N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis.

Background And Objectives: Recent neurobiological evidences along with clinical observations justify the use of N-acetylcysteine (NAC) as a medication for craving. The objective of our study was to assess the evidence of efficacy of NAC for craving in substance use disorders in randomized clinical trials (RCTs).

Methods: Systematic review of the RCTs literature (PROSPERO number 56698) until February, 2017, using MEDLINE, Cochrane Library and clinicaltrials.

Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene.

Abused inhalants are voluntarily inhaled at high concentrations to produce intoxicating effects. Results from animal studies show that the abused inhalant toluene triggers behaviors, such as self-administration and conditioned place preference, which are commonly associated with addictive drugs. However, little is known about how toluene affects neurons within the nucleus accumbens (NAc), a brain region within the basal ganglia that mediates goal-directed behaviors and is implicated in the development and maintenance of addictive behaviors.

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice.

Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily×14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training.

Pharmacologic treatment of alcoholism.

Progress in understanding the neuroscience of addiction has significantly advanced the development of more efficacious medications for the treatment of alcohol use disorders (AUD). While several medications have been approved by regulatory bodies around the world for the treatment of AUD, they are not universally efficacious. Recent research has yielded improved understanding of the genetics and brain circuits that underlie alcohol reward and its habitual use.

The potential utility of drinking motive questions to screen at-risk drinking in socially anxious patients.

Background: Drinking motives are thought to be important mediators of the relationship between social anxiety and alcohol use. This project evaluates whether specific drinking motives accurately reflect alcohol dependence. If so, brief questions about drinking motives could serve as valuable alcohol screening tools with socially anxious patients.

Harmonization of measurement results of the alcohol biomarker carbohydrate-deficient transferrin by use of the toolbox of technical procedures of the International Consortium for Harmonization of Clinical Laboratory Results.

Background: The need for equivalent results of routine measurement procedures for the alcohol biomarker carbohydrate-deficient transferrin (CDT) has been recognized by the IFCC. This article describes a project to harmonize CDT as conducted by an IFCC working group initiated for this purpose.

Methods: We used procedures for achieving harmonization as developed by the Consortium for Harmonization of Clinical Laboratory Results to assess the suitability of a candidate reference measurement procedure (cRMP), candidate reference materials (cRMs), and the success of efforts to achieve harmonization.

Endocannabinoid modulation of cortical up-states and NREM sleep.

Up-/down-state transitions are a form of network activity observed when sensory input into the cortex is diminished such as during non-REM sleep. Up-states emerge from coordinated signaling between glutamatergic and GABAergic synapses and are modulated by systems that affect the balance between inhibition and excitation. We hypothesized that the endocannabinoid (EC) system, a neuromodulatory system intrinsic to the cortical microcircuitry, is an important regulator of up-states and sleep.

Coping motives for drinking affect stress reactivity but not alcohol consumption in a clinical laboratory setting.

Objective: Stress evokes thoughts about alcohol and enhances alcohol's rewarding value in drinkers who use alcohol to cope with negative affect. The present study extends prior research by examining whether this effect applies to actual alcohol consumption following a stressor and whether individuals with high and low coping motives for drinking differ in stress reactivity.

Method: Nondependent drinkers with high scores (﹥1 SD above national norms) on the coping motives subscale on the Drinking Motives Questionnaire (n = 41; 46% women) were enrolled along with age- and gender-matched nondependent drinkers with low coping motives (n = 41).

An online alcohol and oral health curriculum for dental students.

Regular heavy alcohol use can cause or worsen several oral health disorders and is associated with complications during and after dental procedures. Dental student education should provide detailed knowledge of these issues together with skills needed to detect and counsel patients with unhealthy drinking patterns. This project was designed to develop and evaluate a five-module, online program to teach dental students about alcohol and oral health, systemic and oral biological effects of heavy drinking, required changes to treatment protocols for heavy drinkers, reliable methods of alcohol screening, and ways to provide heavy drinkers with brief interventions.

Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry.

Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse.

Deletion of the N-terminal domain alters the ethanol inhibition of N-methyl-D-aspartate receptors in a subunit-dependent manner.

Background: Ethanol (EtOH) inhibition of N-methyl-d-aspartate (NMDA) receptors is poorly understood due in part to the organizational complexity of the receptor that provides ample locations for sites of action. Among these, the N-terminal domain (NTD) of NMDA receptor subunits contains binding sites for a variety of modulatory agents including zinc, protons, and GluN2B selective antagonists such as ifenprodil or Ro-25-6981. EtOH inhibition of neuronal NMDA receptors expressed in some brain areas has been reported to be occluded by the presence of ifenprodil or similar compounds suggesting that the NTD may be important in regulating the EtOH sensitivity of NMDA receptors.

Conditioned reinforcement and locomotor activating effects of caffeine and ethanol combinations in mice.

A growing trend among ethanol drinkers, especially young adults, is to combine caffeinated energy drinks with ethanol during a drinking episode. The primary active ingredient of these mixers is caffeine, which may significantly interact with ethanol. We tested the two hypotheses that caffeine would enhance ethanol-conditioned place preference and also enhance ethanol-stimulated locomotor activity.

Dephosphorylation of GluN2B C-terminal tyrosine residues does not contribute to acute ethanol inhibition of recombinant NMDA receptors.

N-methyl-d-aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate and are highly expressed by neurons. These receptors are critical for excitatory synaptic signaling and inhibition of NMDA receptors leads to impaired cognition and learning. Ethanol inhibits NMDA currents at concentrations associated with intoxication and this action may underlie some of the behavioral effects of ethanol.

Medial prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons.

Toluene is a volatile solvent that is intentionally inhaled by children, adolescents, and adults for its intoxicating effects. Although voluntary use of toluene suggests that it possesses rewarding properties and abuse potential, it is unknown whether toluene alters excitatory synaptic transmission in reward-sensitive dopamine neurons like other drugs of abuse. Here, using a combination of retrograde labeling and slice electrophysiology, we show that a brief in vivo exposure of rats to a behaviorally relevant concentration of toluene vapor enhances glutamatergic synaptic strength of dopamine (DA) neurons projecting to nucleus accumbens core and medial shell neurons.

Interactions between adaptive coping and drinking to cope in predicting naturalistic drinking and drinking following a lab-based psychosocial stressor.

Using alcohol to cope (i.e., coping motivation) and general coping style both are theorized and demonstrated empirically to lead to problematic drinking.

Commentary on Marczinski and colleagues: mixing an energy drink with an alcoholic beverage increases motivation for more alcohol in college students.

Background: This commentary discusses the study by Marczinski and colleagues in which they used an alcohol priming procedure to examine the effects of an alcohol/energy drink mixture on the priming effect.

Methods: The significance of the main findings from this study and new avenues of investigation are discussed.

Results: Using an alcohol priming paradigm, Marczinski and colleagues report that an alcohol/energy drink combination (AmED) prolongs the desire-to-drink rating compared with alcohol alone.

Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice.

Introduction: Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice.

Methods: We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus.

Neurochemical and neurostructural plasticity in alcoholism.

The behavioral manifestations of alcoholism are primarily attributable to the numerous and lasting adaptations that occur in the brain as a result of chronic heavy alcohol consumption. As will be reviewed here, these adaptations include alcohol-induced plasticity in chemical neurotransmission, density and morphology of dendritic spines, as well as neurodegeneration and cerebral atrophy. Within the context of these neuroadaptations that have been observed in both human and animal studies, we will discuss how these changes potentially contribute to the cognitive and behavioral dysfunctions that are hallmark features of alcoholism, as well as how they reveal novel potential pharmacological targets for the treatment of this disorder.

Sensitivity and specificity of urinary ethyl glucuronide and ethyl sulfate in liver disease patients.

Background: It is important to monitor alcohol use in the care of patients with liver disease, but patient self-report can be unreliable. We therefore evaluated the performance of urine ethyl glucuronide (EtG) and ethyl sulfate (EtS) in detecting alcohol use in the days preceding a clinical encounter.

Methods: Subjects (n = 120) were recruited at a university-based hepatology clinic or during hospitalization.

Severity of anxiety in mental health versus addiction treatment settings when social anxiety and substance abuse are comorbid.

There is increasing interest in the co-occurrence of social anxiety and addiction. Each investigation has a specific vantage point, e.g.

Functional neuroimaging studies of alcohol cue reactivity: a quantitative meta-analysis and systematic review.

A comprehensive understanding of the neurobiology of alcohol cue reactivity is critical in identifying the neuropathology of alcohol use disorders (AUD) and developing treatments that may attenuate alcohol craving and reduce relapse risk. Functional neuroimaging studies have identified many brain areas in which alcohol cues elicit activation. However, extant studies have included relatively small numbers of cases, with AUD of varying severity, and have employed many different cue paradigms.

mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior.

Pharmacological blockade of the type 5 metabotropic glutamate receptor (mGluR5) attenuates cue-induced reinstatement of ethanol-seeking behavior, yet the brain regions involved in these effects are not yet known. The purpose of the present study was to determine if local blockade of mGluR5 receptors in the basolateral amygdala (BLA) and/or the nucleus accumbens (NAc), two brain regions known to be involved in stimulus-reward associations, attenuate the reinstatement of ethanol-seeking behavior induced by ethanol-paired cues. As a control for possible non-specific effects, the effects of mGluR5 blockade in these regions on cue-induced reinstatement of sucrose-seeking were also assessed.

Effects of chronic intermittent ethanol exposure on orbitofrontal and medial prefrontal cortex-dependent behaviors in mice.

In humans, stroke or trauma-induced damage to the orbitofrontal cortex (OFC) or medial prefrontal cortex (mPFC) results in impaired cognitive flexibility. Alcoholics also exhibit similar deficits in cognitive flexibility, suggesting that the OFC and mPFC are susceptible to alcohol-induced dysfunction. The present experiments investigated this issue using an attention set-shifting assay in ethanol dependent adult male C57BL/6J mice.

The Alcohol Clinical Trials Initiative (ACTIVE): purpose and goals for assessing important and salient issues for medications development in alcohol use disorders.

Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data).