanine metabolism, arachidonic acid metabolism, porphyrin metabolism, D-arginine and D-ornithine metabolism, steroid hormone biosynthesis, unsaturated fatty acid biosynthesis and steroid biosynthesis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

SophoraflavanoneG (SG), an important prenylated flavonoid isolated from Sophoraalopecuroides.L, is effective for many illnesses. The present study was designed to investigate whether the compound could reverse depressive-like symptoms and investigate its possible mechanisms. Chronic Unpredictable Mild Stress (CUMS) mice were treated with fluoxetine and SG. The immobility time in forced swimming test (FST) and tail suspension test (TST) were recorded. The levels of pro-inflammatory cytokines and neurotransmitters in the hippocampus were evaluated. Furthermore, the protein expressions of PI3K, AKT, mTOR, p70S6K, BDNF, and Trkb in hippocampus were detected. Rapamycin, the selective mTOR inhibitor, was used to estimate the potential mechanism. As a result, after 7 days of SG treatment, the immobility time in FST and TST was declined obviously. The levels of IL-6, IL-1β, and TNF-α in the hippocampus were significantly reduced, and the quantity of 5-HT and NE was raised considerably in SG-treated group compared with the CUMS-exposed group. Additionally, SG could up-regulate the expressions of PI3K, AKT, mTOR, 70S6K, BDNF, and Trkb. The blockade of mammalian target of rapamycin signaling blunted the antidepressant effect and reversed the up-regulation of BDNF expression caused by SG. These findings suggested that SG treatment alleviated depressive-like symptoms via mTOR-mediated BDNF/Trkb signaling., (© 2020 John Wiley & Sons, Ltd.)

The study of inbred mouse strains is a useful animal model to assess differences in ingestive behavior responses, including conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice display differential sensitivity to dopamine (DA) D1, opioid and muscarinic cholinergic receptor antagonism of sucrose or saccharin intake as well as to muscarinic cholinergic antagonism of acquisition (learning) of sucrose-CFP. Given that DA D1, opioid and N-methyl-D-aspartate (NMDA) receptor antagonists differentially alter sucrose-CFP in BALB/c and SWR inbred mice, the present study examined whether systemic administration of naltrexone, SCH23390 or MK-801 altered acquisition and expression of sucrose-CFP in C57BL/6 mice. In acquisition experiments, male food-restricted C57BL/6 mice were treated with vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 µg/kg) 30 min prior to each of ten daily sessions in which they alternately consumed a flavored (CS+, e.g. cherry) 16% sucrose solution and a differently-flavored (CS-, e.g. grape) 0.05% saccharin solution followed by six two-bottle CS choice tests mixed in 0.2% saccharin without injections. SCH23390 and MK-801, but not naltrexone eliminated sucrose-CFP acquisition in food-restricted C57BL/6 mice. In expression experiments, food-restricted C57BL/6 mice underwent the ten training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 µg/kg). SCH23390 more effectively reduced the magnitude of sucrose-CFP expression than naltrexone or MK-801 in food-restricted C57BL/6 mice. Thus, dopamine D1 and NMDA receptor signaling is essential for learning of sucrose-CFP in C57BL/6 mice.

Fundamental nutritional studies on bioactive molecules require minimizing exposure to confounding foreign elements, like solvents. Herein, aqueous formulations of lecithin nanovesicles are proposed to study three individual trans fatty acids relevant to human nutrition: elaidic acid, trans-vaccenic acid and trans-palmitoleic acid. This proof-of-concept study describes the encapsulation of fatty acids, in vivo bioavailability, and the use of nanovesicles in behavioral experiments. The oral bioavailability of the encapsulated molecules and the selective exposure of animals to each trans-fatty acid of interest were confirmed in healthy rats. Behavioral studies also evidenced that nanovesicles can be used to evaluate the palatability of the lipids and investigate food preferences in mice. Altogether this study shows that lecithin nanovesicles offer an elegant tool to efficiently deliver hydrophobic molecules to animal models. This approach paves the way for future studies deconvoluting the nutritional effects of trans-fatty acids., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Depressive disorders are both prevalent and debilitating, and a proportion of patients have treatment resistance to classic antidepressants. Recent evidence has implicated the intracellular WNT signaling pathway as having a key role in the pathogenesis of major depressive disorder. In the present study, we investigated the role of β-catenin and transcription factor-4 (TCF4) in the depression-like and anxiety-like behaviors exhibited by mice exposed to maternal separation, or chronic mild stress. Both rodent models of childhood and adulthood stress showed depression and anxiety-like behaviors. During the last three weeks of medication, we applied AMBMP (2-Amino-4-[3,4- (methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine) to the maternal separation and chronic stress model for the first time. The drug alleviated the depression-like index in saccharin preference test (SPT) and forced swim test (FST), and anxiety-like index in open field test (OFT) and elevated-plus maze (EPM), and reversed the disruption of β-catenin and TCF4 in stressed mice by upregulating the WNT pathway specifically. Therefore, the WNT pathway may be involved in the mediation of patient recovery and could be a target for novel antidepressants., (Copyright © 2020. Published by Elsevier B.V.)

It has been reported that liquiritin produced an antidepressant-like effect in rodents. However, little information is known regarding its antidepressant activity with the regulation of fibroblast growth factor 2 (FGF-2), a protein maintaining development and maturation of the nervous central system. Therefore, the aim of the present study was to investigate the underlying FGF-2 modulation involved in the antidepressant-like effects of liquiritin. In the present study, mice were orally administrated with liquiritin for 7 days prior to LPS injection. The depressive-like behaviors, levels of FGF-2, number of Iba1 positive cells, expression of proinflammatory cytokines and density of dendritic spines were evaluated. The results showed that liquiritin significantly ameliorated the depressive-like behaviors in mice response to LPS injection. Liquiritin reversed the reduction of FGF-2 levels in the hippocampus of LPS induced mice. In addition, the microglial activation caused by LPS was attenuated by liquiritin, in accordance with downregulation in mRNA levels of proinflammatory cytokines. Moreover, liquiritin also increased the density of dendritic spines in the hippocampus, which was suppressed by LPS. In conclusion, our findings demonstrated that liquiritin exerted the antidepressant-like effects in LPS-induced depression through FGF-2 enhancement by inhibiting neuroinflammation and maintaining synaptogenesis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzymeand highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Although fluctuations in energy metabolism are known to influence intake as well as nutrient selection, there are no definitive reports on how food preferences change with changes in habitat temperature. We investigated the effects of habitat temperature on appetite and food preference and elucidated the underlying mechanism by conducting a feeding experiment and a leptin administration test on mice reared at low temperatures. Our results showed that the increased food intake and HFD preference observed in the 10°C group were induced by decrease in plasma leptin concentration. Then, a leptin administration experiment was conducted to clarify the relationship between leptin and food preference with low-temperature acclimation. The control group reared in 10°C significantly preferred the HFD, but the leptin-administered group did not. These results show that the peripheral system appetite-regulating hormone leptin not only acts to suppress appetite but also might inhibit preference for lipids in low-temperature acclimation.

Sodium reduction is an important public health goal. Individual and population approaches are necessary for reducing the sodium content of processed foods and meals. The aim of the present study is to affirm the effect of monosodium L-glutamate (MSG), an umami substance, on the saltiness or palatability of low-salt solutions and to explore the preferred salt concentration in soup. Five hundred and eighty-four healthy participants from nineteen regions in Japan tasted 0.3, 0.6, and 0.9% NaCl solutions with or without 0.3% MSG. Evaluations of saltiness and palatability for each solution were conducted using a visual analog scale in a double-blinded randomized manner. Saltiness gradually increased depending on the concentration of NaCl. The saltiness of the 0.3% NaCl solution with MSG was rated significantly higher than that without MSG. The palatability ratings were higher for the solutions with MSG than for those without MSG for all NaCl concentrations. In particular, the palatability rating of the 0.3% NaCl solution with MSG was twice as high as that without MSG and was significantly higher than that of the other five test solutions. Furthermore, these results were observed to be approximately the same, irrespective of sex, age, region, etc. Salt reduction is believed to result in a loss of palatability. However, our results suggest that umami can compensate for the loss of palatability caused by salt reduction and that the addition of an appropriate amount of an umami substance can facilitate salt reduction from 0.9 to 0.3% without sacrificing palatability.

The incidence of metabolic diseases, such as type 2 diabetes, has increased steadily worldwide. Diet, beverages, and food texture can all markedly influence these metabolic disorders. However, the combined effects of food texture and beverages on energy metabolism remains unclear. In the present study, we examined the effect of food texture on energy metabolism in mice administered high-fructose corn syrup (HFCS). Mice were fed a soft or hard diet along with 4.2% HFCS or tap water. Body weight and total caloric intake were not affected by food texture irrespective of HFCS consumption. However, caloric intake from HFCS (i.e., drinking volume) and diet were higher and lower, respectively, in the hard food group than in the soft food group. The hard food group's preference for HFCS was absent in case of mice treated with the μ-opioid receptor antagonist naltrexone. Despite increased HFCS consumption, blood glucose levels were lower in the hard-diet group than in the soft-diet group. In HFCS-fed mice, insulin levels after glucose stimulation and insulin content in the pancreas were higher in the hard food group than the soft food group, whereas insulin tolerance did not differ between the groups. These food texture-induced differences in glucose tolerance were not observed in mice fed tap water. Thus, food texture appears to affect glucose tolerance by influencing pancreatic β-cell function in HFCS-fed mice. These data shed light on the combined effects of eating habits and food texture on human health., Competing Interests: The authors declare no competing financial interests.

Chronic stress is associated with male sexual problems including ejaculatory dysfunctions. The aim of this study was to determine whether resveratrol (RS) or quercetin (QE) has protective effects on vas deferens (VD) contractility in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were separated into six groups: control, control + RS and control + QE, stress, stress + RS, and stress + QE. Stress groups were subjected to UCMS procedure for 5 weeks. Animals in treatment groups were injected intraperitoneally with RS (20 mg/kg) or QE (30 mg/kg) for 5 weeks during UCMS period. UCMS caused depressive-like behaviors and enhanced systemic levels of corticosterone. The nerve-evoked contractile responses of VD significantly impaired and, noradrenaline- and ATP-induced contractile responses of VD significantly increased in stressed rats. UCMS exposure also markedly enhanced oxidative stress and inflammation in VD tissues. Treatment with RS or QE significantly ameliorated all the aforementioned parameters. The current study demonstrated that RS or QE protected against chronic stress-induced VD dysfunction by their antioxidant and anti-inflammatory effects on VD, suggesting that oxidative stress and inflammation may be synergistic parts in the development of VD dysfunction associated with chronic stress-induced depression.

The mechanisms underlying the pathophysiology of depression remain elusive, and the development of novel, effective antidepressant drugs remains necessary. A dihydroquinoline analog of agomelatine (AGO), N-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)acetamide hydrochloride (NMDEA), was synthesized by employing a scaffold-hopping strategy in our previous study. In this study, NMDEA was demonstrated to attenuate depression-related behaviors in mice models of chronic unpredictable mild stress (CUMS), using a sucrose preference test, a forced swimming test, and a tail suspension test. However, the antidepressant mechanism of NMDEA appears to differ from that for AGO. Based on the analysis of fecal microbiota from mice, stress can alter the richness of the gut bacterial community, increasing the expression of immune-modulating microbiota, such as Clostridia, and decreasing the expression of probiotic bacteria, such as Lactobacillus. Treatment with NMDEA was able to recover the richness and to regulate the dysbiosis among bacterial species. Several studies have demonstrated that the gut microbiota population can induce inflammatory processes. To explore the effects of NMDEA on the suppression of pro-inflammatory factors, we used Western blotting to analyze the levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), p65, and inducible nitric oxide synthase (iNOS). NMDEA suppressed the activation of IL-1β and IL-6, in the hippocampus, and IL-1β, IL-6, p65, and iNOS, in lipopolysaccharide (LPS)-induced BV-2 cells. These results suggested that NMDEA may affect the microbiota-inflammasome-brain axis, regulating relevant neuro-inflammatory markers and gut microbiota. Our data also suggested that using small molecules to modify the gut microbiota population or alter inflammasome signaling may represent a new therapeutic opportunity for the mitigation of depression., Competing Interests: Declaration of competing interest The authors declare no other conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes and obesity because of their beneficial effects on body weight, blood glucose, insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on body weight, food intake, glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with KBP-088 induced significant weight loss, reduction in adiposity, improvement in glucose control, and altered food preference toward food that is less calorie-dense. KBP-088 dosed every other day (3 nmol/kg) was superior to KBP-088 once daily (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with KBP-088 could be feasible. SIGNIFICANCE STATEMENT: Here, we show that food preference can be altered chronically toward choices that are less calorie-dense by pharmacological treatment. Further, pharmacological dosing regimens affect the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference compared with daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of obesity., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements., Methods: Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7-36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference., Results: Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed., Conclusion: Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Suppression of oral sweet sensation (OSS) acutely reduces intake of sweet-tasting food due to lower liking. However, little is known about other physiological responses during both the prandial and postprandial phase. Here, we explored the effects of Gymnema sylvestre (GS)-based suppression of OSS of several types of sweet-tasting food (muffin, sweet yogurt, banana) on gastric emptying, blood glucose (BG), plasma insulin (PI), appetite indices (hunger, fullness and prospective consumption), satisfaction and desire for tastes. Fifteen healthy subjects (22 ± 3 years, 9 women) took part in the study. Subjects rinsed their mouth with either GS solution or distilled water before eating the sweet-tasting food. Subjects felt decreased sweet taste intensity and reduced taste liking associated with GS rinsing after consuming each food, compared with rinsing with distilled water ( p < 0.05). Gastric emptying, BG, PI and appetite indices during and after the prandial phase did not significantly change with GS rinsing compared to rinsing with distilled water ( p > 0.05). Higher desire for sweet taste as well as lower satisfaction ( p < 0.05) in the postprandial phase were observed with GS rinsing. These results suggest that the suppression of OSS does not affect gastric emptying, glycemic response and appetite during and after consumption of sweet-tasting food.

The apolipoprotein E (APOE) ε4 allele hastens cognitive decline, but other non-cognitive behaviours, as well as underpinning interactions with the cholinergic system, have not been systematically addressed. Both C57BL/6 and humanised apoE4 female mice were transiently exposed to subclinical doses (0 or 1 mg/kg body weight) of the cholinesterase inhibitor chlorpyrifos (CPF), a widely-used pesticide, from postnatal days 10-15. At 5 months of age, we assessed the impact of APOE4 genotype, postnatal CPF exposure and APOE4 x CPF interactions on anxiety (open field and light-dark tests), stereotypes (digging test) and neophobia (sucrose preference test), as well as on high-fat diet (HFD)-seeking and consumption (scheduled-feeding paradigm). We found that control APOE4 female carriers displayed a robust anxiety-like phenotype, which was accompanied by exaggerated stereotypes and a subtle neophobic response to rewarding foods. In parallel, we observed an amplified "wanting" response for HFD in these mice, which did not entail enhanced "liking". Notably, postnatal CPF ameliorated the anxiety-like and the heightened HFD-seeking responses in adult apoE4 female mice, while caused them to gain weight steadily compared to control peers. In turn, an early-life transient exposure to CPF fostered the over-consumption of HFD during adulthood without affecting how much this reward was "wanted" or the total caloric intake. These data reveal a role for CPF towards fostering "unhealthy" dietary choices. We conclude that the APOE4 genotype modulates non-cognitive behaviours and we provide support for an APOE4-dependent cholinergic dysfunction., Competing Interests: Declaration of Competing Interest The authors declare they have no actual or potential competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background . Gymnemic acids, from the plant Gymnema sylvestre (GS), selectively suppress taste responses to sweet compounds without affecting the perception of other taste elements. The aim of this study was to investigate the effect of consuming a GS-containing mint on the desire to consume high-sugar sweet foods directly thereafter. Methods . This study utilized a single-blind, crossover design comparing the consumption of a mint (dissolving tablet) containing 4 mg of gymnemic acids with an isocaloric placebo in 56 healthy young men and women. Participants were given samples of their favourite chocolate (varied between 14-18 g; energy varied between 292-370 kJ) and were directed to rate on their hunger on 100-mm visual analogue scales 30 s prior to consuming high-sugar sweet food (chocolate). They then consumed the GS mint or placebo mint and rated their perceived pleasantness and desire for more chocolate on separate visual analogue scales immediately following consumption of the high-sugar sweet food before being offered up to five additional servings (and asked to rate hunger, pleasantness and desire to eat more chocolate between each ingestion period). Results . The number of chocolate bars eaten decreased by 0.48 bars (21.3%) within a 15-min period of consumption of the GS mint ( p = 0.006). Desire to eat more of the high-sugar sweet food ( p = 0.011) and pleasantness of the high-sugar sweet food ( p < 0.001) was reduced after GS mint intake. Those who reported having a 'sweet tooth' had a greater reduction in the pleasantness of chocolate ( p = 0.037) and desire to eat more ( p = 0.004) after consuming the GS mint for the first serving of a high-sugar sweet food following the mint. Conclusion . Consuming gymnema-containing mints compared to placebo significantly reduced the quantity of chocolate eaten mainly due to a decrease in the desire and pleasantness of consuming it.

Marijuana and other cannabinoid compounds are widely used by cocaine users. Preclinical animal studies suggest that these compounds can increase the reinforcing effects of cocaine under some schedules of cocaine self-administration and reinstatement, but not in all cases. To date, no studies have used a food-cocaine concurrent choice procedure, which allows for assessment of drug effects on response allocation, not just changes in cocaine self-administration. The goal of the present study was to examine the effects of compounds differing in their efficacy at the cannabinoid receptor (CBR) on cocaine self-administration using a food-drug choice procedure in monkeys. Four adult male rhesus monkeys were trained to self-administer cocaine in the context of an alternative food (1.0-g banana-flavored pellets) reinforcer, such that complete cocaine dose-response curves (0, 0.003-0.1 mg/kg per injection) were determined each session. Monkeys were tested acutely with the CBR full agonist CP 55,940 (0.001-0.01 mg/kg); the CBR partial agonist Δ 9 -tetrahydrocannabinol (THC; 0.03-0.3 mg/kg), which is also the primary active ingredient in marijuana and the CBR antagonist rimonabant (0.3-3.0 mg/kg). Cocaine choice increased in a dose-dependent manner. Acute treatment with CP 55,940 decreased cocaine choice, whereas THC and rimonabant enhanced the reinforcing effects of cocaine. Chronic (7-day) treatment with CP 55,940 resulted in tolerance to the decreases in cocaine choice. These findings with Δ 9 -THC provide support for a potential mechanism for co-abuse of marijuana and cocaine. Additional research with chronic treatment with full CBR agonists on attenuating the reinforcing strength of cocaine is warranted. SIGNIFICANCE STATEMENT: Co-abuse of tetrahydrocannabinol and cocaine is a significant public health problem. The use of animal models allows for the determination of how cannabinoid receptor stimulation or blockade influences the reinforcing strength of cocaine., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Women who have bilateral oophorectomies prior to the age of natural menopause are at increased risk of developing mild cognitive decline, dementia, anxiety, and depressive type disorders. Clinical and animal studies indicate angiotensin type 1 receptor (AT 1 R) blockers (ARBs) have blood pressure (BP)-independent neuroprotective effects. To investigate the potential use of ARBs in normotensive women at increased risk of developing neurocognitive problems, we studied a rat model of bilateral oophorectomy. Long Evans rats were sham-operated (Sham) or ovariectomized (Ovx) at 3 months of age and immediately treated continuously with vehicle (Veh) or the ARB losartan (Los) for the duration of the experiment. In contrast to many hypertensive rat models, ovariectomy did not increase mean arterial pressure (MAP) in these normotensive rats. Ovariectomized rats spent less time in the open arms of the elevated plus maze (EPM) [(% total time): Veh, 34.1 ± 5.1 vs. Ovx, 18.7 ± 4.4; p < 0.05] and in the center of the open field (OF) [(s): Veh, 11.1 ± 1.7 vs. Ovx, 6.64 ± 1.1; p < 0.05]. They also had worse performance in the novel object recognition (NOR) test as evidenced by a reduction in the recognition index [Veh, 0.62 ± 0.04 vs. Ovx, 0.45 ± 0.03; p < 0.05]. These adverse effects of ovariectomy were prevented by Los. Losartan also reduced plasma corticosterone in Ovx rats compared to Veh treatment [(ng/mL): Ovx-Veh, 238 ± 20 vs. Ovx-Los, 119 ± 42; p < 0.05]. Ovariectomy increased AT 1 R mRNA expression in the CA3 region of the hippocampus (Hc) [(copies x 10 6 /µg RNA): Sham-Veh, 7.15 ± 0.87 vs. Ovx-Veh, 9.86 ± 1.7; p < 0.05]. These findings suggest the neuroprotective effects of this ARB in normotensive Ovx rats involve reduction of plasma corticosterone and blockade of increased AT 1 R activity in the hippocampus. These data suggest ARBs have therapeutic potential for normotensive women at increased risk of developing cognitive and behavioral dysfunction due to bilateral oophorectomy prior to the natural age of menopause.

Low-density lipoprotein receptor-related protein 1 (LRP1) and tau play an important role in developing Alzheimer's disease. This study aimed to explore the involvement of LRP1 in microtubule dynamic and depressive-like behavior in a depressive-like rat model. It also investigated whether fluoxetine blocked the change induced by chronic unpredictable mild stress (CUMS). Sprague-Dawley rats (200-250 g) were exposed to CUMS and fluoxetine for 4 weeks respectively. The body weight was determined, and behavior tests, including sucrose preference test, forced swimming test and open field test were performed. Western blot analysis was conducted to determine the protein levels of LRP1, tubulin, Acet-tub, Tyr-tub and PI3K/Akt/GSK-3β. Real-time quantitative polymerase chain reaction was used for mRNA expression levels of LRP1. Immunohistochemical staining was applied for LRP1 and immunofluorescence staining for the co-location of p-tau (404,262) and Acet-tub. The CUMS group presented a decreased body weight and depressive-like behavior, which was improved by fluoxetine. The protein and mRNA expression levels of LRP1 were elevated in the CUMS group. The levels of Acet-tub increased following CUMS, accompanied by elevated levels of p-tau (404,262). The binding of p-tau and Acet-tub significantly decreased in depressive-like rats, and fluoxetine attenuated microtubule instability. Finally, the inhibition of CUMS-induced PI3K/Akt activated GSK-3β, and fluoxetine reversed the change in the signaling pathway. Hence, LRP1 might impair the microtubule dynamics accompanied by depressive-like behavior via the PI3K/ Akt /GSK3β pathway in adult depressive-like rats, and hippocampal LRP1 might be involved in the development of depression., (Copyright © 2019. Published by Elsevier Inc.)

The simultaneous introduction of wheel running (WR) and diet choice (high-carbohydrate chow vs. high-fat diet) results in sex-specific diet choice patterns in rats. WR induces a high-fat (HF) diet avoidance, and such avoidance persists in the majority of males, but not females, throughout a 2-wk period. Exercise is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis and stimulates glucocorticoid (GC) release, which can alter dietary preferences. Here, we examined the role of the HPA axis and GC signaling in mediating exercise-induced changes in diet preference and the associated neurobiological adaptations that may underlie sex differences in diet choice patterns. Experiment 1 revealed that adrenalectomy did not significantly alter the initiation and persistence of running-induced HF diet avoidance in male rats. Experiment 2 showed that acute WR resulted in greater neural activation than chronic WR in the medial prefrontal (mPFC) and insular cortices (IC) in male rats. Experiment 3 revealed sex differences in the molecular adaptation to exercise and diet preference. First, exercise increased gene expression of fkbp5 in the mPFC, IC, and hippocampus of WR females but had limited influence in males. Second, male and female WR rats that reversed or maintained HF diet avoidance showed distinct sex- and HF diet preference-dependent expression profiles of genes involved in cortical GC signaling (e.g., nr3c1 , nr3c2 , and src1 ). Taken together, our results suggest sex differences in region-specific neural adaptations may underlie sex differences in diet preference and the health benefits from exercise.

Food reward has been studied with highly palatable stimuli that come from natural additives such as sucrose. The most common food additive is sucralose, a noncaloric sweetener present in many food products of daily intake. The role of anandamide [N-arachidonylethanolamide (AEA)], an endogenous cannabinoid, has been widely studied in food behavior. Studies have shown that cannabinoids, such as AEA, 2-Arachidonilglycerol, and Tetrahydrocannabinol, can provoke hyperphagia, because they enhance the preference and intake of sweet and high-fat food. Taste perception is mediated by receptors taste type 1 receptor 3 (T1R3); therefore, there could be a synergistic effect between receptors CB1 and T1R3. This could explain why cannabinoids could change sweet taste perception and therefore the activity of neural nuclei involved in taste and reward. In this study, we evaluated the activity of dopaminergic nuclei implicated in food reward after the chronic administration of AEA (0.5 mg/kg bw) and sucralose intake (0.02%). We analyzed the expression of ΔFosB by immunohistochemistry. Our results show that the chronic administration of AEA and sucralose intake induces an overexpression of ΔFosB in the infralimbic cortex (Cx), nucleus accumbens (NAc) core, shell, and central nucleus of amygdala (Amy). These results suggest that the possible interaction between receptors CB1 and T1R3 has consequences not only in taste perception but also that AEA intervenes in the activity of dopaminergic nuclei such as the NAc, and that the chronic administration AEA and sucralose intake induce long-term changes in the reward system.

Sugar-sweetened beverages are the major source of added calories in the Western diet and their prevalence is associated with obesity and metabolic disruption. Despite the critical role of the taste system in determining food selection and consumption, the effects of chronic sucrose consumption on the peripheral taste system in mammals have received limited attention. We offered female Sprague Dawley rats free access to water and one of three diets for up to 40 days: (1) sucrose-free chow or "NS" diet; (2) a high-sucrose dry diet or "HS"; or (3) 30% sucrose solution and the NS diet, designated "LiqS" diet. Sucrose consumption by LiqS rats gradually increased and by day 14 was equal to that of HS rats. Food intake decreased in LiqS rats, but their energy intake remained higher than for NS or HS rats. There was no significant difference in weight gain of the groups during the study. Recordings from the chorda tympani nerve (CT), which innervates taste buds on the anterior tongue, revealed decreased responses to 1 M sucrose in both LiqS and HS rats and to acesulfame K and salt tastants in LiqS rats after 40 days on diet. Umami, bitter, and acid response magnitudes were unchanged in both groups. These results demonstrate that chronic sucrose exposure inhibits taste responses to higher concentrations of sweet stimuli. More surprisingly, CT responses to NaCl and 0.5M NaAc were significantly reduced in rats on the LiqS diet. Thus, the physical form of the diet influences taste responsiveness to salt and sweet taste function. These data suggest that taste buds are previously unappreciated targets of chronic sucrose consumption., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Diets high in sugar or fat are associated with multiple health conditions, including binge eating disorder (BED). BED affects approximately 2% of the US adult population, and occurs more frequently in females. It is important to develop animal models of palatable food consumption and food seeking that may have relevance for BED and other conditions associated with excessive food intake. The catecholamine uptake blocker and d-amphetamine prodrug lisdexamfetamine is used to treat BED. The present experiments studied the effect of lisdexamfetamine on food intake and food-reinforced effort-based choice in female Wistar rats. Three groups of rats received different food exposure conditions in the home cage randomly spread over several weeks: a chocolate exposure group (CE; brief access of chocolate and additional lab chow, n = 15), a lab chow exposure (LChE) group given additional access to lab chow (n = 8), and a third group given empty food dishes (n = 7). In tests of food intake under non-restricted conditions, lisdexamfetamine (0.1875-1.5 mg/kg IP) significantly reduced intake of both chocolate and chow in the CE group. In the LChE group, there was a trend towards reduced chow intake induced by lisdexamfetamine. All rats were trained on a Progressive Ratio/chow feeding choice task, in which they had a choice between working for high carbohydrate chocolate flavored pellets by lever pressing vs. approaching and consuming a concurrently available lab chow. The LChE group and the empty food dish group were combined to create one control group (n = 15). There was a significant overall dose-related suppressive effect of lisdexamfetamine on lever pressing but no group difference, and no dose x group interaction. Lisdexamfetamine significantly decreased chow intake in the CE group, but not in the control group. In conclusion, lisdexamfetamine affected both food intake and food-reinforced operant behavior, with larger effects seen in the group exposed to chocolate., (Copyright © 2020. Published by Elsevier Inc.)

Food palatability and caloric content are crucial factors in guiding diet choice and amount consumed; as a result, sweet caloric tastes are associated with a positive hedonic value. Recent evidence in rodents indicates that consumption of artificial (non-caloric) sweeteners, in which sweet taste is dissociated from normal caloric consequences, could induce changes in energy and body weight regulation, suggesting that sweeteners not only modify intake and appetitive behavior, but could also change taste-learning processes. Particularly, there are different properties in some artificial sweeteners, like saccharin, that might differ from sugar in the reward responses that, after long-term consumption, could also be associated with the inability to learn new negative consequences related to the same taste. Thus, the main goal of this study was to determine, in adult rats, the effects of long-term consumption (14 days) of sugar or saccharin, on taste preference, on new aversive learning, i.e. latent inhibition (LI) of conditioned taste aversion (CTA), and appetitive taste re-learning after aversive taste associations. The results showed that 14 days' exposure to sugar, but not to saccharin, induced a significant increment in the LI of CTA and that taste preference is rapidly recovered during the next 3 days (e.g. CTA extinctions), indicating that long-term sugar consumption significantly accelerates aversive memory extinction during appetitive re-learning of a specific sweet taste; furthermore, high familiarization to sugar, but not to saccharin, promotes appetitive learning for the same taste. Overall, the results indicate that long-term consumption of sugar, but not saccharin, produces changes in appetitive re-learning and suggests that long-term sugar consumption could trigger escalating consumption due to the inability to learn new negative consequences associated with the same taste.