Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats.

Aberrant glucocorticoid signaling via glucocorticoid receptors (GR) plays a critical role in alcohol use disorder (AUD). Acute alcohol withdrawal and protracted abstinence in dependent rats are associated with increased GR signaling and changes in GR-mediated transcriptional activity in the rat central nucleus of the amygdala (CeA). The GR antagonist mifepristone decreases alcohol consumption in dependent rats during acute withdrawal and protracted abstinence. Regulation of CeA synaptic activity by GR is currently unknown. Here, we utilized mifepristone and the selective GR antagonist CORT118335 (both at 10 µM) as pharmacological tools to dissect the role of GR on GABA transmission in male, adult Sprague-Dawley rats using slice electrophysiology. We subjected rats to chronic intermittent alcohol vapor exposure for 5-7 weeks to induce alcohol dependence. A subset of dependent rats subsequently underwent protracted alcohol withdrawal for 2 weeks, and air-exposed rats served as controls. Mifepristone reduced the frequency of pharmacologically-isolated spontaneous inhibitory postsynaptic currents (sIPSC) in the CeA (medial subdivision) without affecting postsynaptic measures in all groups, suggesting decreased GABA release with the largest effect in dependent rats. CORT118335 did not significantly alter GABA transmission in naïve, but decreased sIPSC frequency in dependent rats. Similarly, mifepristone decreased amplitudes of evoked inhibitory postsynaptic potentials only in dependent rats and during protracted withdrawal. Collectively, our study provides insight into regulation of CeA GABAergic synapses by GR. Chronic ethanol enhances the efficiency of mifepristone and CORT118335, thus highlighting the potential of drugs targeting GR as a promising pharmacological avenue for the treatment of AUD.

The future of translational research on alcohol use disorder.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.

Existing and Future Drugs for the Treatment of the Dark Side of Addiction.

The identification of a heuristic framework for the stages of the addiction cycle that are linked to neurocircuitry changes in pathophysiology includes the binge/intoxication stage, the withdrawal/negative affect stage, and the preoccupation/anticipation (craving) stage, which represent neuroadaptations in three neurocircuits (basal ganglia, extended amygdala, and frontal cortex, respectively). The identification of excellent and validated animal models, the development of human laboratory models, and an enormous surge in our understanding of neurocircuitry and neuropharmacological mechanisms have provided a revisionist view of addiction that emphasizes the loss of brain reward function and gain of stress function that drive negative reinforcement (the dark side of addiction) as a key to compulsive drug seeking. Reversing the dark side of addiction not only explains much of the existing successful pharmacotherapies for addiction but also points to vast new opportunities for future medications to alleviate this major source of human suffering.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Supporting Clinical Nurses Through a Research Fellowship.

After reviewing the literature, nurses at the bedside seeking answers to clinical questions may find their inquiries remain unanswered. This article describes the yearlong Research Fellows Program in which candidates, funded for 12 hours per month of research release time, answered formal research questions in a curriculum designed to provide the skills to complete their study. Five have completed their studies; 1 has received a grant to continue. Two are in process of submitting manuscripts to journals.

Shared leadership and group identification in healthcare: The leadership beliefs of clinicians working in interprofessional teams.

Despite the proposed benefits of applying shared and distributed leadership models in healthcare, few studies have explored the leadership beliefs of clinicians and ascertained whether differences exist between professions. The current article aims to address these gaps and, additionally, examine whether clinicians' leadership beliefs are associated with the strength of their professional and team identifications. An online survey was responded to by 229 healthcare workers from community interprofessional teams in mental health settings across the East of England. No differences emerged between professional groups in their leadership beliefs; all professions reported a high level of agreement with shared leadership. A positive association emerged between professional identification and shared leadership in that participants who expressed the strongest level of profession identification also reported the greatest agreement with shared leadership. The same association was demonstrated for team identification and shared leadership. The findings highlight the important link between group identification and leadership beliefs, suggesting that strategies that promote strong professional and team identifications in interprofessional teams are likely to be conducive to clinicians supporting principles of shared leadership. Future research is needed to strengthen this link and examine the leadership practices of healthcare workers.

Plasma profile of pro-inflammatory cytokines and chemokines in cocaine users under outpatient treatment: influence of cocaine symptom severity and psychiatric co-morbidity.

The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1ß), chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1ß was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1ß, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma cytokine/chemokine monitoring could improve the stratification of cocaine consumers seeking treatment and thus facilitate the application of appropriate interventions, including management of heightened risk of psychiatric co-morbidity. Further research is necessary to elucidate the role of the immune system in the etiology of cocaine addiction.

A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder.

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats.

Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse. Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i. v., 8 h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0-20 mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20 mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD. Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20 mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females. Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.

Preclinical and clinical evidence for suppression of alcohol intake by apremilast.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Acamprosate for alcohol dependence: a sex-specific meta-analysis based on individual patient data.

BACKGROUND: It is unknown whether women derive comparable benefits and have a similar safety and tolerability profile as men from acamprosate, a widely prescribed drug for the maintenance of abstinence in alcohol dependence. The objective of this study was to assess sex-specific differences in the efficacy, safety, and tolerability of acamprosate in the treatment of women and men with alcohol dependence. METHODS: A sex-specific meta-analysis was conducted based on individual patient data (IPD). Data were obtained from double-blind, randomized controlled trials with quantitative drinking measures in patients with alcohol dependence receiving oral acamprosate or placebo. Sources included PubMed, PsychInfo, and Cochrane electronic databases; reference lists from retrieved articles and presentations at professional meetings; and direct access to authors and companies who provided IPD. RESULTS: Individual records were obtained from 1,317 women and 4,794 men who participated in 22 eligible studies conducted in 18 countries. IPD meta-analyses found a significant beneficial effect of acamprosate relative to placebo across all 4 efficacy end points: an incremental gain of 10.4% (95% CI 7.1 to 13.7, p < 0.001) in percentage of abstinent days, an incremental gain of 11.0% (7.4 to 14.6, p < 0.001) in percentage of no heavy drinking days, an odds ratio of 1.9 (1.6 to 2.2, p < 0.001) for rate of complete abstinence, and an odds ratio of 1.9 (1.6 to 2.3, p < 0.001) for rate of no heavy drinking, over the study duration. Acamprosate was also associated with significantly higher rates of treatment completion (p = 0.004) and medication compliance (p < 0.001) than placebo. Men and women did not differ on any measure of acamprosate efficacy, safety, or tolerability. CONCLUSIONS: This sex-specific IPD meta-analysis provides evidence that acamprosate has a significant effect compared with placebo in improving rates of abstinence and no heavy drinking in both women and men with alcohol dependence. Further, acamprosate was associated with significantly higher rates of treatment completion and medication compliance than placebo among both women and men and had a comparable safety and tolerability profile.

Sleep disturbance in alcoholism: proposal of a simple measurement, and results from a 24-week randomized controlled study of alcohol-dependent patients assessing acamprosate efficacy.

AIMS: Sleep disturbance symptom (SDS) is commonly reported in alcoholic patients. Polysomnography studies suggested that acamprosate decreased SDS. We assessed this hypothesis by using data of a randomized controlled trial. As a secondary objective, we suggested and tested the validity of a simple measurement of SDS based on the Hamilton depression and anxiety inventory subset. METHODS: We re-analysed a multi-center study evaluating the efficacy of acamprosate compared with placebos on alcohol-dependent patients in concentrating on SDS change in time. The Sleep sum score index (SAEI) was built from check-lists on adverse effects reported at each visit and constituted our main endpoint. We also tested the validity of the short sleep index (SSI) defined by the four sleep items of the Hamilton depression and anxiety scales. Statistical analyses were conducted on an intention to treat basis. RESULTS: A total of 592 patients were included, and 292 completed the 6-month trial. Compared with SAEI considered as our reference, the observed specificity and sensitivity of SSI were 91.6 and 87.6%. From 40.2% of patients experiencing SDS at baseline, this proportion decreased until 26.1% at M6 in the placebo group and 19.5% in the acamprosate group (relative risk placebo/acamprosate = 1.49, 95% confidence interval 1.10, 1.98, P = 0.04). CONCLUSION: Treating alcoholic patients to enhance abstinence has a beneficial effect in reducing SDS, and the duration of abstinence during the treatment constitutes the main positive factor. An additional effect of acamprosate is conjectured from its effect on the glutamatergic tone. The SSI constitutes a simple, reasonably sensitive and specific instrument tool to measure SDS.

Looking Back, Looking Forward: Current Medications and Innovative Potential Medications to Treat Alcohol Use Disorder.

This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Mason's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.

Leveraging Telehealth for Delivery of Palliative Care to Remote Communities: A Rapid Review.

Background: Palliative care encompasses supportive health care for patients at any stage of illness aimed at relieving symptoms, controlling pain, managing stress, offering respite for caregivers, and optimizing the quality of life. Objective: To explore strategies for increasing access to palliative care among individuals living in remote/rural communities, a rapid review was conducted on studies that explored the use of telehealth applications with this population. Methods: From December 2019 to February 2020, the PRISMA methodology was used to gather peer-reviewed studies published in the English language. MedLine, Google Scholar, and EBSCO were searched; no date limitations were set. Given the diversity of study methodologies and outcomes, the findings were synthesized narratively. The Cochrane Collaboration's tool for assessing the risk of bias was also employed. Lastly, the studies were mapped to clinical guidelines for the various aspects of quality palliative care. Results: The 18 studies found, published between 2004 and 2019, were conducted in seven countries and on five continents. Aims included evaluating feasibility, efficacy, and user satisfaction. Insights draw from a combined pool of 3,313 patients and 250 providers. Most studies involved oncology patients and employed videoconferencing or a web platform/online software with videoconferencing. Three themes emerged: delivery of care, symptom management and quality of life, and patient/caregiver/provider satisfaction levels. Telehealth proved effective for patient and medication monitoring, provider and specialist appointments, and palliative care consultations. Operational benefits included clinician time saved, shorter appointment wait times, and reduced no show rates; implementation challenges also emerged. Statistical improvements in quality of life and symptom management were reported. Nearly two-thirds of the studies reported positive experiences among patients, caregivers, and providers; about half included an interprofessional team. The studies primarily focused on the structure/process and physical aspects of quality palliative care, there was a paucity of insights on the spiritual, cultural, end of life, and ethical/legal aspects of care. Two-thirds (12/18) of the studies employed a descriptive design. Risk for selection, performance, detection, and reporting biases emerged for all the studies; for example, only four of the studies included control groups and less than 20% (3/18) reported on attrition of study participants. Additional limitations include the rapid review methodology which relied heavily on the lead author's decisions and the restriction of studies published only in the English language. Conclusion: More rigorous research is required to confirm the viability of clinical care delivery and establish best practices for quality, virtual palliative care to remote/rural areas.

Alternative use of suvorexant (Belsomra®) for the prevention of alcohol drinking and seeking in rats with a history of alcohol dependence.

Alcohol use disorder (AUD) is one of the most treatment-resistant medical conditions globally. The orexin (Orx) system regulates diverse physiological processes, including stress, and is a system of interest for the development of pharmaceuticals to treat substance use disorders, particularly AUD. The present study tested the ability of the dual orexin receptor antagonist suvorexant (SUV), marketed by Merck as Belsomra®, for the treatment of insomnia, to decrease alcohol self-administration and the stress-induced reinstatement of alcohol-seeking behavior in male Wistar rats with a history of alcohol dependence. Rats were trained to orally self-administer 10% alcohol (30 min/day for 3 weeks) and were either made dependent via chronic intermittent alcohol vapor exposure (14 h ON, 10 h OFF) for 6 weeks or exposed to air (non-dependent). Starting on week 7, the effect of SUV (0-20 mg/kg, p.o.) was tested on alcohol self-administration at acute abstinence (8 h after vapor was turned OFF) twice weekly. A separate cohort of rats that were prepared in parallel was removed from alcohol vapor exposure and then subjected to extinction training for 14 sessions. Once extinction was achieved, the rats received SUV (0 and 5 mg/kg, p.o.) and were tested for the footshock stress-induced reinstatement of alcohol-seeking behavior. Suvorexant at 5, 10, and 20 mg/kg selectively decreased alcohol intake in dependent rats. Furthermore, 5 mg/kg SUV prevented the stress-induced reinstatement of alcohol-seeking behavior in dependent rats only. These results underscore the significance of targeting the Orx system for the treatment of substance use disorders generally and suggest that repurposing SUV could be an alternative approach for the treatment of AUD.

Alcohol Use Disorder: The Role of Medication in Recovery.

The misuse of alcohol in the United States continues to take a large toll on society, resulting in the deaths of about 88,000 Americans per year. Moreover, it is estimated that nearly 14.6 million Americans currently meet diagnostic criteria for current alcohol use disorder (AUD). However, very few individuals receive treatment, with an even smaller portion receiving medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of AUD, despite scientifically rigorous evidence showing the benefits of combining medication approved for treating AUD with evidence-based behavioral therapy. These benefits include higher rates of abstinence and less risk of relapse to heavy drinking, with associated improvements in medical and mental health and in quality of life. This review provides an overview of FDA-approved medications and "off-label" drugs for the treatment of AUD. The article emphasizes that AUD medical advice and prescription recommendations should come from professionals with training in the treatment of AUD and that treatment plans should consider medication in conjunction with evidence-based behavioral therapy. Finally, this review notes the limited number of medications available and the continued need for the development of new pharmacotherapies to optimize AUD recovery goals.

Neuropsychological performance in young adults with cannabis use disorder.

BACKGROUND AND AIMS: Cannabis is a commonly used recreational drug in young adults. The worldwide prevalence in 18- to 25-year-olds is approximately 35%. Significant differences in cognitive performance have been reported previously for groups of cannabis users. However, the groups are often heterogeneous in terms of cannabis use. Here, we study daily cannabis users with a confirmed diagnosis of cannabis use disorder (CUD) to examine cognitive performance on measures of memory, executive function and risky decision-making. METHODS: Forty young adult daily cannabis users with diagnosed CUD and 20 healthy controls matched for sex and premorbid intelligence quotient (IQ) were included. The neuropsychological battery implemented was designed to measure multiple modes of memory (visual, episodic and working memory), risky decision-making and other domains of executive function using subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Our results showed that young adult daily cannabis users with CUD perform significantly poorer on tasks of visual and episodic memory compared with healthy controls. In addition, executive functioning was associated with the age of onset. CONCLUSIONS: Further research is required to determine whether worse performance in cognition results in cannabis use or is a consequence of cannabis use. Chronic heavy cannabis use during a critical period of brain development may have a particularly negative impact on cognition. Research into the persistence of cognitive differences and how they relate to functional outcomes such as academic/career performance is required.

Glucocorticoid receptor modulators decrease alcohol self-administration in male rats.

Alcohol use disorder (AUD) is associated with the dysregulation of brain stress and reward systems, including glucocorticoid receptors (GRs). The mixed glucocorticoid/progesterone receptor antagonist mifepristone and selective GR antagonist CORT113176 have been shown to selectively reduce alcohol consumption in alcohol-dependent rats. Mifepristone has also been shown to decrease alcohol consumption and craving for alcohol in humans with AUD. The present study tested the effects of the GR modulators CORT118335, CORT122928, CORT108297, and CORT125134 on alcohol self-administration in nondependent (air-exposed) and alcohol-dependent (alcohol vapor-exposed) adult male rats. Different GR modulators recruit different GR-associated transcriptional cofactors. Thus, we hypothesized that these GR modulators would vary in their effects on alcohol drinking. CORT118335, CORT122928, and CORT125134 significantly reduced alcohol self-administration in both alcohol-dependent and nondependent rats. CORT108297 had no effect on alcohol self-administration in either group. The present results support the potential of GR modulators for the development of treatments for AUD. Future studies that characterize genomic and nongenomic effects of these GR modulators will elucidate potential molecular mechanisms that underlie alcohol drinking in alcohol-dependent and nondependent states.

Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial.

OBJECTIVES: Recent observational studies have highlighted the beneficial role of dairy ingestion in gout prevention. The aims of this study were to determine the acute effects of milk ingestion on serum urate concentrations and examine the mechanisms of these effects. METHODS: This was a short-term randomised controlled crossover trial of milk in 16 healthy male volunteers. The following products were tested (each 80 g protein): soy control, early season skim milk, late season skim milk (containing high concentrations of orotic acid, a naturally occurring uricosuric agent) and ultrafiltrated MPC 85 skim milk. Each participant received a single dose of each product in random order. Serum and urine were obtained immediately before and then hourly over a 3 h period after ingestion of each study product. RESULTS: Ingestion of the soy control led to an increase in serum urate concentrations by approximately 10%. In contrast, ingestion of all milks led to a decrease in serum urate concentrations by approximately 10% (p<0.0001). All products (including soy) rapidly increased the fractional excretion of uric acid (FEUA). Late season milk led to a greater increase in FEUA than MPC 85 (p=0.02) and early season milk (p=0.052). There were no differences over time in serum oxypurines or purine-containing nucleosides. However, all products increased the fractional excretion of xanthine. CONCLUSIONS: Intact milk has an acute urate-lowering effect. These data provide further rationale for long-term intervention studies to determine whether such dietary interventions have an adjunctive role in the management of individuals with hyperuricaemia and gout.