Search Results (63)

Excessive drinking or even alcoholism poses noticeable health risks to society, and investigating ways to improve alcohol metabolism may be a potential strategy to address this public health issue. The aim of this study was to explore the efficacy of freshwater clam aqueous extract (CE) in promoting alcohol metabolism and to further elucidate its potential mechanism. Male Wistar rats were divided into four groups: (1) control group (C); (2) vehicle group (V), which was given a single dose of 2 g/kg bw ethanol; (3) low-dose CE group (CEL), which was given ethanol and 128 mg/kg bw CE; and (4) high-dose CE group (CEH), which was given ethanol and 256 mg/kg bw CE. Blood was drawn from the tails of the rats at 0, 1, 2, 3, and 4 h after alcohol administration, and serum samples were collected. The results showed that compared with the V group, oral administration of CE reduced the ethanol concentration in the serum of the rats, with the area under the serum ethanol curve (AUC) of the CEH group decreased by 32.6%, exhibiting a significant difference (p < 0.05). Moreover, the high-dose CE (CEH) treatment significantly increased the activities of alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH), catalase (CAT), and superoxide dismutase (SOD) in the liver of the rats by 41.5%, 42.4%, 40.6%, and 34.6%, respectively, compared with those in group V (p < 0.05). The Western blot results indicated that CE reduced the expression of ethanol-induced inflammation-related proteins COX-2, iNOS, and TNF-α in the liver by 66.4%, 90.6%, and 41.4%, respectively. In conclusion, it can be inferred that CE can help reduce the ethanol concentration in the serum of rats fed with alcohol, and its possible mechanism is to promote the metabolism of ethanol by increasing the activities of ADH and ALDH and the antioxidant capacity in the liver. Full article

Background: Most animals display different defensive behavioral strategies during imminent or potential threats. These responses are relevant for understanding human behavioral disorders. In addition, α1 adrenergic receptors (α1ARs) are blocked by prazosin and regulate a diverse set of behaviors, including alcohol drinking related to anxiety in humans, alcohol intake in rats, responses to strong acute stresses (like restraint), and several forms of cognitive flexibility. However, the role of α1ARs in regulating panic-like escape behavior remains unexplored. Methods: Male and female Wistar rats were chronic alcohol drinkers and age-matched alcohol naïves. Animals received an injection of 0.75 mg/kg of prazosin or vehicle and then were exposed to the elevated T maze (ETM) to evaluate avoidance and escape behavior. One week later, animals underwent the light-dark test (LDT) and open field test. Results: α1AR inhibition with prazosin increased latency for escape in male and female alcohol drinkers, with no significant effects in alcohol-naïve controls. There were also interesting impacts from alcohol drinking, including a decrease in ETM avoidance in female but not male drinkers. In addition, prazosin increased latency to enter the dark in LDT in female drinkers and male naïves. Although prazosin also decreased the number of transitions in males, no differences were found in open-field locomotion. Conclusions: These results suggest that α1ARs mediate escape-like behavior in male and female alcohol drinkers, shedding light on a novel therapy for alcohol problems related to panic and anxiety. Full article

Alcohol use disorder (AUD) is a chronic relapsing disorder afflicting millions of people worldwide. Malnutrition is frequently associated with AUD, which could be the result of reduced nutritional intake and impairment in the absorption/metabolism of nutrients because of excessive alcohol drinking. Interestingly, the higher consumption of high calorie/palatable foods is reported in recovering alcoholics who stayed sober. However, it is unclear if the higher calorie or rewarding properties of these palatable foods accounted for the protective effect in these conditions. In the present study, we evaluated the palatable food intake in male and female alcohol-preferring (P-rats) and compared it to alcohol-non-preferring rats (NP-rats). Importantly, alcohol-preferring (P-rats) were selectively bred for a higher alcohol preference and are regarded as a well-characterized model of alcoholism. A group of P- and NP-rats received a high-fat diet (40% fat) on four separate days over a two-week period, and their 24 h caloric intake and change in body weight were recorded. Standard chow and water were available unrestricted to all groups for the entire duration of the study. Total caloric intake in both P- and NP-rats was significantly increased on HFD access days compared to chow-only days, an effect observed in both males and females. Further analysis revealed that the total caloric intake in the P-rats was significantly lower compared to the NP-rats, an effect more significant and pronounced in the female group of rats. Furthermore, body weight increase during this period was significantly lower in the P-rats than the NP-rats, an effect more significant and pronounced in the male group of rats. These data not only document the important differences in the palatable diet intake between alcohol-preferring and non-preferring rats and the sex differences but also highlight that a higher alcohol preference does not necessarily equate to a higher intake of high calorie/palatable food. Full article

Alcoholic beverages are among the most widely enjoyed leisure drinks around the world. However, irresponsible drinking habits can have detrimental effects on human health. Therefore, exploring strategies to alleviate discomfort following alcohol consumption would be beneficial for individuals who inevitably need to consume alcohol. In this study, three different models were used to determine the efficacy of a patented alcohol degradation protein (ADP) extracted from Bos taurus on ethanol metabolism. In an ethanol-challenged HepG2 cell model, ADP significantly protected the cell from ethanol-induced toxicity. Subsequently, results demonstrated that ADP significantly alleviated the effect of ethanol, as reflected by the increased distance and activity time of zebrafish during the testing period. Additionally, in a rat model, ADP promoted ethanol degradation at 1 and 2 h after ethanol consumption. Mechanistic studies found that ADP treatment increased ADH and ALDH activity in the gastrointestinal tract. ADP also exhibited potent antioxidation effects by lowering HO-1 expression in the liver. In conclusion, we believe that ADP is a promising product for relieving hangover symptoms after ethanol consumption, with demonstrated safety and effectiveness at the recommended dosage. Full article

Adolescence is a critical period when the effects of ethanol and stress exposure are particularly pronounced. Argan oil (AO), a natural vegetable oil known for its diverse pharmacological benefits, was investigated for its potential to mitigate addictive-like behaviors and brain damage induced by adolescent intermittent ethanol intoxication (IEI) and unpredictable mild stress (UMS). From P30 to P43, IEI rats received a daily ip ethanol (3 g/kg) on a two-day on/two-day off schedule. On alternate days, the rats were submitted to UMS protocol. Next, a two-bottle free access paradigm was performed over 10 weeks to assess intermittent 20% ethanol voluntary consumption. During the same period, the rats were gavaged daily with AO (15 mL/kg). Our results show that IEI/UMS significantly increased voluntary alcohol consumption (from 3.9 g/kg/24 h to 5.8 g/kg/24 h) and exacerbated withdrawal signs and relapse-like drinking in adulthood. Although AO treatment slightly reduced ethanol intake, it notably alleviated withdrawal signs during abstinence and relapse-like drinking in adulthood. AO’s effects were associated with its modulation of the HPA axis (elevated serum corticosterone), restoration of amygdala oxidative balance, BDNF levels, and attenuation of neurodegeneration. These findings suggest that AO’s neuroprotective properties could offer a potential therapeutic avenue for reducing ethanol/stress-induced brain damage and addiction. Further research is needed to explore its mechanisms and therapeutic potential in alcohol use disorders. Full article

The liver is the main organ responsible for the metabolism of ethanol, which suffers significantly as a result of tissue damage due to oxidative stress. It is known that C₆₀ fullerenes are able to efficiently capture and inactivate reactive oxygen species in in vivo and in vitro systems. Therefore, the purpose of this study is to determine whether water-soluble C₆₀ fullerene reduces the level of pathological process development in the liver of rats induced by chronic alcohol intoxication for 3, 6, and 9 months, depending on the daily dose (oral administration; 0.5, 1, and 2 mg/kg) of C₆₀ fullerene throughout the experiment. In this context, the morphology of the C₆₀ fullerene nanoparticles in aqueous solution was studied using atomic force microscopy. Such biochemical parameters of experimental animal blood as ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGT (gamma-glutamyl transferase) and ALP (alkaline phosphatase) enzyme activities, CDT (carbohydrate-deficient transferrin) level, values of pro-antioxidant balance indicators (concentrations of H₂O₂ (hydrogen peroxide) and GSH (reduced glutathione), activities of CAT (catalase), SOD (superoxide dismutase) and GP_x (selenium-dependent glutathione peroxidase)), and pathohistological and morphometric features of liver damage were analyzed. The most significant positive change in the studied biochemical parameters (up to 29 ± 2% relative to the control), as markers of liver damage, was recorded at the combined administration of alcohol (40% ethanol in drinking water) and water-soluble C₆₀ fullerenes in the optimal dose of 1 mg/kg, which was confirmed by small histopathological changes in the liver of rats. The obtained results prove the prospective use of C₆₀ fullerenes as powerful antioxidants for the mitigation of pathological conditions of the liver arising under prolonged alcohol intoxication. Full article

Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25–57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration. Full article

Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium–calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play a role in controlling alcohol consumption. Here, we investigated how two potent inhibitors of NCX reverse mode activity, SN-6 (NCX1) and KB-R7943 (NCX3), affect voluntary alcohol consumption in adult male and female rats using the intermittent alcohol access two-bottle choice paradigm. Initially, animals were trained to drink 7.5% ethanol and water for four weeks before administering SN-6 and KB-R7934. Afterward, their alcohol intake, preference, and water intake were recorded 2 and 24 h after exposure to water and 7.5% ethanol. SN-6 significantly reduced alcohol consumption by 48% in male and 36% in female rats without affecting their water intake. Additionally, SN-6 significantly reduced alcohol preference in females by 27%. However, KB-R7943 reduced alcohol consumption by 42% in female rats and did not affect alcohol preference or water intake. These findings suggest that alcohol exposure increased NCX reverse activity, and targeting NCX1 could be an effective strategy for reducing alcohol consumption in subjects susceptible to withdrawal seizures. Full article

Background: The link between epilepsy and alcohol consumption is complex, with conflicting reports. To enhance our understanding of this link, we conducted a study to determine how inherited seizure susceptibility affects voluntary alcohol consumption and influences alcohol withdrawal seizures in male and female genetically epilepsy-prone rats (GEPR-3s) compared to Sprague Dawley (SD) rats. Methods: In the first experiment, animals were given access to two bottles simultaneously, one containing water and the other 7.5%, 15%, or 30% (v/v) alcohol three times a week for each dose after acclimation to drinking water. In a second experiment, animals were tested for acoustically evoked alcohol seizures 24 h after the last session of voluntary alcohol consumption. Results: Analysis revealed that GEPR-3s (males and females) had lower alcohol intake and preference than SD rats, particularly at lower alcohol concentrations. However, female GEPR-3s consumed more alcohol and had a higher alcohol preference than males. Furthermore, withdrawal from voluntary alcohol consumption facilitated the onset and duration of seizures in GEPR-3s. Conclusions: Our study suggests that genetic seizure susceptibility in GEPR-3s is negatively associated with alcohol consumption. However, withdrawal from low to moderate amounts of alcohol intake can promote epileptogenesis in the epileptic GEPR-3s. Full article

Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5–6/grp) and post-CIE (n = 6–8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking. Full article

Alcoholic liver disease (ALD) remains a major cause of liver-related morbidity and mortality worldwide. Tea polyphenols (TPs) possess strong antioxidant activity; cassia seed extract (CSE) has the effect of brightening the eyes; and Ampelopsis grossedentata extract (AGE) has the function of protecting the liver. However, the synergistic hepatoprotective effect of TP, AGE and CSE as a joint formulation is unknown. This study aimed to investigate the role of a tea solid beverage, composed of TP, AGE and CSE, on chronic alcoholic liver injury in rats and its underlying mechanisms via the analysis of transcriptomics and gut microbiota. The histopathological findings revealed that the tea solid beverage could reduce the production of fat vacuoles and inflammatory cell infiltration. Additionally, the tea solid beverage was found to effectively relieve the increase in the AST (from 424.85 U/L to 180.17 U/L), ALT (from 139.95 U/L to 85.88 U/L) and LDH (from 21.16 U/L to 13.35 U/L) enzyme activities and the expression of the inflammatory factors TNF-α (from 394.02 pg/mL to 214.44 pg/mL) and IL-6 (from 208.46 pg/mL to 116.59 pg/mL) caused by alcohol consumption. Further, it significantly enhanced the GSH concentration (from 4.53 pg/mL to 8.08 pg/mL) and SOD activity (from 84.70 U/mL to 156.94 U/mL) and decreased the MDA (from 58.61 mmol/mL to 36.58 mmol/mL) and TG (from 7.07 mmol/L to 3.43 mmol/L)) concentrations in the liver of rats. The analysis and identification of transcriptomics showed that the tea solid beverage intervention primarily protected the liver of rats with chronic alcoholic injury by up-regulating the differential gene Hmgcs1 in order to increase the synthesis of ketone bodies and by down-regulating the differential gene Pfkfb1 for the purpose of decreasing the glucose metabolism. Additionally, it was found that the tea solid beverage could significantly change the composition of intestinal flora in drinking rats by regulating mineral absorption, the pathways of bile secretion, the adipocytokine signaling pathway and the peroxisome balance of the intestinal flora, in order to protect alcohol-drinking rats’ livers. In conclusion, the tea solid beverage, consisting of TP, AGE and CSE, is a functional drink that prevents ketone metabolism, glucose metabolism and microbiome disorders induced by alcohol intake. Full article

During adolescence, the brain is highly susceptible to alcohol-induced damage and subsequent neuroimmune responses, effects which may enhance development of an alcohol use disorder (AUD). Neuroimmune reactions are implicated in adolescent alcohol exposure escalating adulthood drinking. Therefore, we investigated whether intermittent alcohol exposure in male, adolescent rats (AIE) escalated adult drinking via two-bottle choice (2BC). We also examined the influence of housing environment across three groups: standard (group-housed with enrichment during 2BC), impoverished (group-housed without enrichment during 2BC), or isolation (single-housed without bedding or enrichment throughout). In the standard group immediately after AIE/saline and after 2BC, we also examined the expression of microglial marker, Iba1, reactive astrocyte marker, vimentin, and neuronal cell death dye, FluoroJade B (FJB). We did not observe an escalation of adulthood drinking following AIE, regardless of housing condition. Further, only a modest neuroimmune response occurred after AIE in the standard group: no significant microglial reactivity or neuronal cell death was apparent using this model, although some astrocyte reactivity was detected in adolescence following AIE that resolved by adulthood. These data suggest that the lack of neuroimmune response in adolescence in this model may underlie the lack of escalation of alcohol drinking, which could not be modified through isolation stress. Full article

A total of 29.5 million people aged 12 and older met the diagnostic criteria for alcohol use disorder (AUD) in the United States in 2021, which presents a significant social and economic burden to modern society. Impaired nutritional status has been frequently documented in patients with AUDs and could contribute to escalated alcohol consumption and behavioral impairments commonly observed in AUD. Interestingly, increased highly palatable food intake during recovery has been reported in patients with AUD, suggesting the importance of understanding the relationship between palatable food and problematic alcohol drinking. We have previously shown that patterned feeding of a palatable diet attenuated alcohol drinking in Long Evans rats. The present study evaluated the impact of patterned feeding on high and low alcohol drinking. Individually housed male high-drinking (P), moderate-drinking (Long Evans), and low-drinking (Wistar) rats received intermittent access (24 h, Tuesdays, and Thursdays) to a nutritionally complete high-fat diet (Int-HFD) or standard chow (controls). Normal chow and water were available ad libitum to all groups of rats. Intermittent HFD access induced a feeding pattern in which the Int-HFD group of rats escalated their caloric intake on Tuesdays and Thursdays. Two weeks of Int-HFD pre-exposure preceded any alcohol access, after which all rats were given unsweetened alcohol (20% v/v) in their home cages via a two-bottle choice paradigm of voluntary alcohol drinking. Alcohol was available for 24 h on chow-only days (Mondays, Wednesdays, and Fridays) while Int-HFD feeding continued. Long Evans rats receiving the Int-HFD displayed a significant ~50% reduction in alcohol drinking when compared to controls. The Int-HFD group of P rats also reduced their alcohol intake significantly (p < 0.05) by ~20%, in comparison to respective controls. Interestingly, alcohol drinking in Wistar rats was not affected (p > 0.05) by intermittent HFD exposure. These data highlight rat strain-specific differences in alcohol intake following patterned feeding of a palatable diet and identify Long Evans rats as an ideal model to evaluate the impact of palatable diet on alcohol drinking. Full article

High ethanol consumption triggers neuroinflammation, implicated in sustaining chronic alcohol use. This inflammation boosts glutamate, prompting dopamine release in reward centers, driving prolonged drinking and relapse. Fibrate drugs, activating peroxisome proliferator-activated receptor alpha (PPAR-α), counteract neuroinflammation in other contexts, prompting investigation into their impact on ethanol-induced inflammation. Here, we studied, in UChB drinker rats, whether the administration of fenofibrate in the withdrawal stage after chronic ethanol consumption reduces voluntary intake when alcohol is offered again to the animals (relapse-type drinking). Furthermore, we determined if fenofibrate was able to decrease ethanol-induced neuroinflammation and oxidative stress in the brain. Animals treated with fenofibrate decreased alcohol consumption by 80% during post-abstinence relapse. Furthermore, fenofibrate decreased the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukins IL-1β and IL-6, and of an oxidative stress-induced gene (heme oxygenase-1), in the hippocampus, nucleus accumbens, and prefrontal cortex. Animals treated with fenofibrate showed an increase M2-type microglia (with anti-inflammatory proprieties) and a decrease in phagocytic microglia in the hippocampus. A PPAR-α antagonist (GW6471) abrogated the effects of fenofibrate, indicating that they are dependent on PPAR-α activation. These findings highlight the potential of fenofibrate, an FDA-approved dyslipidemia medication, as a supplementary approach to alleviating relapse severity in individuals with alcohol use disorder (AUD) during withdrawal. Full article

Non-alcoholic fatty liver disease is a sexual dimorphic disease, with adipose tissue playing an essential role. Our previous work showed that female rats fed a high-fat high-fructose diet devoid of cholesterol (HFHFr) developed simple hepatic steatosis dissociated from obesity. This study assessed the impact of the HFHFr diet on the male rat metabolism compared with data obtained for female rats. A total of 16 Sprague Dawley (SD) male rats were fed either a control (standard rodent chow and water) or HFHFr (high-fat diet devoid of cholesterol, plus 10% fructose in drinking water) diet for 3 months. Unlike female rats, and despite similar increases in energy consumption, HFHFr males showed increased adiposity and hyperleptinemia. The expression of hormone-sensitive lipase in the subcutaneous white adipose tissue was enhanced, leading to high free fatty acid and glycerol serum levels. HFHFr males presented hypertriglyceridemia, but not hepatic steatosis, partially due to enhanced liver PPARα-related fatty acid β-oxidation and the VLDL-promoting effect of leptin. In conclusion, the SD rats showed a sex-related dimorphic response to the HFHFr diet. Contrary to previous results for HFHFr female rats, the male rats were able to expand the adipose tissue, increase fatty acid catabolism, or export it as VLDL, avoiding liver lipid deposition. Full article