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AbstractObjective: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose.Research Methods and Procedures: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice.Results: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern.Discussion: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

This study is divided into two parts; each designed to answer a separate but related question: Which brain regions are activated in humans by the rewarding properties of ethanol administration? Is it possible to demonstrate a conditioned response to a stimulus paired with rising blood alcohol concentrations (BAC) in humans and can this response be observed in the brain using functional magnetic resonance images (fMRI) techniques? Part 1. In order to determine which brain regions are activated by the rewarding properties of ethanol administration, we propose to use Blood Oxygenation Level Dependent (BOLD) fMRI techniques to test the hypothesis that during the time of rising and peak BAC, mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain will show significant increases in cerebral blood flow. Healthy, non-alcoholic subjects will be given intravenous (IV) ethanol or placebo infusions on separate days. The infusions will have three phases. On each day, during the first phase a saline infusion will be used to measure basal brain blood flow. The second phase will be an ethanol infusion delivered at rates calculated to produce a BAC of 0.08 plus or minus 0.005 g/dl at 10 minutes. The rate of the infusion for the next 10 minutes (third phase) will be calculated to maintain BAC at the target level of 0.08 plus or minus 0.005 g/dl for the duration of the infusion. On the placebo day, subjects will receive a saline infusion at the same set of rates for phases two and three as used during their ethanol infusion. Continuous multi-slice fMRI data will be collected during each infusion. Part 2. In order to investigate conditioned response to ethanol, three groups of healthy, non-alcoholic subjects will be given a series of IV infusions on separate days. The experimental group will receive ethanol infusion paired with a conditioned stimulus (CS) which will be presented while the BAC is rising. One control group (I) of healthy, non-alcoholic subjects will also be given a series of intravenous ethanol infusions on separate days, but these infusions will not be paired with a CS. The other control group (II) will be given only saline infusions during the CS presentation. After three training sessions, all three groups will undergo an fMRI scan during which the CS will be paired with saline infusion. This will allow the response to the CS alone to be observed. After 10 minutes of CS presentation, the ethanol infusion will begin and continue for another 15 minutes. Conditioned response (CR) will be demonstrated if the experimental group shows greater increase in BOLD signal than the control groups in motivation areas such as mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain in response to the CS while they receive the saline infusion. Control group II will also undergo an fMRI scan and will be given saline infusion followed by ethanol infusion during their last 15 minutes in the scanner to control for the non-specific effects of repeated infusions & scans on BOLD response to ethanol. If we are able to produce a CR in brain regions associated with motivation, it may be possible to use this CR as an experimental model for human alcohol craving. This study is designed to answer four questions: 1. Which brain regions are activated in humans by the rewarding properties of ethanol administration? 2. How does ethanol administration affect the brain response to visual cues known to evoke positive or negative emotion? 3. Do individuals who regularly drink in ethanol in large amounts (heavy drinkers) differ from individuals who do not regularly drink large amounts of ethanol (social drinkers) in how ethanol affects brain function? 4. Does ethanol administration affect the brain regions activated in a risk-taking task in social drinkers and heavy drinkers? In order to determine which brain regions are activated by the rewarding properties of ethanol administration, we propose to use Blood Oxygenation Level Dependent (BOLD) fMRI techniques to test the hypothesis that during the time of rising and peak BAC, mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain will show significant increases in cerebral blood flow. Healthy, subjects who are not seeking treatment for an alcohol use disorder will be given intravenous (IV) ethanol or placebo infusions on separate days. An ethanol infusion will delivered at rates calculated to produce a BAC of 0.08 plus or minus. An ethanol infusion will delivered at rates calculated to produce a BAC of 0.08 plus or minus 0.005 g/dl at 15 minutes. Then the rate of the infusion will be adjusted so that for the next 30 minutes (second phase) BAC will be maintained at the target level of 0.08 0.005 g/dl. On the placebo day, subjects will receive a saline infusion at the same set of rates as used during their ethanol infusion. Continuous multi-slice fMRI data will be collected during each infusion. During each infusion, BOLD response to visual stimuli designed to evoke emotion will also be examined. In addition, we will compare the BOLD response of healthy social drinkers to that of healthy heavy drinkers. We will also compare the BOLD response elicited by risk-taking during the ethanol infusion to that during the placebo infusion in both social and heavy drinkers.

Background:  A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed. Methods:  Forty‐nine drinking but not yet alcoholic matched pairs of 18‐ to 25‐year‐old subjects (N = 98; 53% women) with low and high LRs as established in separate alcohol challenges were evaluated in 2 event‐related functional magnetic resonance imaging (fMRI) sessions (placebo and approximately 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session. Results:  Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level–dependent (BOLD) signal during error and inhibitory processing, despite similar LR group performance on the task. In most clusters with significant (corrected p < 0.05, clusters > 1,344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition‐related activation after alcohol compared with placebo. Conclusions:  This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks of a future life‐threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk of future heavy drinking and alcohol dependence.

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1–0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003–0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1–3.0 mg/kg) and antagonist raclopride (0.01–0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6–2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.

The nucleus accumbens (NAc) is a ventral striatal structure underlying reward, reinforcement, and motivation, with extensive anatomic and functional connections to a wide range of affective processing structures (medial prefrontal cortex (mPFC), amygdala, and insula). Characterizing how acute alcohol intake affects resting state functional connectivity (rsFC) between the nucleus accumbens (NAc) and these regions will improve mechanistic understanding of alcohol's neurobehavioral effects, including the neural overlap between acute alcohol effects and pain processing.Fifteen healthy social drinkers (10 women; age: 25-45 years) were included in the study. Participants completed one session in which they consumed an alcohol dose targeting a breath alcohol concentration of 0.08 g/dL, and in a second a placebo beverage. Nine-minute resting state fMRI scans were acquired 30-35 min after beverage administration during each session. rsFC between NAc and a priori corticolimbic regions of interest (mPFC, amgydala, and insula), were compared between beverage conditions. We also conducted an exploratory whole-brain seed-to-voxel analysis of NAc FC.Alcohol intake reduced rsFC between NAc and mPFC, as well as NAc and amygdala. Alcohol also reduced rsFC between NAc and a 97-voxel cluster including bilateral paracingulate cortex and anterior cingulate cortex.Findings suggest that acute alcohol intake reduces rsFC between NAc and several structures, including mPFC, amygdala, and rostral ACC in healthy social drinkers. These structures underlie reward, motivated behavior, and emotion regulation, and may provide mechanistic insight to how alcohol affects related processes, including pain.

Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use.In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine.Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively.These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

Prenatal ethanol exposure is associated with, and is a risk factor for, developmental disorders with abnormal social behaviors, including autism spectrum disorders. We hypothesize that the specific effects of ethanol on social behavior are defined by the timing of the exposure as well as subsequent changes in brain regions such as the amygdala and ventral striatum. We recently reported that in utero ethanol exposure on gestational day 12 alters social behaviors of weanling [postnatal day (P) 28], adolescent (P42), and young adult (P75) rats. Male, but not female, offspring of the ethanol-exposed dams showed significant decreases in social investigation (sniffing of a social partner), contact behavior (grooming or crawling over/under the partner), and play fighting (following, chasing, nape attacks, or pinning) at all ages tested with maximal effects at P28 and P42. Furthermore, ethanol-exposed males and females showed evidence of social avoidance at P42 and P75. The present study sought to test whether a form of social enrichment could normalize any of the social deficits and what the molecular mechanisms of such effects might be. We found that housing rats with nonmanipulated control rats normalized the social avoidance phenotype normally seen when they are housed with sex-matched prenatal ethanol-exposed littermates. There was no mitigation of the other ethanol-induced behavioral deficits. Conversely, male control-treated rats housed with nonlittermates showed deficits in play fighting, social investigation and contact behavior. Molecular analyses of the amygdala and ventral striatum of adolescent rats following fetal ethanol exposure indicated several specific neurotransmitter systems and pathways that might underlie the social avoidance phenotype as well as its reversal.

The use of alcohol has been associated with both an increased risk of acquisition of HIV‐1 infection and an increased rate of disease progression among those already infected by the virus. The potential for alcohol to exacerbate the effects of HIV infection is especially important in the central nervous system (CNS) because this area is vulnerable to the combined effects of alcohol and HIV infection. The effects of alcohol on glial cells are mediated through receptors such as Toll‐like receptor 4 and N‐methyl‐d‐aspartate receptor. This causes the activation of signaling molecules such as interleukin‐1 receptor‐associated kinase and various members of the P38 mitogen‐activated protein kinase family and subsequent activation of transcription factors such as nuclear factor‐kappa beta and activator protein 1. The eventual outcome is an increase in pro‐inflammatory cytokine production by glial cells. Alcohol also induces higher levels of NADPH oxidase in glial cells, which leads to an increased production of reactive oxygen species (ROS). Viral invasion of the CNS occurs early after infection, and HIV proteins have also been demonstrated to increase levels of pro‐inflammatory cytokines and ROS in glial cells through activation of some of the same pathways activated by alcohol. Both cell culture systems and animal models have demonstrated that concomitant exposure to alcohol and HIV/HIV proteins results in increased levels of expression of pro‐inflammatory cytokines such as interleukin‐1 beta and tumor necrosis factor‐alpha, along with increased levels of oxidative stress. Clinical studies also suggest that alcohol exacerbates the CNS effects of HIV‐1 infection. This review focuses on the mechanisms by which alcohol causes increased CNS damage in HIV‐1 infection.

We have recently demonstrated that eight, daily flurothyl-induced generalized clonic seizures, followed by a four week stimulus-free interval, results in a long-lasting reduction in generalized seizure threshold and a change in the type of seizure expressed in response to flurothyl from clonic to tonic. There is a progressive increase in the probability that a mouse will express a tonic seizure during the four week interval, suggesting that prior flurothyl seizures initiate a proepileptogenic process that requires time to develop. In this study, the immunohistochemical detection of the c-fos protein (Fos) was used to evaluate whether seizure-induced epileptogenesis resulted in regional differences in the degree of neuronal activation. Fos immunoreactivity was examined 1.5 h following either a single generalized seizure, the last of eight consecutive daily seizures or a retest seizure evoked two weeks after the last of eight seizures. In each condition, generalized seizure behaviours were elicited in C57BL/6 mice using flurothyl and classified as either "forebrain" (face and forelimb clonus) or "brainstem" (running/bouncing, treading, tonic extension). The spatial distribution of Fos induction was compared on the basis of the seizure phenotype and the seizure history. The predominant differences in Fos distribution were found to be related to the type of seizure expressed regardless of the seizure history. Furthermore, the different motor components that make up a "brainstem" seizure could not be distinguished by the pattern of Fos labelling suggesting that multiple convulsive behaviours are mediated by one anatomical system. Finally, Fos induction in the ventromedial hypothalamic nucleus preceded and predicted the change in seizure type from "forebrain" to "brainstem". These data support the concept that separate anatomical systems mediate the expression of the two generalized seizure phenotypes. In addition, the ventromedial nucleus of the hypothalamus may be a point of interaction between the systems and may play a role in seizure-induced neural reorganization.

To establish a mouse model of alcohol-driven hepatocellular carcinoma (HCC) that develops in livers with alcoholic liver disease (ALD).Adult C57BL/6 male mice received multiple doses of chemical carcinogen diethyl nitrosamine (DEN) followed by 7 wk of 4% Lieber-DeCarli diet. Serum alanine aminotransferase (ALT), alpha fetoprotein (AFP) and liver Cyp2e1 were assessed. Expression of F4/80, CD68 for macrophages and Ly6G, MPO, E-selectin for neutrophils was measured. Macrophage polarization was determined by IL-1β/iNOS (M1) and Arg-1/IL-10/CD163/CD206 (M2) expression. Liver steatosis and fibrosis were measured by oil-red-O and Sirius red staining respectively. HCC development was monitored by magnetic resonance imaging, confirmed by histology. Cellular proliferation was assessed by proliferating cell nuclear antigen (PCNA).Alcohol-DEN mice showed higher ALTs than pair fed-DEN mice throughout the alcohol feeding without weight gain. Alcohol feeding resulted in increased ALT, liver steatosis and inflammation compared to pair-fed controls. Alcohol-DEN mice had reduced steatosis and increased fibrosis indicating advanced liver disease. Molecular characterization showed highest levels of both neutrophil and macrophage markers in alcohol-DEN livers. Importantly, M2 macrophages were predominantly higher in alcohol-DEN livers. Magnetic resonance imaging revealed increased numbers of intrahepatic cysts and liver histology confirmed the presence of early HCC in alcohol-DEN mice compared to all other groups. This correlated with increased serum alpha-fetoprotein, a marker of HCC, in alcohol-DEN mice. PCNA immunostaining revealed significantly increased hepatocyte proliferation in livers from alcohol-DEN compared to pair fed-DEN or alcohol-fed mice.We describe a new 12-wk HCC model in adult mice that develops in livers with alcoholic hepatitis and defines ALD as co-factor in HCC.