Binge eating promotes ethanol self-administration in female rats with a history of intermittent ethanol exposure at adolescence.

BACKGROUND: Ethanol drinking begins during adolescence and, particularly when occurs in a binge-like pattern, exerts lingering adverse consequences. Pre-clinical studies indicate that intermittent ethanol exposure (IEA, a model of repeated ethanol intoxication), or binge eating (BE) can increase subsequent ethanol consumption. It is unknown if the promoting effects of BE upon ethanol drinking are found in female rats and are modulated by IEA at adolescence. This study assessed interactive effects between IEA and BE, upon ethanol drinking. METHODS: Female Wistar rats were given 4.0 g/kg ethanol, every other day from postnatal day 25-45. At adulthood, they were exposed to sessions in which a brief offering of a sizeable portion of highly palatable sugary pills was followed by a 120-min exposure to an ethanol bottle. RESULTS: Exploratory activity and recognition memory was not affected by the IEA. Glutathione peroxidase and catalase activity, and lipid peroxidation (measured in blood and brain at the end of the procedure) were not significantly affected by IEA or BE exposure. BE alone had a mild promoting effect on ethanol ingestion. Those rats that underwent IEA and BE, however, exhibited heightened and sustained ethanol self-administration (average of 2.12 g/kg/120 min, vs 1.15 g/kg/120 min of the other groups), that persisted throughout the BE sessions. IEA and a history of BE also promoted ethanol intake or preference in a two-bottle endpoint test. CONCLUSION: The study suggests that exposure to IEA exerts, when followed by BE at adulthood, promoting effects upon ethanol intake, particularly at concentrations ≥ 6%.

Minocycline prevents chronic restraint stress-induced vulnerability to developing cocaine self-administration and associated glutamatergic mechanisms: a potential role of microglia.

Stressful experience-induced cocaine-related behaviors are associated with a significant impairment of glutamatergic mechanisms in the Nucleus Accumbens core (NAcore). The hallmarks of disrupted glutamate homeostasis following restraint stress are the enduring imbalance of glutamate efflux after a cocaine stimulus and increased basal concentrations of extracellular glutamate attributed to GLT-1 downregulation in the NAcore. Glutamate transmission is tightly linked to microglia functioning. However, the role of microglia in the biological basis of stress-induced addictive behaviors is still unknown. By using minocycline, a potent inhibitor of microglia activation with anti-inflammatory properties, we determined whether microglia could aid chronic restraint stress (CRS)-induced glutamate homeostasis disruption in the NAcore, underpinning stress-induced cocaine self-administration. In this study, adult male rats were restrained for 2 h/day for seven days (day 1-7). From day 16 until completing the experimental protocol, animals received a vehicle or minocycline treatment (30 mg/Kg/12h i.p.). On day 21, animals were assigned to microscopic, biochemical, neurochemical or behavioral studies. We confirm that the CRS-induced facilitation of cocaine self-administration is associated with enduring GLT-1 downregulation, an increase of basal extracellular glutamate and postsynaptic structural plasticity in the NAcore. These alterations were strongly related to the CRS-induced reactive microglia and increased TNF-α mRNA and protein expression, since by administering minocycline, the impaired glutamate homeostasis and the facilitation of cocaine self-administration were prevented. Our findings are the first to demonstrate that minocycline suppresses the CRS-induced facilitation of cocaine self-administration and glutamate homeostasis disruption in the NAcore. A role of microglia is proposed for the development of glutamatergic mechanisms underpinning stress-induced vulnerability to cocaine addiction.

Learning experiences comprising central ethanol exposure in rat neonates: Impact upon respiratory plasticity and the activity of brain catalase.

Fetal ethanol exposure represents a risk factor for sudden infant death syndrome, and the respiratory effects of fetal ethanol exposure promote hypoxic ischemic consequences. This study analyzes central ethanol's effects upon breathing plasticity during an ontogenetic stage equivalent to the human third gestational trimester. Ethanol's unconditioned breathing effects and their intervention in learning processes were examined. Since central ethanol is primarily metabolized via the catalase system, we also examined the effects of early history with the drug upon this system. During postnatal days 3, 5, and 7 (PDs 3-7), pups were intracisternally administered with vehicle or ethanol (300 mg%). They were tested in a plethysmograph scented or not scented with ethanol odor. The state of intoxication attenuated the onset of apneas, a phenomenon that is suggestive of ethanol's anxiolytic effects given the state of arousal caused by the novel environment and the stress of ethanol administration. At PD9, pups were evaluated when sober under sequential air conditions (initial-normoxia, hypoxia, and recovery-normoxia), with or without the presence of ethanol odor. Initial apneic episodes increased when ethanol intoxication was previously associated with the odor. Pups then ingested ethanol, and brain catalase activity was determined. Pre-exposure to ethanol intoxication paired with the odor of the drug resulted in heightened enzymatic activity. Central ethanol exposure appears to exert antianxiety effects that attenuate apneic disruptions. However, during withdrawal, the cues associated with such effects elicit an opposite reaction. The activity of the catalase system was also dependent upon learning processes that involved the association of environmental stimuli and ethanol intoxication.

Brain ethanol-metabolizing enzymes are differentially expressed in lead-exposed animals after voluntary ethanol consumption: Pharmacological approaches.

Developmentally-lead (Pb)-exposed rats showed an enhanced vulnerability to the stimulating and motivational effects of ethanol (EtOH). This is accompanied by differential activity of the brain EtOH-metabolizing enzymes catalase (CAT) and mitochondrial aldehyde dehydrogenase (ALDH2). Based on the theory that brain acetaldehyde accumulation is associated with the reinforcing properties of EtOH, this study sought to determine brain CAT and ALDH2 expression in limbic areas of control and Pb-exposed animals after voluntary EtOH intake. Thirty-five-day-old rats perinatally exposed to 220 ppm Pb were offered with water or increasing EtOH solutions (2-10% v/v) during 28 days until postnatal day (PND) 63. Once intake was stable, the animals were administered: 1) saline (SAL; test days 21-24 or 21-28, as corresponds), or 2) a CAT inhibitor: 3-amine 1, 2, 4-triazole (AT; 250 mg/kg intraperitoneally [i.p.], 5 h before the last eight EtOH intake sessions -test days 21-24 and 25-28), or 3) a CAT booster: 3-nitropropionic acid (3NPA; 20 mg/kg subcutaneously [s.c.], 45 min before the last four EtOH intake sessions -test days 25-28). Two additional groups were centrally-administered cyanamide (CY, an ALDH2 inhibitor, 0.3 mg i.c.v. immediately before the last four EtOH sessions, test days 25-28) or its corresponding vehicle (VEH). Lead exposure increased EtOH intake, an effect potentiated in both groups by 3NPA or CY pretreatments and reduced by AT, albeit selectivity in the Pb group. Catalase abundance in limbic areas parallels these observations in the Pb group, showing higher CAT expression in all areas after EtOH consumption respect to the controls, an effect prevented by AT administration. In contrast, ALDH2 expression was reduced in the Pb animals after EtOH intake, with CY potentiating this effect in all brain areas under study. Based on these results and on previous evidences, we suggest that Pb exposure promotes acetaldehyde accumulation in limbic regions, providing some insights into the mechanism of action that underlies the vulnerability to the excessive EtOH consumption reported in these animals.

Phenolics composition, antioxidant properties and toxicological assessment of Prosopis alba exudate gum.

The objective of this work was to deepen on the study of functional properties of the phytochemicals present in Prosopis alba exudate gum (G), as well as to rule out possible adverse effects of some of its components. Commonly employed purification methods were compared. Filtration prevents further loss of potentially bioactive compounds. The filtrated gum showed a higher concentration of phenolics, flavonoids and tannins than arabic gum, which was correlated with better in vitro antioxidant properties. Particularly, tannins, commonly considered as toxic compounds in exudate gums, were found in lower concentration than in others gums obtained from genus Prosopis and Acacia. The toxicological evaluation performed on rats did not show symptoms of intoxication associated with the administration of the gum. These results provide useful evidence to support the potential use of G as a safe functional food additive with the added benefit of taking advantage of a non-exploited natural resource.

Silencing brain catalase expression reduces ethanol intake in developmentally-lead-exposed rats.

Lead (Pb) is a developmental neurotoxicant. We have demonstrated that perinatally Pb-exposed rats consume more ethanol than their control counterparts, a response that seems to be mediated by catalase (CAT) and centrally-formed acetaldehyde, ethanol's first metabolite with attributed reinforcing effects in the brain. The present study sought to disrupt ethanol intake (2-10% ethanol v/v) in rats exposed to 220 ppm Pb or filtered water during gestation and lactation. Thus, to block brain CAT expression, a lentiviral vector coding for a shRNA against CAT (LV-antiCAT vector) was microinfused in the posterior ventral tegmental area (pVTA) either at the onset or towards the end of a chronic voluntary ethanol consumption test. At the end of the study, rats were euthanized and pVTA dissected to measure CAT expression by Western blot. The LV-antiCAT vector administration not only reversed, but also prevented the emergence of the elevated ethanol intake reported in the perinatally Pb-exposed animals, changes that were supported by a significant reduction in CAT expression in the pVTA. These results provide further evidence of the crucial role of this enzyme in the reinforcing properties of ethanol and in the impact of the perinatal Pb programming to challenging events later in life.

Aldehyde dehydrogenase 2 in the spotlight: The link between mitochondria and neurodegeneration.

Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity.

Flavonoids as protective agents against oxidative stress induced by gentamicin in systemic circulation. Potent protective activity and microbial synergism of luteolin.

The flavonoids effect on gentamicin (GEN)-induced oxidative stress (OS) in systemic circulation was evaluated in terms of reactive oxygen species (ROS) production, enzymatic antioxidant defenses superoxide dismutase (SOD) and catalase (CAT), and lipid peroxidation (LP) in vitro on human leukocytes and in vivo on rat whole blood. The inhibitory activity of ROS was ATS < QTS < isovitexin < vitexin < luteolin. Luteolin, the most active, showed more inhibition in ROS production than vitamin C (reference inhibitor) in mononuclear cells and a slightly lower protective behavior compared to this inhibitor in polymorphonuclear cells. In both cellular systems, luteolin tends to level SOD and CAT activities modified by GEN, reaching basal values and preventing LP. In Wistar rats, GEN plus luteolin can suppress ROS generation, collaborate with SOD and CAT and diminish LP produced by GEN at therapeutic doses. Finally, luteolin and antibiotic association was evaluated on the antimicrobial activity in S. aureus and E. coli showing a synergism between GEN and luteolin on S. aureus ATCC and an additive effect on E. coli ATCC. Therefore, simultaneous administration of luteolin and GEN could represent a potential therapeutic option capable of protecting the host against OS induced by GEN in the systemic circulation while enhancing the antibacterial activity of GEN.

Developmental lead exposure induces opposite effects on ethanol intake and locomotion in response to central vs. systemic cyanamide administration.

Lead (Pb) is a developmental neurotoxicant that elicits differential responses to drugs of abuse. Particularly, ethanol consumption has been demonstrated to be increased as a consequence of environmental Pb exposure, with catalase (CAT) and brain acetaldehyde (ACD, the first metabolite of ethanol) playing a role. The present study sought to interfere with ethanol metabolism by inhibiting ALDH2 (mitochondrial aldehyde dehydrogenase) activity in both liver and brain from control and Pb-exposed rats as a strategy to accumulate ACD, a substance that plays a major role in the drug's reinforcing and/or aversive effects. To evaluate the impact on a 2-h chronic voluntary ethanol intake test, developmentally Pb-exposed and control rats were administered with cyanamide (CY, an ALDH inhibitor) either systemically or intracerebroventricularly (i.c.v.) on the last 4 sessions of the experiment. Furthermore, on the last session and after locomotor activity was assessed, all animals were sacrificed to obtain brain and liver samples for ALDH2 and CAT activity determination. Systemic CY administration reduced the elevated ethanol intake already reported in the Pb-exposed animals (but not in the controls) accompanied by liver (but not brain) ALDH2 inactivation. On the other hand, a 0.3 mg i.c.v. CY administration enhanced both ethanol intake and locomotor activity accompanied by brain ALDH2 inactivation in control animals, while an increase in ethanol consumption was also observed in the Pb-exposed group, although in the absence of brain ALDH2 blockade. No changes were observed in CAT activity as a consequence of CY administration. These results support the participation of liver and brain ACD in ethanol intake and locomotor activity, responses that are modulated by developmental Pb exposure.

Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity.

We have evaluated the effect of gentamicin and gentamicin plus quercetin on ROS production, endogenous antioxidant defenses (SOD and CAT) and lipid peroxidation in vitro on human leukocytes and in vivo on whole rat blood. Gentamicin generated ROS production in human leukocytes, produced a dual effect on both enzymes dosage-dependent and generated an increase in lipid peroxidation. Quercetin, in leukocytes stimulated by gentamicin, showed more inhibitory capacity in ROS production than the reference inhibitor (vitaminC) in mononuclear cells and a similar protective behavior at this inhibitor in polymorphonuclear cells. Quercetin, in both cellular systems, tend to level SOD and CAT activities, reaching basal values and could prevent lipidic peroxidation induced by gentamicin. The results in Wistar rats confirmed that therapeutic doses of gentamicin can induce oxidative stress in whole blood and that the gentamicin treatment plus quercetin can suppress ROS generation, collaborate with SOD and CAT and diminish lipid peroxidation. Finally, flavonoid and antibiotic association was evaluated on the antimicrobial activity in S. aureus and E. coli, showing that changes were not generated in the antibacterial activity of gentamicin against E. coli strains, while for strains of S. aureus a beneficial effect observes. Therefore, we have demonstrated that gentamicin could induce oxidative stress in human leukocytes and in whole blood of Wistar rats at therapeutic doses and that quercetin may to produce a protective effect on this oxidative stress generated without substantially modifying the antibacterial activity of gentamicin against E. coli strains, and it contributes to this activity against S. aureus strains.

El estres oxidativo como mecanismo de accion del plomo. Implicancias terapeuticas / Oxidative stress as a mechanism of action of lead. Therapeutic implications

El plomo (Pb) es un metal no esencial altamente toxico que afecta a diversos organos y tejidos. Si bien aun no ha sido descripto un mecanismo unico mediante el cual este metal ejerce sus efectos toxicos, un gran numero de estudios han puesto en evidencia el rol fundamental del estres oxidativo en la intoxicacion por Pb. A este respecto, ha sido informado que en la intoxicaci¨®n por Pb el estres oxidativo puede ocurrir a diferentes niveles: por generacion de acido ¦Ã-aminolevulinico (¦Ã-ALA), por la capacidad per se que posee el Pb para inducir peroxidacion lipidica en presencia de ion ferroso (Fe2+), o por deplecion de glutati¨®n (GSH) y enzimas antioxidantes. Sobre la base de estos antecedentes, el objetivo de esta revision es presentar evidencias recientes sobre la implicancia del estres oxidativo en los efectos adversos ocasionados por Pb, destacar la posibilidad de utilizacion de biomarcadores de estres oxidativo como un metodo complementario al diagnostico temprano de exposicion y revelar la importancia de los compuestos antioxidantes como nuevas herramientas en la prevencion y tratamiento de la intoxicacion por este metal.

Lead (Pb) is a highly toxic non-essential metal that affects different organs and tissues. Although at the present a unique mechanism by which this metal exerts its toxic effects has not been described, a large number of studies have highlighted the fundamental role of oxidative stress in the pathophysiology of Pb poisoning. In this regard, it has been reported that Pb-induced oxidative stress can occur at different levels: by the generation of ¦Ã-aminolevulinic acid (¦Ã-ALA), through its ability to induce lipid peroxidation in the presence of ferrous ion (Fe2+), or via glutathione (GSH) or antioxidant enzyme depletion. On the basis of these antecedents, the aim of this review is to present recent evidence regarding the implication of oxidative stress in the adverse effects caused by Pb, to emphasize the possibility to use oxidative stress biomarkers as a complementary method for early detection of Pb exposure, and to reveal the importance of antioxidant compounds as novel tools in the prevention and treatment of Pb exposure.