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Acute alcohol effects may differ in social drinkers with a positive family history of alcohol use disorders (FHP) compared to FH negative (FHN) controls.To investigate whether FHP subjects prefer higher levels of brain alcohol exposure than do FHN controls.Twenty-two young healthy nondependent social drinkers participated in two identical sessions of computer-assisted self-infusion of ethanol (CASE); the first for practicing the procedures, the second to test hypotheses. All 12 FHP (four women) and ten FHN (three women) participants received a priming exposure, increasing arterial blood alcohol concentration (aBAC) to 30 mg% at 10 min and decreasing it to 15 mg% at 25 min. A 2-h self-administration period followed, during which only the subjects could increase their aBAC by pressing a button connected to a computer controlling the infusion pump. Infusion rate profiles were calculated instantaneously to increase aBAC by precisely 7.5 mg% within 2.5 min after each button press, followed by a steady descent. Subjects were instructed to produce the same alcohol effects as they would do at a weekend party.The mean and maximum aBAC during the self-administration period and the number of alcohol requests (NOAR) were significantly higher in the FHP vs. FHN participants.This is the first laboratory experiment demonstrating higher alcohol self-administration in FHP compared to FHN subjects. A practice session increases the sensitivity of CASE experiments for detection of subtle differences in human alcohol self-administration.

AbstractThe mood‐altering properties of alcohol are a key motivation for drinking, and people commonly report that they drink alcohol to alleviate stress or to relax. To date, the neural processes associated with the self‐reported calming effects of alcohol are not well understood. Existing data imply that alcohol may target and disrupt activity within anterior insula (aINS) and amygdala‐based neural networks, which are regions implicated in threat detection and anxious responding. The aims of the current study were (1) to examine the acute effect of alcohol upon functional connectivity within aINS and amygdala circuits and (2) to assess relationships between alcohol effects on functional connectivity and self‐reported subjective mood. Healthy men and women (N = 39) who reported regular binge drinking completed a within‐subjects, double‐blind, placebo‐controlled pharmacological functional magnetic resonance imaging experiment with i.v. infusions of either alcohol or placebo. Infusion profiles were personalized for each participant and raised breath alcohol concentration to 80 mg percent. Before, during and after infusions, participants rated their subjective mood (stimulation, sedation and calm). Results showed that alcohol dampened functional connectivity between bilateral aINS seed‐regions‐of‐interest and the dorsal anterior cingulate cortex (dACC), key nodes of the salience network. Additionally, the more that alcohol reduced right aINS‐dACC functional connectivity, the calmer participants felt during alcohol administration. Alcohol had no effect on amygdala functional connectivity. These findings suggest that alcohol disrupts aINS‐dACC functional connectivity, which may impair detection and appraisal of emotionally salient information and relate to acute relaxing effects of the drug.

Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [11C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol's transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [11C]PBR28 binding. [11C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [11C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [11C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [11C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [11C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.

Abstract Background A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. Results Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. Conclusions Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence.

To explore the time of day effects of alcohol on sleep, we examined sleep following alcohol administered at four times of day and three homeostatic loads during a 20-hr forced desynchrony (FD) protocol.Twenty-six healthy young adults (21-25 yrs) were studied.Participants were dosed at 4 clock times: 0400 (n = 6; 2 females), 1600 (n = 7; 4 females), 1000 (n = 6; 1 female) or 2200 (n = 7; 2 females). Participants slept 2300 to 0800 for at least 12 nights before the in-lab FD study. Double blind placebo and alcohol (vodka tonic targeting 0.05g% concentration) beverages were each administered three times during FD at different homeostatic loads: low (4.25 or 2.24 hrs awake), medium (8.25 or 6.25 hrs awake), high (12.25 or 10.25 hrs awake) in the 0400 and 1600 or 1000 and 2200 groups, respectively. Sleep was staged and subjected to spectral analysis.Breath Alcohol Concentration (BrAC) confirmed targeted maximal levels. At bedtime, BrAC was 0 in the low and medium homeostatic load conditions; however, at high homeostatic load, BrAC was still measurable. Spectral characteristics of sleep were unaffected with alcohol at any time of day. Few alcohol related changes were seen for sleep stages; however, with alcohol given at 0400 at a high homeostatic load there was an increase in wake.These data lend support to the idea that alcohol may be disruptive to sleep; however, our findings are inconsistent with the idea that a low dose of alcohol is a useful sleep aid when attempting to sleep at an adverse circadian phase.

We used positron emission tomography imaging with [11C]raclopride to examine the effects of consumption of alcohol or placebo beverage by participants with alcohol use disorder (AUD) compared with healthy participants with and without family history of AUD. We sought to assess dopamine release following alcohol exposure in relation to AUD risk.Three groups were enrolled: participants with AUD (n = 15) and healthy participants with family history negative (n = 34) or positive (n = 16) for AUD. Participants consumed a placebo (n = 65) or alcohol (n = 63) beverage in counterbalanced order before positron emission tomography scanning (128 scans). Binding potential (BPND) in the two drink conditions and the percent change in BPND between conditions were evaluated across striatal subregions. Subjective effects of beverage consumption were rated. Effects of group, drink order, and sex were evaluated.Alcohol resulted in greater dopamine release than did placebo in the ventral striatum (p < .001). There were no main effects of group, drink order, or sex on ventral striatum BPND or percent change in BPND. However, there was a drink order-by-group interaction (p = .02) whereby family history-positive participants who received placebo first had both lower placebo BPND and less difference between placebo and alcohol BPND than all other groups, consistent with expectation of alcohol powerfully evoking dopamine release in this group. Subjective responses showed the same order-by-group interaction.Hyper-responsivity of the dopaminergic system in family history-positive participants to expectation of alcohol may contribute to the expression of familial risk for AUD.

Individuals who experience greater stimulation and less sedation from alcohol are at increased risk for alcohol-related problems. However, little is known regarding the neurobiological mechanisms underlying subjective response to alcohol. The current study examined the degree to which alcohol-induced brain activation correlates with ratings of stimulation and sedation, using a within-subjects, double-blind, placebo-controlled design. Participants (N = 34 healthy adults with no history of alcohol use disorder) completed three sessions: a calibration session to determine the duration of infusion needed to bring the breath alcohol to 80 mg/dl for each subject, and two counterbalanced fMRI sessions with placebo and alcohol administration. During the fMRI sessions, participants underwent 50 min scans, which included a 10 min baseline period, the IV infusion period needed to bring breath alcohol concentration (BrAC) to a peak 80 mg/dl (on the alcohol session), followed by a post-peak decline period. Participants rated their subjective stimulation and sedation at regular intervals throughout the scan. A priori VOI analyses showed that the time course of stimulation correlated with BOLD signal in the striatum. The time course of sedation did not correlate with BOLD signal in any VOIs. There were no correlations in primary visual cortex, which served as a control. These findings are the first to show that alcohol effects in the striatum are linked to the positive, stimulant-like effects of the drug and advance our understanding of the neurobiological mechanisms underlying individual differences in subjective responses to alcohol, and more broadly, risk for alcohol use disorders.