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Prenatal ethanol exposure produces severe changes in brain, liver, and kidney through mechanisms involving growth factors. These molecules regulate survival, differentiation, maintenance, and connectivity of brain, liver, and kidney cells. Despite the abundant available data on the short and mid-lasting effects of ethanol intoxication, only few data show the long-lasting damage induced by early ethanol administration. The aim of this study was to investigate changes in nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) in brain areas, liver, and kidney of 18-mo-old male mice exposed perinatally to ethanol at 11% vol or to red wine at the same ethanol concentration. The authors found that ethanol per se elevated NGF, BDNF, HGF, and VEGF measured by ELISA in brain limbic system areas. In the liver, early exposure to ethanol solution and red wine depleted BDNF and VEGF concentrations. In the kidney, red wine exposure only decreased VEGF. In conclusion, the present study shows that, in aged mice, early administration of ethanol solution induced long-lasting damage at growth factor levels in frontal cortex, hippocampus, and liver but not in kidney. Otherwise, in mice exposed to red wine, significant changes were observed in the liver and kidney but not in the hippocampus and frontal cortex. The brain differences in ethanol-induced toxicity when ethanol is administered alone or in red wine may be related to compounds with antioxidant properties present in the red wine.

The effects of maternal ethanol consumption for 4 weeks before and throughout gestation on polyamine content and diamine oxidase activity of maternal, embryonal and fetal tissues are reported. At the 12th day of pregnancy, a decrease of putrescine in the liver of the mother and marked increases in putrescine, cadaverine and spermidine in embryos were observed. At day 18, putrescine and cadaverine diminished in maternal liver and placenta, and no changes in amine content in fetal liver and brain were found. At day 12, diamine oxidase activity increased in maternal liver and placenta, whereas it greatly diminished in embryos. At day 18, enzyme activity decreased in maternal liver, placenta, fetal liver and brain. These results indicate that chronic ethanol ingestion induces alterations in polyamine concentrations and metabolism in growing and developing tissues during pregnancy that might contribute to the adverse effect of ethanol on conceptual development.

A growing body of evidence indicates that the practice of consuming alcohol mixed with energy drinks (ED) (AMED) in a binge drinking pattern is significantly diffusing among the adolescent population. This behavior, aimed at increasing the intake of alcohol, raises serious concerns about its long-term effects. Epidemiological studies suggest that AMED consumption might increase vulnerability to alcohol abuse and have a gating effect on the use of illicit drugs. The medial prefrontal cortex (mPFC) is involved in the modulation of the reinforcing effects of alcohol and of impulsive behavior and plays a key role in the development of addiction. In our study, we used a binge-like protocol of administration of alcohol, ED, or AMED in male adolescent rats, to mimic the binge-like intake behavior observed in humans, in order to evaluate whether these treatments could differentially affect the function of mesocortical dopaminergic neurons in adulthood. We did so by measuring: i) physiological sensorimotor gating; ii) voluntary alcohol consumption and dopamine transmission before, during, and after presentation of alcohol; iii) electrophysiological activity of VTA dopaminergic neurons and their sensitivity to a challenge with alcohol. Our results indicate that exposure to alcohol, ED, or AMED during adolescence induces differential adaptive changes in the function of mesocortical dopaminergic neurons and, in particular, that AMED exposure decreases their sensitivity to external stimuli, possibly laying the foundation for the altered behaviors observed in adulthood.

Acetaldehyde (ACD) has been postulated to mediate some of the neurobehavioral effects of ethanol (EtOH). In this study we sought to evaluate whether the stimulatory effects of EtOH on mesolimbic dopamine (DA) transmission are affected by the administration of ACD-sequestering agent D-penicillamine (Dp). To this end we studied the effect of EtOH and ACD in the rat mesoaccumbens pathway by in vivo microdialysis in the nucleus accumbens shell (NAccs), and by single cell extracellular recordings from antidromically identified mesoaccumbens DA neurons in the ventral tegmental area (VTA). Both EtOH (1g/kg) and ACD (20mg/kg) administration increased DA levels in the NAccs and increased the activity of mesoaccumbens DA neurons. Pretreatment with Dp (50mg/kg i.p. 1h before drug challenge) prevented both EtOH- and ACD-induced stimulation of the DA mesolimbic system without affecting morphine stimulatory actions. These observations add further support to the notion that EtOH-derived ACD stimulates the mesolimbic DA system and is essential in EtOH-induced stimulation of the DA mesoaccumbens system. We conclude that modulation of ACD bioavailability may influence the addictive profile of EtOH by decreasing its psychotropic effects and possibly leading the way to new pharmacological treatments of alcoholism.

Background: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention. Objective: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure. Methods: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways. Results: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns. Conclusion: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present in vivo brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. As a consequence of the oral administration of a pharmacologically relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product of condensation between DA and ethanol’s first by-product, acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via μ opioid receptor (μOR) stimulation. In fact, inhibition of salsolinol’s generation in the pVTA or blockade of pVTA μORs prevents ethanol-increased ipsilateral, but not contralateral, AcbSh DA release. This evidence discloses the long-sought key mechanism of ethanol’s addictive potential and suggests the grounds for developing preventive and therapeutic strategies against abnormal consumption.

Naltrindole, a specific delta-opioid antagonist, infused by reverse dialysis in the nucleus accumbens of freely moving rats completely prevented the increase in extracellular dopamine concentrations elicited in the nucleus accumbens by ethanol (1.0 g/kg i.p.) as well as by the delta-opioid receptor agonist [D-Ala2]deltorphin II (50 microM), also perfused by reverse dialysis, but not by cocaine (15 mg/kg s.c.). The results provide in vivo evidence for a critical role of delta-opioid receptors in the dopamine-releasing properties of ethanol in vivo.

For several decades, genetically selected alcohol-preferring rats have been successfully used to mimic and study alcohol use disorders (AUD). These rat lines have been instrumental in advancing our understanding of the neurobiology of alcoholism and enabling pharmacological studies to evaluate drug efficacy on alcohol drinking and relapse. Moreover, the results of these studies have identified genetic variables that are linked to AUD vulnerability. This is an up-to-date review that focuses on genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. To support the translational relevance of the findings that are obtained from msP rats and highlight important similarities to AUD patients, we also discuss the results of recent brain imaging studies. Finally, to demonstrate the importance of studying sex differences in animal models of AUD, we present original data that highlight behavioral differences in the response to alcohol in male and female rats. Female msP rats exhibited higher alcohol consumption compared with males. Furthermore, msP rats of both sexes exhibit higher anxiety- and depressive-like behaviors in the elevated plus maze and forced swim test, respectively, compared with unselected Wistar controls. Notably, voluntary alcohol drinking decreases foot-shock stress and depressive-like behavior in both sexes, whereas anxiety-like behavior in the elevated plus maze is attenuated only in males. These findings suggest that male and female msP rats both drink high amounts of alcohol to self-medicate negative affective symptoms. For females, this behavior may be driven by an attempt to treat stress and depressive-like conditions. For males, generalized anxiety appears to be an important additional factor in the motivation to drink alcohol. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'