Saccharin Intake Research Articles

Associations of saccharin intake with all-cause, cardiovascular and cancer mortality risk in USA adults.

Saccharin is a widely used sugar substitute, but little is known about the long-term health effects of saccharin intake. Our study aimed to examine the association between saccharin intake and mortality in diabetic and pre-diabetic population and overweight population from NHANES 1988-1994. Cox proportional hazard models were used to evaluate the association between saccharin intake and CVD, cancer and all-cause mortality. After multivariable adjustment, increased absolute saccharin intake was associated with the risk of all-cause mortality (hazard ratio (HR): 1·41, 95 % CI: 1·05, 1·90), CVD mortality (HR: 1·93, 95 % CI: 1·15, 3·25) and cancer mortality (HR: 2·26, 95 % CI: 1·10, 4·45) in diabetic and pre-diabetic population. Among overweight population, higher absolute saccharin intake was associated with the risk of cancer mortality (HR: 7·369, 95 % CI: 2·122, 25·592). Replacing absolute saccharin intake with total sugar significantly reduced all-cause mortality by 12·5 % and CVD mortality by 49·7 % in an equivalent substitution analysis in the diabetic and pre-diabetic population. Aspartame substitution reduced all-cause mortality by 29·2 % and cancer mortality by 30·2 %. Notably, the relative daily intake of saccharin also had similar effects as the absolute intake on all-cause, cardiovascular and cancer mortality in all analyses. This was despite the fact that the relative daily intake in our study was below the Food and Drug Administration limit of 15 mg/kg. In conclusion, our study showed a considerable risk of increased saccharin intake on the all-cause, CVD mortality and cancer mortality.

The Effects of Ubiquinone on the Antioxidant System in Male Rats Exposed to Saccharin-Induced the Hepatic Toxicity

Saccharin (Sac) is a widely used artificial sweetener with significant applications in the food industry, pharmaceutical formulations, and tobacco products. Despite its popularity, saccharin has drawn attention due to its potential carcinogenic effects and associations with various health risks, including renal impairment, hepatic dysfunction, obesity, and diabetes. This study aimed to investigate the protective effects of Ubiquinone, or coenzyme Q10 (COQ10), on liver toxicity induced by saccharin, focusing on oxidative stress and antioxidant markers. In this experiment, rats were divided into six groups of ten. The control group received no treatment, while the second group was administered COQ10 at a dosage of 20 mg per kilogram of body weight. The third and fourth groups were given saccharin at 1/10 and 1/20 of the lethal dose 50 (LD50), respectively. The fifth and sixth groups received saccharin at the same dosages as the third and fourth groups, but with additional COQ10 supplementation. All treatments were administered orally for 30 days, after which liver tissues were collected to assess oxidative stress and antioxidant markers. The results revealed that saccharin significantly increased oxidative stress in the liver, as evidenced by elevated levels of malondialdehyde (MDA) and oxidized glutathione (GSSG). Additionally, saccharin-treated groups exhibited a marked decrease in antioxidant markers, including reduced glutathione (GSH) and superoxide dismutase (SOD). However, the groups that received COQ10 alongside saccharin showed significant improvement, with oxidative stress and antioxidant levels nearly returning to those observed in the control group. These findings suggest that saccharin consumption promotes the generation of reactive oxygen species and contributes to liver damage, characterized by necrotic hepatocytes, sinusoidal dilatation, and inflammatory infiltration. The protective effects of COQ10 in mitigating saccharin-induced oxidative stress highlight its potential as a therapeutic agent for preventing liver damage associated with saccharin intake.

Preclinical evidence of the effects of sweet flavors: Sweetness increases nicotine intake and seeking.

The influence of early exposure to sweet and fruit flavors on subsequent nicotine use behaviors during adolescence remains poorly understood. To address this gap, we utilized a rodent model to simulate childhood flavor exposure and examine its effects on later nicotine use behaviors. We employed a two-bottle choice paradigm in weanling rats to mimic human childhood flavor exposure. Subsequently, we investigated the impact of early exposure to sweet (saccharin) and cherry fruit (benzaldehyde) flavors on adolescent nicotine use behaviors. This included assessing subsequent nicotine acquisition, maintenance, and seeking behaviors using intraoral flavor and intravenous nicotine self-administration. Our findings reveal that rats exposed to saccharin during early development exhibited altered patterns of nicotine intake and seeking behaviors during adolescence. Specifically, rats demonstrated increased nicotine intake and seeking of saccharin flavored solutions when paired with nicotine, indicating a potential predisposition towards nicotine use following childhood flavor exposure. Intraoral benzaldehyde did not affect nicotine reinforcement in early sessions of self-administration, but significantly decreased nicotine reinforcement during later sessions. Both saccharin exposure alone or in combination with benzaldehyde promoted nicotine reinforcement. No significant sex differences in nicotine-related behaviors were observed. This study highlights the significance of early flavor exposure in shaping adolescent nicotine use behaviors. The findings suggest that childhood exposure to sweet flavors may contribute to heightened susceptibility to nicotine use and addiction later in life. Understanding these early influences is crucial for developing targeted interventions to prevent the onset of nicotine addiction during adolescence. Our study highlights the importance of how sweetness can contribute to and possibly even alter the effects of the flavor itself. The sweetness of a tobacco product does not solely stem from sweeteners, but it is also influenced by other components such as the PG/VG ratio (e.g., higher VG) and the inclusion of flavors associated with sweetness (e.g., vanillin and ethyl maltol). Therefore, sweet-associated constituents in tobacco products should be investigated further to inform regulatory policy. We believe that our findings can inform regulatory decisions on controlling sweet associated constituents in tobacco products.

Saccharin aversion learning in male and female laboratory rats

The three experiments reported in the present research demonstrated that male rats acquire stronger saccharin aversion than females. Experiment 1 revealed that male rats were better than females in a single-trial saccharin aversion learning with a lithium chloride injection as the unconditioned stimulus (US), when normalizing saccharin intake data. Experiment 2 replicated this finding. The stronger saccharin aversion learning in male rats was also observed in Experiment 3 with wheel running as the US, assessed by the saccharin-vs.-water choice test conducted after six saccharin-running pairing days. Experiments 2 and 3 also showed that the magnitude of induced nausea, reflected in the kaolin clay ingestion, is equivalent between the sexes. Experiment 4 excluded the possibility that the observed sex difference in saccharin aversion is due to the sex difference in inherent saccharin preference. These results, taken together, suggest that potential factors of the sex difference in rats' conditioned taste aversion could include sex disparities in taste perception, the ability to associate taste with nausea, and/or the expression of association learning.

Scopolamine infusion in the basolateral amygdala after saccharin intake induces conditioned taste avoidance in rats

RationaleMuscarinic receptor activity in the basolateral amygdala (BLA) is known to be involved in plasticity mechanisms that underlie emotional learning. The BLA is involved in the Attenuation of Neophobia, an incidental taste learning task in which a novel taste becomes familiar and recognized as safe.ObjectiveHere we assessed the role of muscarinic receptor activity in the BLA in incidental taste learning.MethodsYoung adult male Wistar rats were bilaterally implanted with cannulas aimed at BLA. After recovery, rats were randomly assigned to either vehicle or muscarinic antagonist group, for each experiment. We tested the effect of specific and non-specific muscarinic antagonists administered either 1) 20 min before novel taste presentation; 2) immediately after novel taste presentation; 3) immediately after retrieval (the second taste presentation on Day 5 -S2-) or immediately after the fifth taste presentation on Day 8 (S5).ResultsNon-specific muscarinic receptor antagonist scopolamine infused prior to novel taste, while not affecting novel taste preference, abolished AN, i.e., the increased preference observed in control animals on the second presentation. When administered after taste consumption, intra-BLA scopolamine not only prevented AN but caused a steep decrease in the taste preference on the second presentation. This scopolamine-induced taste avoidance was not dependent on taste novelty, nor did it generalize to another novel taste. Targeting putative postsynaptic muscarinic receptors with specific M1 or M3 antagonists appeared to produce a partial taste avoidance, while M2 antagonism had no effect.ConclusionThese data suggest that if a salient gustatory experience is followed by muscarinic receptors antagonism in the BLA, it will be strongly and persistently avoided in the future. The study also shows that scopolamine is not just an amnesic drug, and its cognitive effects may be highly dependent on the task and the structure involved.

A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol.

A strong relationship exists between individual sensitivity to the aversive properties of ethanol and risk for alcohol use disorder (AUD). Despite this, our understanding of the neurobiological mechanisms underlying the subjective response to ethanol is limited. A major contributor to this lack of knowledge is the absence of preclinical models that enable exploration of this individual variability such as is possible in studies of humans. Adult male and female Long-Evans rats were trained to associate a novel tastant (saccharin) with acute exposure to either saline or ethanol (1.5 g/kg or 2.0 g/kg i.p.) over three conditioning days using a standard conditioned taste aversion (CTA) procedure. Variability in sensitivity to ethanol-induced CTA was phenotypically characterized using a median split across the populations studied. When examining group averages, both male and female rats exposed to saccharin paired with either dose of ethanol exhibited lower saccharin intake relative to saline controls indicative of ethanol-induced CTA. Examination of individual data revealed a bimodal distribution of responses uncovering two distinct phenotypes present in both sexes. CTA-sensitive rats exhibited a rapid and progressive reduction in saccharin intake with each successive ethanol pairing. In contrast, saccharin intake was unchanged or maintained after an initial decrease from baseline levels in CTA-resistant rats. While CTA magnitude was similar between male and female CTA-sensitive rats, among CTA-resistant animals females were more resistant to the development of ethanol-induced CTA than males. Phenotypic differences were not driven by differences in baseline saccharin intake. These data parallel work in humans by revealing individual differences in sensitivity to the aversive properties of ethanol that emerge immediately after initial exposure to ethanol in both sexes. This model can be used in future studies to investigate the neurobiological mechanisms that confer risk for AUD.

Reducing sugar intake through chronic swimming training: Exploring palatability changes and central vasopressin mechanisms

Excessive sugar intake has been associated with the onset of several non-communicable chronic diseases seen in humans. Physical activity could affect sweet taste perception which may affect sugar intake. Therefore, it was investigated the chronic effects of swimming training on sucrose intake/preference, reactivity to sucrose taste, self-care in neurobehavioral stress, and the possible involvement of the vasopressin type V1 receptor in sucrose solution intake. Male Wistar rats, of from different cohorts were used, subjected to a sedentary lifestyle (SED) or swimming training (TR - 1 h/day, 5×/week, for 8 weeks, with no added load). Weekly intake was verified in SED and TR rats after access to a sucrose solution 1×/week, 2 h/day, for eight weeks. Chronic effects of swimming and/or a sedentary lifestyle were carried out three days after the end of the physical exercise protocol. Swimming training reduced the intake of sucrose solution from the third week onwards in the two-bottle test measured once a week for 8 weeks. After the ending of the swimming protocol, sucrose intake was also reduced as per its preference. This reduced intake is probably correlated with the carbohydrate aspect of sucrose since saccharin intake was not affected. In addition, chronic swimming training was shown to reduce ingestive responses, increase neutral responses, without interfering with aversive, in the sucrose solution taste reactivity test. In addition, these results are not related to a depressive-like behavior, nor to neurobehavioral stress. Furthermore, treatment with vasopressin V1 receptor antagonist abolished the reduced sucrose intake in trained rats. The results suggest that swimming performed chronically is capable of reducing intake and preference for sucrose by decreasing the palatability of sucrose without causing depressive-type behavior or stress. In addition, the results also suggest that central V1 vasopressin receptors are part of the mechanisms activated to reduce sucrose intake in trained rats.

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

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30–45 with vehicle or THC (escalating doses, 3–20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3–4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3β (GSK3β), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3β signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

Long-term aspartame and saccharin intakes are related to greater volumes of visceral, intermuscular, and subcutaneous adipose tissue: the CARDIA study

BackgroundArtificial sweetener (ArtSw) intakes have been previously associated with higher BMI in observational studies and may promote visceral and skeletal muscle adipose tissue (AT) accumulation. This study aimed to determine whether habitual, long-term ArtSw or diet beverage intakes are related to greater AT depot volumes and anthropometry-related outcomes.MethodsA validated diet history questionnaire was administered at baseline, year 7, and year 20 examinations in 3088 men and women enrolled in the Coronary Artery Risk Development in Young Adults cohort (CARDIA), mean age of 25.2 years and mean BMI of 24.5 kg/m2 at baseline. Volumes of visceral (VAT), intermuscular (IMAT), and subcutaneous adipose tissue (SAT) were assessed by computed tomography at year 25. Linear regression evaluated associations of aspartame, saccharin, sucralose, total ArtSw, and diet beverage intakes with AT volumes, anthropometric measures, and 25-year change in anthropometry. Cox regression estimated associations of ArtSw with obesity incidence. Adjustments were made for demographic and lifestyle factors, total energy intake, and the 2015 healthy eating index.ResultsTotal ArtSw, aspartame, saccharin, and diet beverage intakes were positively associated with VAT, SAT, and IMAT volumes (all ptrend ≤ 0.001), but no associations were observed for sucralose intake (all ptrend > 0.05). In addition, total ArtSw, saccharin, aspartame, and diet beverage intakes were associated with greater body mass index, body weight, waist circumference, and their increases over a 25-year period. Except for saccharin (ptrend = 0.13), ArtSw, including diet soda, was associated with greater risks of incident obesity over a median 17.5-year follow-up (all ptrend < 0.05).ConclusionsResults suggest that long-term intakes of aspartame, saccharin, or diet soda may increase AT deposition and risk of incident obesity independent of diet quality or caloric intake. Coupled with previous evidence, alternatives to national recommendations to replace added sugar with ArtSw should be considered since both may have health consequences.

Effects of combined use of alcohol and delta-9-tetrahydrocannibinol on working memory in Long Evans rats

The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake. Periadolescent male and female Long-Evans rats were allowed to orally self-administer ethanol, Δ9-tetrahydrocannibinol (THC), both drugs, or their vehicle controls from postnatal day (P) 30 to P47. They were subsequently trained and tested on an instrumental behavior task that assesses attention, working memory and behavioral flexibility. Similar to previous work, consumption of THC reduced both ethanol and saccharin intake in both sexes. Blood samples taken 14 h following the final self-administration session revealed that females had higher levels of the THC metabolite THC-COOH. There were modest effects of THC on our delayed matching to position (DMTP) task, with females exhibiting reduced performance compared to their control group or male, drug using counterparts. However, there were no significant effects of co-use of ethanol or THC on DMTP performance, and drug effects were also not apparent in the reversal learning phase of the task when non-matching to position was required as the correct response. These findings are consistent with other published studies in rodent models showing that use of these drugs in low to moderate doses does not significantly impact memory or behavioral flexibility following a protracted abstinence period.

Behavioral and biochemical effects of alcohol withdrawal in female C3H/HeNRj and C57BL/6JRj mice.

Alcohol use disorder (AUD) is a major problem of our society and is often characterized and worsened by relapse. Prolonged alcohol exposure leads to numerous biochemical alterations that, upon cessation of alcohol intake, cause an array of immediate and lasting withdrawal symptoms. Acute withdrawal and neuroinflammation can be harmful in themselves, and lasting withdrawal symptoms contribute to relapse. Here, we conducted an initial feasibility study assessing several behavioral and neurochemical factors in female C3H/HeNRj (C3H) and C57BL/6JRj (B6) mice to determine which strain showed the clearest alcohol withdrawal symptoms during long-term abstinence and neurochemical alterations following re-exposure. Female C3H and B6 mice (n = 12 per group/strain) were intermittently exposed to alcohol-containing or control liquid diets for 3 weeks. Acute and prolonged withdrawal symptoms were assessed over a period of 3 weeks using a battery of behavioral test, comprised of alcohol self-administration, anhedonia, hyperalgesia, anxiety-like and depressive-like disturbances. Brain inflammation was measured by multiplex cytokine assay. Monoamine levels in the hippocampus and striatum, as well as exploratory analyses of cations levels in the cerebellum, were assessed by High-Performance Liquid Chromatography (HPLC). Both C3H and B6 alcohol-exposed mice displayed decreased saccharin intake or preference and higher stress levels assessed by ultrasonic vocalizations (USVs) recordings. B6 but not C3H alcohol-exposed mice also exhibited a slower decline of alcohol oral self-administration (OSA), hyperalgesia, elevated brain TNF-α and elevated serotonin turnover. Our findings highlight the suitability of the B6 strain to study the behavioral and neurochemical alterations caused by alcohol withdrawal and the potential efficacy of experimental treatments, not only in early detoxification, but also in prolonged abstinence. The feasibility of these assays is important because long-lasting withdrawal symptoms are often the main cause of relapse in alcohol-dependent patients.

Differential patterns of opioid and dopamine D1 receptor antagonism on nutritive and non-nutritive sweetener intakes in C57BL/6:129 hybrid mice relative to inbred C57BL/6 and 129 mice

Opioid and dopamine (DA) D1 receptor antagonists differentially reduce nutritive and non-nutritive sweetener intakes in inbred mouse strains. Sucrose intake was more effectively reduced by naltrexone in C57BL/6 (B6) mice relative to 129P3 (129) mice, but more effectively reduced by SCH23390 in 129 mice relative to B6 mice. Opioid and DA D1 antagonists differentially reduced saccharin intakes in B6 mice relative to other strains. Given these differential patterns in sweetener intake in B6 and 129 mice, the present study examined whether systemic naltrexone (0.01–5 mg/kg) and SCH23390 (50–1600 nmol/kg) reduced intakes of 10 % sucrose or 0.2 % saccharin solutions over a 120 min time course in first-generation hybrid mice (B6:129) of B6 and 129 parents and reduced low-nutritive sweetener intakes in 129 mice. Naltrexone (5 mg/kg) significantly reduced 10 % sucrose intake in B6:129 hybrid mice more like that of 129 than B6 mice. In contrast, SCH23390 (400–1600 nmol/kg) reduced 10 % sucrose intake in B6:129 hybrid mice more effectively than that observed in B6 or 129 parental strains. Because 129 mice consumed relatively low amounts of 0.2 % saccharin, they were tested with a more attractive low-nutritive solution containing 0.2 % saccharin and 2 % sucrose. Naltrexone failed to reduce saccharin intake in B6:129 hybrid mice but suppressed saccharin+sucrose intake in 129 mice more like that observed in B6 mice. SCH23390 similarly inhibited saccharin or saccharin+sucrose intakes in hybrid B6:129, 129, and B6 mice with B6 mice more resistant to the lowest SCH23390 dose. Thus, whereas sucrose intake in B6:129 hybrid mice exhibited similar sensitivity to opioid and to a lesser degree DA D1 antagonism to their 129, but not B6 parents, opioid and DA D1 mediation of low- and non-nutritive sweet intake produced unique profiles among B6:129 hybrid and B6 and 129 strains which does not support a simple heritability explanation.

Selective pressure on a saccharin intake phenotype and its correlates: a replication study.

The Occidental High- and Low-Saccharin rats (respectively, HiS and LoS lines) were selectively bred for decades to examine mechanisms and correlates of a saccharin intake phenotype. Observed line differences ranged from taste and eating to drug self-administration and defensive behavior, paralleling human research on relationships between gustation, personality, and psychopathology. The original lines were terminated in 2019, and replicate lines (HiS-R and LoS-R) were selectively bred for 5 generations to test for reproducible, rapid selection for the phenotype and its correlates. The line differences chosen for replication included intake of tastants (saccharin, sugars, quinine-adulterated sucrose, sodium chloride, and ethanol) and foods (cheese, peas, Spam, and chocolate) and several noningestive behaviors (deprivation-induced hyperactivity, acoustic startle, and open field behavior). The HiS-R and LoS-R lines diverged on intake of saccharin, disaccharides, quinine-adulterated sucrose, sodium chloride, and complex foods, and open field behavior. Differences from the original lines also were observed. Reasons for and implications of the pattern of replication and lack thereof in 5 generations are discussed.

Chemogenetic inhibition of the bed nucleus of the stria terminalis suppresses the intake of a preferable and learned aversive sweet taste solution in male mice

Conditioned taste aversion (CTA) is established by pairing a taste solution as a conditioned stimulus (CS) with visceral malaise as an unconditioned stimulus (US). CTA decreases the taste palatability of a CS. The bed nucleus of the stria terminalis (BNST) receives taste inputs from the brainstem. However, the involvement of the BNST in CTA remains unclear. Thus, this study examined the effects of chemogenetic inhibition of the BNST neurons on CS intake after CTA acquisition. An adeno-associated virus was microinjected into the BNST of male C57/BL6 mice to induce the inhibitory designer receptor hM4Di. The mice received a pairing of 0.2% saccharin solution (CS) with 0.3 M lithium chloride (2% BW, intraperitoneal). After conditioning, the administration of clozapine–N–oxide (CNO, 1 mg/kg) significantly enhanced the suppression of CS intake on the retrieval of CTA compared with its intake following saline administration (p < 0.01). We further assessed the effect of BNST neuron inhibition on the intake of water and taste solutions (saccharin, sucralose, sodium chloride, monosodium glutamate, quinine hydrochloride, and citric acid) using naïve (not learned CTA) mice. CNO administration significantly decreased the intake of saccharin and sucralose (p < 0.05). Our results indicate that BNST neurons mediate sweet taste and regulate sweet intake, regardless of whether sweets should be ingested or rejected. BNST neurons may be inhibited in the retrieval of CTA, thereby suppressing CS intake.

Greater avoidance of a saccharin cue paired with passive delivery of heroin is associated with a select increase in expression of CRFR2 and CRFbp in the hippocampus in rats

As a drug of abuse tightens its hold on addicted individuals, aspects of life that once brought pleasure lose their appeal while attention and motivation are turned toward acquiring drug. In a rodent model of self-administration and reward devaluation, we previously showed that animals that suppress intake of a drug-paired saccharin cue show greater addiction-like behaviors, as well as increased gene-expression of elements of the corticotropin releasing factor (CRF) pathway in the prefrontal cortex (mPFC), hippocampus (Hipp), and ventral tegmental area (VTA). In the present study, we explored whether the observed differences in components of the CRF signaling pathway were a function of self-administration or devaluation of the cue. Moreover, as an increasing body of work illustrates, functional and molecular hemispheric differences in reward pathway components, we examined whether these CRF pathway components exhibited hemispheric differences in response to heroin administration. Over a period of 7 trials, 30 male rats received brief access to saccharin followed by passive (IP) injection of heroin (n = 20) or saline (n = 10). Saccharin intakes between large saccharin suppressors (LS; 12 animals) and small suppressors (SS; 8 animals) were statistically different after trial 1 and separated further with ensuing trials. We then assessed gene expression for components of the CRF pathway in the mPFC, Hipp, VTA, Amygdala, and nucleus accumbens (NAc). Within the Hipp, LS showed greater expression of CRF binding protein (CRFbp). No differences were observed in the mPFC, VTA, NAc or Amygdala. Several hemisphere differences in CRF signaling pathway genes were detected. These findings indicate that avoidance of the experimenter delivered heroin-paired saccharin cue, do not recapitulate findings observed for avoidance of the iv self-administered heroin-paired saccharin cue, at least in terms of the expression of genes within the CRF pathway, and provide further evidence that consideration should be given to hemisphere differences when exploring molecular phenomena.

Systemic administration of racemic baclofen reduces both acquisition and maintenance of alcohol consumption in male and female mice.

Baclofen is a GABAB receptor agonist with proposed use as a treatment for alcohol use disorder (AUD). In preclinical studies, racemic baclofen decreases alcohol consumption in both mice and rats; however, there is a significant disparity in the efficacy of the drug across species. We previously demonstrated that baclofen is enantioselective, with the racemic enantiomer successfully reducing binge-like alcohol consumption during Drinking-in-the-Dark (DID) in C57BL/6J (B6) mice, as well as 24-h consumption during two-bottle choice (2BC) preference drinking in replicate 1 High Alcohol Preferring (HAP) mice. Here we extend these findings by investigating the effects of racemic baclofen on the acquisition and maintenance of alcohol consumption, locomotor activity, and saccharin drinking in two different mouse genotypes and drinking paradigms. Adult male and female B6 mice were allowed free access to 20% (v/v) alcohol for 2h daily in a 14-day DID procedure. Adult male and female replicate 2 HAP (HAP2) mice were allowed 24-h access to 10% (v/v) alcohol versus tap water in a 2BC procedure for 14 days. Systemic injections of baclofen (0.0 or 3.0mg/kg) were given 3h into the dark cycle on days 1-5 in alcohol acquisition experiments and days 6-10 in alcohol maintenance experiments. We found that racemic baclofen significantly reduces acquisition of DID and 2BC alcohol drinking in male and female B6 and HAP2 mice, whereas it only significantly reduces the maintenance of DID alcohol intake in B6 mice. Racemic baclofen did not alter home cage locomotor activity but did alter saccharin intake, suggesting it may have nonspecific effects. The current data add to literature suggesting that smaller doses of racemic baclofen may be an effective treatment of AUD. Future work should focus on the longitudinal efficacy of racemic baclofen in high-drinking mouse genotypes to further investigate whether it is effective for those with a genetic predisposition to AUD.

Effects of chronic psychosocial stress on ‘binge-like’ sucrose intake in mice

Binge eating episodes are persistent and are essential features of numerous eating disorders (EDs). Susceptibility to EDs is largely presumed to be associated with early life stress. In fact, converging evidence from preclinical animal studies have implicated stress as a driver of binge eating. Still, literature examination indicates that vulnerability to EDs may depend on factors such as severity, time, and the type of stressor. Therefore, we aimed at exploring the link between chronic psychosocial stress and ‘binge-like’ sucrose intake in adolescent mice. To this aim, intruders' experimental mice were exposed to the chronic subordinate colony (CSC) housing, in the presence of a resident aggressive mouse for 2 weeks. At the end of the stress period, mice were tested for anxiety-like behavior then assessed for ‘binge-like’ intake of sucrose using a long-term drinking in the dark (DID) method that successfully replicates binge eating in humans. As expected, and compared to single housed colony controls (SHC), CSC exposure elicited an anxiogenic-like response in the open field (OF) and elevated-plus maze (EPM) tests and reduced weight gain. Most importantly, we report here for the first time, that mice exposed to chronic psychosocial stress displayed a ‘binge-like’ consumption of sucrose. However, neither quinine (bitter) nor saccharin (sweet) intakes were affected by CSC exposure. Finally, using Pearson's correlation, results showed a strong correlation between anxiety-like behavior parameters and sucrose intake. Overall these findings support the validity of our chronic psychosocial stress to model binge EDs and establish the long-term consequences of stress on ‘binge-like’ eating in male mice. These data suggest that chronic psychosocial stress is a risk factor for developing anxiety-associated EDs.

Chronic intake of nutritive sweeteners and saccharin increases levels of glycolytic and lipogenic enzymes in rat liver

There are doubts about the impact of non-nutritive sweeteners consumption on lipogenic and glycolytic metabolism. Therefore, the objective was to determine the effects of chronic consumption of sweeteners on the activity levels of the enzymes glucokinase (GK), phosphofructokinase-1 (PFK-1), pyruvate kinase (PKL), acetyl coenzyme A carboxylase (ACC), and fatty acid synthase (FAS) in livers’ extracts. Groups of male and female Wistar rats drank solutions of sweeteners for 480 days: Sucrose 10%, glucose 14%, fructose 7%, acesulfame K 0.05%, aspartame:acesulfame mixture 1.55%, sucralose 0.017%, saccharin 0.033%, and a control group. The enzymatic activity in livers’ extracts was determined. Likewise, the levels of glucose, triglycerides, insulin, glucagon, and leptin were determined. In both genders, there were significant differences in the levels of enzymatic activity, hormonal, and biochemical parameters due to sweeteners consumption. The highest glycolytic and lipogenic enzyme activity levels were observed in the groups that ingested nutritive sweeteners and saccharin.

Consumption of Sugar-Sweetened or Artificially Sweetened Beverages and Semen Quality in Young Men: A Cross-Sectional Study.

Background: Existing literature suggests that frequent consumption of sugar-sweetened drinks may be associated with lower semen quality. Studies performed in mice suggest a dose-response relationship between intake of saccharin or aspartame, two artificial sweeteners, and sperm and testis function. Methods: A cross-sectional study based on data from The Fetal Programming of Semen Quality (FEPOS) Cohort, including 1047 young men (mean age = 19 years) was performed. Each male participant completed an online questionnaire on health, health behavior and diet, and provided a semen sample. The associations between consumption of sugar-sweetened or artificially sweetened beverages (moderate ≥ 3 days/week; infrequent < 3 days/week) and semen quality were analyzed using a multivariable, negative, binomial regression model. Results: Sugar-sweetened or artificially sweetened beverage consumption was not strongly associated with either semen volume, sperm concentration, total sperm count or total motility in young men. The proportion of morphologically normal sperm was 11% lower (0.89 (95% CI 0.76, 1.04)) for moderate (≥3 days/week) consumption of artificially sweetened beverages relative to infrequent (<3 days/week). Conclusion: Consumption of sugar-sweetened or artificially sweetened beverages, at the levels present in this study had limited effect on the measured markers of semen quality in young men.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer's Disease in an Animal Model.

Alzheimer’s disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.