Brain proteomic atlas of alcohol use disorder in adult males.

Alcohol use disorder (AUD) affects transcriptomic, epigenetic and proteomic expression in several organs, including the brain. There has not been a comprehensive analysis of altered protein abundance focusing on the multiple brain regions that undergo neuroadaptations occurring in AUD. We performed a quantitative proteomic analysis using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of human postmortem tissue from brain regions that play key roles in the development and maintenance of AUD, the amygdala (AMG), hippocampus (HIPP), hypothalamus (HYP), nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral tegmental area (VTA). Brain tissues were from adult males with AUD (n = 11) and matched controls (n = 16). Across the two groups, there were >6000 proteins quantified with differential protein abundance in AUD compared to controls in each of the six brain regions. The region with the greatest number of differentially expressed proteins was the AMG, followed by the HYP. Pathways associated with differentially expressed proteins between groups (fold change > 1.5 and LIMMA p < 0.01) were analyzed by Ingenuity Pathway Analysis (IPA). In the AMG, adrenergic, opioid, oxytocin, GABA receptor and cytokine pathways were among the most enriched. In the HYP, dopaminergic signaling pathways were the most enriched. Proteins with differential abundance in AUD highlight potential therapeutic targets such as oxytocin, CSNK1D (PF-670462), GABAB receptor and opioid receptors and may lead to the identification of other potential targets. These results improve our understanding of the molecular alterations of AUD across brain regions that are associated with the development and maintenance of AUD. Proteomic data from this study is publicly available at www.lmdomics.org/AUDBrainProteomeAtlas/ .

Economic Value of Initial Implementation Activities for Proposed Ban on Sales of Over-The-Counter Diet Pills and Muscle-Building Supplements to Minors.

Introduction: Over-the-counter diet pills, weight-loss supplements, and muscle-building supplements often contain harmful ingredients and are associated with eating disorder diagnoses and other negative health outcomes. This study estimated the value of state initial implementation activities, for example, regulation development, to implement a ban on the sale of dangerous over-the-counter diet pills and muscle-building supplements to minors. Methods: We enumerated minimum, best, and maximum values for 22 inputs among 11 activities state employees may undertake if the legislation were signed into law. For employment costs, we estimated staff hours on the basis of data from 10 key informants and obtained salary ranges from a state government website. Data were collected and analyzed between September 2021 and January 2022. We calculated 95% CIs using 10,000 Monte Carlo simulations that varied inputs simultaneously and probabilistically. We conducted two sensitivity analyses using all minimum and all maximum salaries. Results: The estimated value of state start-up activities was $47,536 (95% CI=$36,831-$57,381). Inputs with the largest impact on this estimate corresponded to combinations of the highest salary and greatest hours per task. Conclusions: The state's one-time opportunity cost to initiate this age-restriction policy would be minimal considering potential health gains. Sensitivity analyses did not change the conclusion, especially if the state produces subregulations linked to existing law rather than new regulations.

Investigating the relationship between early life adversity, inflammation and alcohol use.

Early life adversity (ELA) has long-lasting and potentially harmful effects on adult mental and physical health, including a higher likelihood of developing psychiatric conditions such as depression, anxiety and alcohol use disorder (AUD). It has been suggested that inflammation may play a role in linking ELA to the development of AUD. Here, we evaluated a number of predictive factors of high sensitivity C-reactive protein (hsCRP), a key inflammatory marker, and the potential mediating role of hsCRP in the relationship between ELA and alcohol misuse in adulthood. Data was collected from participants who participated in NIAAA screening protocols between January 2013 and December 2019. In this secondary analysis, we first tested, via multiple linear regression, potential predictors of hsCRP levels among adults with AUD (N = 781) and non-AUD (N = 440) individuals. We subsequently conducted mediation analyses to evaluate the potential role of hsCRP in the relationship between early life stress and alcohol use. Regression analysis showed that stress in early life, but not childhood trauma, significantly predicted increased hsCRP levels in adulthood (p < 0.05). Additionally, a greater amount of alcohol drinking, but not a diagnosis of AUD, significantly predicted increased hsCRP levels (p < 0.05). Furthermore, hsCRP mediated the relationship between early life stress and alcohol consumption. Early life stress and heavier alcohol drinking both predicted increased hsCRP levels; however, an AUD diagnosis did not. Elevated inflammation, due to and/or predicted by greater early life stress, may contribute to the development of unhealthy alcohol use in adulthood.

Oxytocin receptors mediate oxytocin potentiation of methylphenidate-induced stimulation of accumbens dopamine in rats.

While the illicit use and misuse of stimulants like cocaine and methylphenidate (MP) has increased, there remains no FDA-approved treatments for psychostimulant use disorders (PSUD). Oxytocin (OT) has shown promise as a potential pharmacotherapy for PSUD. Dopamine (DA) neurotransmission plays a significant role in PSUD. We have recently shown that OT blunts the reinforcing effects of MP but, surprisingly, enhanced MP-induced stimulation of DA levels. Such effects have been suggested as a result of activation of OT receptors or, alternatively, could be mediated by direct actions of OT on MP blockade of the DA transporter. Here, we employed fast scan cyclic voltammetry (FSCV) to investigate the effects of systemic OT on MP-induced changes in the dynamics of DA, phasic release and uptake, in the nucleus accumbens shell (NAS) of Sprague-Dawley rats. We also tested the systemic effects of an antagonist of OT receptors, atosiban, to counteract the OT enhancement of dopaminergic effects of MP under microdialysis procedures in the NAS in rats. Administration of OT alone (2 mg/kg; i.p.) did not significantly modify evoked NAS DA dynamics measured by FSCV, and when administered 10 min before MP (0.1, 0.3, 1.0 mg/kg; i.v.), OT did not potentiate MP-induced increases in phasic DA release and did not alter DA clearance rate, suggesting no direct interactions of OT with the MP-induced blockade of DA uptake. Also, OT alone did not elicit significant changes in tonic, extracellular NAS DA levels measured by microdialysis. However, consistent with previous studies, we observed that OT pretreatments (2 mg/kg; i.p.) potentiated MP-induced (0.1, 0.3, 1.0 mg/kg; i.v.) efflux of extracellular NAS DA levels. This effect was abolished when rats were pretreated with atosiban (2 mg/kg; i.p.), suggesting that OT receptors mediate this OT action. Overall, our results suggest that OT receptors mediated OT potentiation of MP-induced stimulation of extracellular NAS DA levels, likely driven by modulation of DA receptor signaling pathways, without affecting MP blockade of DAT.

Corticotropin-Releasing Factor receptor 1 (CRF1) antagonism in patients with alcohol use disorder and high anxiety levels: effect on neural response during Trier Social Stress Test video feedback.

In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.

Advances in human oxytocin measurement: challenges and proposed solutions.

Oxytocin, a neuropeptide known for its role in reproduction and socioemotional processes, may hold promise as a therapeutic agent in treating social impairments in patient populations. However, research has yet to uncover precisely how to manipulate this system for clinical benefit. Moreover, inconsistent use of standardized and validated oxytocin measurement methodologies-including the design and study of hormone secretion and biochemical assays-present unresolved challenges. Human studies measuring peripheral (i.e., in plasma, saliva, or urine) or central (i.e., in cerebrospinal fluid) oxytocin concentrations have involved very diverse methods, including the use of different assay techniques, further compounding this problem. In the present review, we describe the scientific value in measuring human endogenous oxytocin concentrations, common issues in biochemical analysis and study design that researchers face when doing so, and our recommendations for improving studies using valid and reliable methodologies.

A closer look at alcohol-induced changes in the ghrelin system: novel insights from preclinical and clinical data.

Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.

Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking.

A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p's < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p's < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

Understanding identification-based trust in the light of affiliative bonding: Meta-analytic neuroimaging evidence.

Trust is vital for establishing social relationships and is a crucial precursor for affiliative bonds. Investigations explored the neuropsychological bases of trust separately (e.g., measured by the trust game) and affiliative bonding (e.g., measured by parental care, pair-bonding, or friendship). However, direct empirical support for the shared neural mechanisms between trust and affiliative bonding is missing. Here, we conducted a coordinate-based meta-analysis on functional magnetic resonance imaging studies on interpersonal trust and affiliative bonding using the activation likelihood estimation method. Our results demonstrated that decisions to trust strangers in repeated interactions (i.e., identification-based trust) engaged the ventral striatum (vSTR, part of the mesolimbic dopaminergic pathway), likely signaling the reward anticipation. Further, both feedbacks in repeated interactions and affiliative bonding engaged the dorsal striatum (dSTR, part of the nigrostriatal dopaminergic pathway), likely encoding learning dynamics. Our findings suggest that identification-based trust can be understood in the light of affiliative bonding, involving the mesocorticolimbic "reward" pathway (vSTR) and nigrostriatal "habit formation" pathway (dSTR) in building and sustaining social relationships.

Nasal oxytocin for the treatment of psychiatric disorders and pain: achieving meaningful brain concentrations.

There is evidence of the therapeutic potential of intranasal oxytocin for the treatment of pain and various psychiatric disorders, however, there is scant evidence that oxytocin reaches the brain. We quantified the concentration and distribution pattern of [125I]-radiolabeled oxytocin in the brains and peripheral tissues of rats after intranasal delivery using gamma counting and autoradiography, respectively. Radiolabel was detected in high concentrations in the trigeminal and olfactory nerves as well as in brain regions along their trajectories. Considerable concentrations were observed in the blood, however, relatively low levels of radiolabel were measured in peripheral tissues. The addition of a mucoadhesive did not enhance brain concentrations. These results provide support for intranasal OT reaching the brain via the olfactory and trigeminal neural pathways. These findings will inform the design and interpretation of clinical studies with intranasal oxytocin.

Effect of oral alcohol administration on plasma cytokine concentrations in heavy drinking individuals.

BACKGROUND: Alcohol is known to modulate the immune system, including cytokines, under conditions of both acute consumption and chronic use. The specific pro- and anti-inflammatory effects and mechanisms whereby alcohol consumption modulates circulating cytokine concentrations are not well understood. Few studies in humans have investigated the effect of acute alcohol consumption on plasma cytokine concentrations in individuals who are heavy drinkers. METHODS: Data were pooled from two studies involving a total of 25 non-treatment seeking, heavy drinking individuals who undertook an oral alcohol administration procedure. Plasma cytokine [Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-18 (IL-18) and Tumor Necrosis Factor-alpha (TNF-α)] concentrations were measured at two baseline timepoints, then three hours after alcohol administration, and finally when breath alcohol concentrations returned to zero. Linear mixed models were conducted to determine whether there was a significant effect of time on cytokine concentrations. RESULTS: There was a significant reduction in TNF-α concentration (F [3, 20.42] = 4.96, p = 0.01, η2p = 0.42) post alcohol administration, compared to baseline concentrations, and a significant increase in IL-6 concentrations (F [3, 27.81] = 9.06, p < 0.001, η2p = 0.49) post alcohol administration, compared to baseline. There were no significant changes in IL-18 or IL-10 concentrations. CONCLUSIONS: To our knowledge, this is the first study to examine the acute effect of oral alcohol consumption on peripheral inflammatory markers in individuals with alcohol use disorder. Results indicate a clinically relevant increase in proinflammatory cytokines approximately 3 h after initial alcohol ingestion. Further research should be done to elucidate the complex interaction between alcohol and the immune system.

Neuroendocrine Response to Exogenous Ghrelin Administration, Combined With Alcohol, in Heavy-Drinking Individuals: Findings From a Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

BACKGROUND: Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals. METHODS: This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol clamp. Each paradigm consisted of 2 counterbalanced sessions of i.v. ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1, pancreatic polypeptide, gastric inhibitory peptide, insulin, insulin-like growth factor-1, cortisol, prolactin, and aldosterone. RESULTS: Despite some statistical differences, findings were consistent across the 2 alcohol administration paradigms: i.v. ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1, pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session. CONCLUSION: These findings, gathered from a clinically relevant sample of heavy-drinking individuals with alcohol use disorder, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.

A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation.

Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen's effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3,9 = 6.03, p = 0.01; alcohol sedation: F3,6 = 7.16, p = 0.01) on the total amount of alcohol self-administered. Considerable interindividual variability in baclofen pharmacokinetic parameters was observed. Maximum plasma concentrations of baclofen negatively correlated with cue-induced alcohol craving (r = -0.57, p = 0.03) and priming-induced ratings of 'like more' (r = -0.59, p = 0.02). In conclusion, baclofen may work by dissociating the link between an initial drink (priming) and subsequent alcohol consumption (self-administration). Considerable pharmacokinetic variability is an important factor to take into account when employing baclofen as a treatment for alcohol use disorder.

Oxytocin and the Neurobiology of Prosocial Behavior.

Humans are an unusually prosocial species, who engage in social behaviors that include altruism-whereby an individual engages in costly or risky acts to improve the welfare of another person-care, and cooperation. Current perspectives on the neurobiology of human prosociality suggest that it is deeply rooted in the neuroendocrine architecture of the social brain and emphasize the modulatory role of the neuropeptide hormone oxytocin. In this review, we provide a conceptual overview of the neurobiology of prosocial behavior with a focus on oxytocin's modulatory role in human prosociality. Specifically, we aim to encourage a better understanding of the peptide's susceptibility to diverse factors that produce heterogeneity in outcomes and the resulting methodological implications for measuring the behavioral effects of oxytocin in humans. After providing an overview of the state-of-the-art research on oxytocin's exogenous use, we elaborate on the peptide's modulatory role in the context of care-based altruism, cooperation, and conflict and discuss its potential for therapeutic interventions in psychiatric disorders characterized by social dysfunction.

Brief Report: Relationship Between Cotinine Levels and Peripheral Endogenous Concentrations of Oxytocin, ß-Endorphin, and Orexin in Individuals With Both Alcohol and Nicotine Use Disorders.

BACKGROUND AND OBJECTIVES: In this secondary analysis of a pilot clinical trial with individuals with alcohol and nicotine use disorders, we investigate the relationship between serum concentrations of oxytocin, ß-endorphin, melatonin, α-melanocyte-stimulating hormone, substance P, and orexin, with objective biomarkers (salivary cotinine and serum γ-glutamyl transferase [GGT]) as well as with self-reported smoking and alcohol drinking. METHODS: Biomarkers for a total of N = 19 participants were analyzed using multiplexed, competitive format immune-assay (peptides) and enzyme competitive immunoassay (saliva). A regression analysis using Pearson's correlation coefficient was utilized to determine correlations. We controlled for multiple comparisons, checked for collinearities, and ran two-sided statistical tests. RESULTS: We found significant positive correlations for cotinine and oxytocin (P = .002), ß-endorphin (P = .008), and orexin (P < .001), but not for either GGT or self-reported smoking or alcohol drinking. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These preliminary results suggest a relationship between cotinine and oxytocin, ß-endorphin, and orexin, which opens up new potential hypotheses on the potential role of these endocrine pathways in tobacco smokers. (Am J Addict 2021;30:88-91).

A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers.

BACKGROUND AND OBJECTIVES: The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders. PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat alcohol use disorder. We present a population pharmacokinetic model for PF-5190457 in non-heavy (alcohol consumption status = 0) and heavy alcohol drinkers (alcohol consumption status = 1), and identify relevant factors that can influence its pharmacokinetics. METHODS: Plasma concentration-time data from non-heavy (n = 35) and heavy drinkers (n = 12) were pooled for the population pharmacokinetic model development. The influence of various covariates including alcohol consumption status was evaluated. The accuracy, precision, and robustness of the model were also evaluated using bootstrapping and visual predictive checks. RESULTS: A two-compartment model best described the pharmacokinetics of PF-5190457. The apparent volume of distribution of 44.5 L, apparent clearance of 72.0 L/h, apparent peripheral volume of distribution of 271 L, apparent distributional clearance of 28.7 L/h, and first-order absorption rate constant of 0.27/h were accurate and precise. The apparent volume of distribution was 3.8-fold higher (169 L) in heavy drinkers, and correlated with a lower maximum plasma concentration in heavy drinkers compared with non-heavy drinkers at the same dose; and a corresponding reduced incidence of somnolence in heavy drinkers at doses > 50 mg. CONCLUSIONS: This work provides an accurate, precise, and robust two-compartment model that describes the pharmacokinetics of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers NCT01247896 and NCT02039349.

Differences in Sociodemographic and Alcohol-Related Clinical Characteristics Between Treatment Seekers and Nontreatment Seekers and Their Role in Predicting Outcomes in the COMBINE Study for Alcohol Use Disorder.

BACKGROUND: One of the challenges in early-stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD. AIMS: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol-related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome. METHODS: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes. RESULTS: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part-time or unemployed (p's < 0.05); they met fewer DSM-IV AD criteria and had significantly lower scores on alcohol-related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD. CONCLUSIONS: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD.

Investigating the link between serum concentrations of brain-derived neurotrophic factor and behavioral measures in anxious alcohol-dependent individuals.

Brain-derived neurotrophic factor (BDNF) plays a role in different neurophysiological processes, including those involved in alcohol- and anxiety-related behaviors. Preclinical and clinical studies indicate that chronic excessive alcohol use leads to a downregulation of BDNF production in the periphery and in the brain. In addition, a decrease in BDNF concentrations in the blood has been reported to be associated with increased anxiety levels. Non-treatment-seeking alcohol-dependent individuals with high trait anxiety were studied to assess whether serum BDNF concentrations may be linked to self-reported levels of alcohol drinking, anxiety, and other behavioral measures. Participants had a current diagnosis of alcohol dependence, high trait anxiety score, and were not seeking treatment for alcohol dependence or anxiety. A fasting blood sample was collected from each participant and serum BDNF was measured using an enzyme-linked immunosorbent assay (ELISA). Behavioral data were collected on the same day, including measures of alcohol drinking, craving, dependence severity, and anxiety. Bivariate correlations were run between BDNF levels and behavioral measures. Serum BDNF concentrations were negatively correlated with average drinks per drinking days (r = -0.41, p = 0.02) and positively correlated with obsessive-compulsive drinking scale (r = 0.48, p = 0.007) and state-trait anxiety inventory (r = 0.52, p = 0.003) scores. These findings shed light on the possible role of the BDNF system in the neurobiology of alcohol- and anxiety-related behaviors.

Regulatory peptides and systems biology: A new era of translational and reverse-translational neuroendocrinology.

Recently, there has been a resurgence in regulatory peptide science as a result of three converging trends. The first is the increasing population of the drug pipeline with peptide-based therapeutics, mainly in, but not restricted to, incretin-like molecules for treatment of metabolic disorders such as diabetes. The second is the development of genetic and optogenetic tools enabling new insights into how peptides actually function within brain and peripheral circuits to accomplish homeostatic and allostatic regulation. The third is the explosion in defined structures of the G-protein coupled receptors to which most regulatory peptides bind and exert their actions. These trends have closely wedded basic systems biology to drug discovery and development, creating a "two-way street" on which translational advances travel from basic research to the clinic, and, equally importantly, "reverse-translational" information is gathered, about the molecular, cellular and circuit-level mechanisms of action of regulatory peptides, comprising information required for the fine-tuning of drug development through testing in animal models. This review focuses on a small group of 'influential' peptides, including oxytocin, vasopressin, pituitary adenylate cyclase-activating polypeptide, ghrelin, relaxin-3 and glucagon-like peptide-1, and how basic discoveries and their application to therapeutics have intertwined over the past decade.