Amylin in Alcohol Addiction: A Potential New Treatment Target or an Adjuvant to Other Treatments?

Amylin is a neuroendocrine hormone with a potential role in addictive disorders, including alcohol use disorder (AUD). In addition to reducing appetitive behavior, amylin has been shown to affect alcohol-related behaviors in rodents. Delineating the biobehavioral correlates of amylin in relation to alcohol seeking and consumption has the potential of identifying new treatment targets for AUD, yet additional translational and human research is needed.

The glucagon-like peptide-1 system is modulated by acute and chronic alcohol exposure: Findings from human laboratory experiments and a post-mortem brain study.

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F3,28 = 6.52, p = 0.002; oral alcohol, fixed dose: F7,75.94 = 5.08, p < 0.001; intravenous alcohol, variable dose: F4,37.03 = 20.72, p < 0.001; intravenous alcohol, fixed dose: F4,13.92 = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F1,21 = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F1,20 = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.

Changes in plasma ghrelin levels following surgical and non-surgical weight-loss in female rats predict alcohol use.

The weight-loss surgery Roux-en Y gastric bypass (RYGB) is a relatively effective, long-term treatment option for patients with morbid obesity. However, accumulating clinical evidence suggests that patients receiving RYGB may be at increased risk of developing alcohol use disorder. This observation has been repeatedly supported by preclinical studies showing rodents increase intake of ethanol (EtOH) after RYGB, and has been further confirmed by human studies. A promising alternative to RYGB is sleeve gastrectomy (SG), which has resulted in decreased EtOH consumption in some rodent studies. The exact mechanism underlying the differential alcohol outcomes after RYGB versus SG has yet to be elucidated. However, the gut hormone ghrelin has emerged as a potential candidate from previous preclinical studies specific to RYGB surgeries and due to its action to stimulate food and alcohol intake and cravings. To directly assess changes in plasma ghrelin levels following weigh loss surgeries in the context of alcohol intake, 24 female rats were separated into three surgical groups receiving RYGB, SG, or Sham surgery followed by caloric restriction to produce adiposity matched controls (Sham-AM). Blood was drawn for fasted and fed plasma ghrelin (acyl and des-acyl) assays at multiple time points: while on a normal diet (ND), after 5-week exposure to a high fat diet (HFD), following surgery, and after a series of two-bottle alcohol choice test with increasing concentrations (2%, 4%, 6%, 8%) of EtOH. Consistent with previous observations, RYGB rats drank more EtOH than SG rats across all concentrations. As expected, fasted ghrelin levels were blunted after HFD feeding, compared to normal diet baseline. After RYGB, fasted ghrelin levels returned to higher levels while remained blunted after SG and Sham-AM. Fed acyl ghrelin levels were significantly increased to above "normal" levels after RYGB, but remain low after SG and Sham-AM. Given that post-RYGB acyl ghrelin levels are raised to a fasted state regardless of actual prandial status, we conclude that RYGB may results in a hormonal state reminiscence of a fasted state with the inability of feeding to inhibit ghrelin production, an effect which could potentially contribute to increased EtOH intake following the surgery. In contrast, following SG, ghrelin levels in rats remain consistent with the fed state regardless of prandial status, potentially explaining lower alcohol intake and lower risk of developing AUD.

Racial Differences in the Association Between Alcohol Drinking and Cigarette Smoking: Preliminary Findings From an Alcohol Research Program.

AIMS: Important differences have been shown in alcohol drinking and cigarette smoking prevalence, patterns and consequences among individuals from different racial backgrounds. Alcohol and nicotine are often co-used, and the association between drinking and smoking may differ between racial groups-a question explored in the present study. METHODS: Data from the NIAAA natural history and screening protocols were utilized; non-Hispanic Black and non-Hispanic White individuals were included in the analyses [N = 1692; 65.2% male; 58.3% met criteria for current alcohol use disorder (AUD); 37.8% were current cigarette smokers]. Bivariate associations between assessments related to alcohol drinking and cigarette smoking were examined, and the strength and direction of these associations were compared between the two groups. RESULTS: The sample included 796 Black and 896 White individuals. Black participants had higher frequency (P < 0.0001) and severity (P = 0.007) of AUD, as well as higher frequency (P < 0.0001) of cigarette smoking. Bivariate analyses showed that the expected positive associations between alcohol drinking and cigarette smoking, observed among White individuals, were blunted or absent among Black individuals [age at first cigarette-AUD identification test (AUDIT) score: F(1, 292) = 7.60, P = 0.006; cigarette pack years-AUDIT score: F(1, 1111) = 10.97, P = 0.001]. CONCLUSIONS: Some decoupling in the association between alcohol drinking and cigarette smoking was found among Black compared to White individuals. The sample was drawn from a specific population enrolled in alcohol research protocols, which is a limitation of the present study. These preliminary findings highlight the importance of considering racial/ethnic background in preventive and therapeutic strategies for comorbid alcohol and nicotine use.

Leptin Gene and Leptin Receptor Gene Polymorphisms in Alcohol Use Disorder: Findings Related to Psychopathology.

Comorbidity between alcohol use disorder (AUD) and other addictive and psychiatric disorders is highly prevalent and disabling; however, the underlying biological correlates are not fully understood. Leptin is a peptide hormone known for its role in energy homeostasis and food intake. Furthermore, leptin plays a key role in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of several neurotransmitter systems that regulate emotionality and behavior. However, human studies that have investigated circulating leptin levels in relation to AUD and affective disorders, such as anxiety and depression, are conflicting. Genetic-based analyses of the leptin gene (LEP) and leptin receptor gene (LEPR) have the potential of providing more insight into the potential role of the leptin system in AUD and comorbid psychopathology. The aim of the current study was to investigate whether genotypic variations at LEP and LEPR are associated with measures of alcohol use, nicotine use, anxiety, and depression, all of which represent common comorbidities with AUD. Haplotype association analyses were performed, using data from participants enrolled in screening and natural history protocols at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Analyses were performed separately in European Americans and African Americans due to the variation in haplotype diversity for most genes between these groups. In the European American group, one LEP haplotype (EB2H4) was associated with lower odds of having a current AUD diagnosis, two LEPR haplotypes (EB7H3, EB8H3) were associated with lower cigarette pack years and two LEPR haplotypes (EB7H2, EB8H2) were associated with higher State-Trait Anxiety Inventory (STAI-T) scores. In the African American group, one LEP haplotype (AB2H8) was associated with higher cigarette pack years and one LEP haplotype (AB3H2) was associated with lower Fagerström Test for Nicotine Dependence (FTND) scores. Overall, this study found that variations in the leptin and leptin receptor genes are associated with measures of alcohol use, nicotine use, and anxiety. While this preliminary study adds support for a role of the leptin system in AUD and psychopathologies, additional studies are required to fully understand the underlying mechanisms and potential therapeutic implications of these findings.

A population-based investigation of the association between alcohol intake and serum total ghrelin concentrations among cigarette-smoking, non-alcohol-dependent male individuals.

BACKGROUND: Ghrelin plays significant roles in regulating appetite, food intake, and metabolism. Furthermore, the ghrelin system is increasingly being studied in relation to alcohol seeking behaviors. To this end, it is important to understand the possible effects of alcohol intake on the ghrelin system. The aim of the present study was to investigate the association between alcohol drinking and circulating ghrelin levels in a large sample of cigarette-smoking, non-alcohol-dependent male individuals. METHODS: We utilized data from two nested case-control studies (study A, n = 807; study B, n = 976) based within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial. Data on alcohol consumption (grams of pure alcohol consumed per day) were obtained via a food frequency questionnaire. Blood samples were also collected (after 12 h of fasting), and serum concentrations of total ghrelin were measured by radioimmunoassay. RESULTS: Dichotomous comparison between alcohol drinkers (>0 g/day of alcohol intake) and non-drinkers (0 g/day of alcohol intake) found higher total ghrelin levels among individuals who drank alcohol than those who did not, with statistically significant results in study A [F (1, 798) = 4.32, P = 0.03] and less robust results in study B [F (1, 966) = 2.62, P = 0.10], controlling for a list of factors that may influence ghrelin levels and/or differ between drinkers and non-drinkers. Bivariate correlational analysis among drinkers found no association between the quantity of daily alcohol intake and blood total ghrelin concentrations. CONCLUSION: These results indicate elevated ghrelin levels among alcohol drinkers and provide additional/relevant information on the complex interaction between alcohol use and the ghrelin system.

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.

Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies.

The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the "crosstalk" between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms - an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) - each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F3,36 = 3.345, p = 0.030) and IL-10 (F3,53.2 = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.

Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers.

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. CLINICALTRIALS.GOV: NCT02039349. This article is part of the special issue on 'Neuropeptides'.

Substance Use among Economically Disadvantaged African American Older Adults; Objective and Subjective Socioeconomic Status.

Purpose. This study investigated the effects of objective and subjective socioeconomic status (SES) indicators on two health behaviors, cigarette smoking and alcohol drinking, among African American older adults. Methods. This community-based study recruited 619 economically disadvantaged African American older adults (age ≥ 65 years) residing in South Los Angeles. Structured face-to-face interviews were conducted to collect data. Data on demographic factors (age and gender), subjective SES (financial difficulties), objective SES (educational attainment), living arrangement, marital status, healthcare access (insurance), and health (number of chronic medical conditions, self-rated health, sick days, depression, and chronic pain) and health behaviors (cigarette smoking and alcohol drinking) were collected from participants. Logistic regressions were used to analyze the data. Results. High financial difficulties were associated with higher odds of smoking cigarettes and drinking alcohol, independent of covariates. Educational attainment did not correlate with our outcomes. Similar patterns emerged for cigarette smoking and alcohol drinking. Conclusion. Subjective SES indicators such as financial difficulties may be more relevant than objective SES indicators such as educational attainment to health risk behaviors such as cigarette smoking and alcohol drinking among African American older adults in economically constrain urban environments. Smoking and drinking may serve as coping mechanisms with financial difficulty, especially among African American older adults. In line with the minorities' diminished returns (MDR) theory, and probably due to discrimination against racial minorities, educational attainment has a smaller protective effect among economically disadvantaged African American individuals against health risk behaviors.

The Role of the Ghrelin System in Drug Addiction.

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research.

N-acetylcysteine as an adjunctive therapy to risperidone for treatment of irritability in autism: a randomized, double-blind, placebo-controlled clinical trial of efficacy and safety.

OBJECTIVES: According to the proposed interference of N-acetylcysteine (NAC) with pathophysiologic processes of autistic disorders (ADs), we aimed to assess the effectiveness and safety of NAC as an adjunct to risperidone in the treatment of ADs in a randomized, double-blind, clinical trial. METHODS: The participants were referred outpatients between 4 and 12 years of age with the diagnosis of ADs and a score of more than 12 on Aberrant Behavior Checklist-Community (ABC-C) Irritability subscale score. The participants were randomized into 2 groups. One group received risperidone plus NAC, and the other group received risperidone plus placebo. The dose of risperidone was titrated between 1 and 2.0 mg/d, and the dose of NAC was 600 to 900 mg/d. The main outcome was mean decrease in the ABC-C irritability subscale score from baseline at 5 and 10 weeks. Changes in other subscales were considered as secondary outcome measures. RESULTS: Forty patients completed the 10-week trial. Baseline characteristics including age, sex and body weight, as well as baseline scores in 5 subscales did not demonstrate statistically significant difference between the 2 groups. Repeated-measures analysis showed significant effect for time × treatment interaction in irritability (P = 0.01) and hyperactivity/noncompliance (P = 0.02) subscales. By week 10, the NAC group showed significantly more reduction in irritability (P = 0.02) and hyperactivity/noncompliance (P = 0.01) subscales scores. CONCLUSIONS: N-acetylcysteine can be considered as an adjuvant therapy for ADs with beneficial therapeutic outcomes.

N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Despite the burden of negative symptoms on quality of life in schizophrenic patients, no completely effective treatment has been developed to address such symptoms yet. Abnormalities in oxidative stress pathways have been recently demonstrated to be involved in the pathophysiology of schizophrenia, and a growing interest in antioxidant agents is emerging for targeting negative symptoms of schizophrenia. N-Acetylcysteine (NAC) is a potent antioxidant with neuroprotective properties. This study aimed to evaluate the possible effects of NAC as an adjunct to risperidone in treating negative symptoms of schizophrenia. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, 42 patients with chronic schizophrenia and a score of 20 or greater on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. The participants were equally randomized to receive NAC (up to 2 g/d) or placebo, in addition to risperidone (up to 6 mg/d) for 8 weeks. The participants were rated using PANSS every 2 weeks, and the decrease of PANSS negative subscale score was considered as our primary outcome. RESULTS: By the study end point, NAC-treated patients showed significantly greater improvement in the PANSS total (P = 0.006) and negative subscale (P < 0.001) scores than that in the placebo group, but this difference was not significant for positive and general psychopathology subscales. There was no significant difference between the 2 groups in the frequency of adverse effects. CONCLUSIONS: NAC add-on therapy showed to be a safe and effective augmentative strategy for alleviating negative symptoms of schizophrenia.