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Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABA<sub>B</sub> receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness.<div class="boxTitle">Methods</div>This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABA<sub>B</sub> PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABA<sub>B</sub> PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABA<sub>B</sub> PAMs to attenuate multiple alcohol-related behaviors will be discussed.<div class="boxTitle">Results</div>Positive allosteric modulators (PAMs) of the GABA<sub>B</sub> receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABA<sub>B</sub> agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABA<sub>B</sub> PAMs for addiction treatment.<div class="boxTitle">Conclusions</div>Preclinical studies indicate that GABA<sub>B</sub> PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABA<sub>B</sub> agonism. This predicts that GABA<sub>B</sub> PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.</span>

Does Advice Based on Biomarkers of Liver Injury or Non-Invasive Tests of Liver Fibrosis Impact High-Risk Drinking Behaviour: A Systematic Review With Meta-analysis
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background and Aims</div>Alcohol dependence affects over 240 million people worldwide and attributed to 3 million deaths annually. Early identification and intervention are key to prevent harm. We aim to systematically review literature on the effectiveness of adding advice based on biomarkers of liver injury or non-invasive tests of liver fibrosis (intervention-based advice) to prevent alcohol misuse.<div class="boxTitle">Methods</div>Electronic search was conducted on Ovid Medline, PubMed, EMBASE, Psychinfo and CINAHL for articles published up to end of February 2020. Additionally, we searched study citations, Scopus, Ethos and Clinical trials. The primary outcome measure was changed in self-reported alcohol consumption analysed by random-effects meta-analysis. Secondary outcomes included change to liver blood markers and alcohol-related health outcomes.<div class="boxTitle">Results</div>Fourteen randomized controlled trials (RCTs) and two observational studies comprising <span style="font-style:italic;">n</span> = 3763 participants were included. Meta-analyses showed a greater reduction in alcohol consumption and liver biomarkers for the intervention compared to control group: mean difference for weekly alcohol intake was −74.4 g/week (95% confidence interval (CI) −126.1, −22.6, <span style="font-style:italic;">P</span> = 0.005) and mean difference for gamma-glutamyl transferase (GGT) −19.7 IU/l (95% CI −33.1, −6.4, <span style="font-style:italic;">P</span> = 0.004). There was a higher incidence of alcohol-attributed mortality, number of days spent in the hospital, physician visits and sickness absence in the non-intervention group. The quality of the included studies was moderate for RCTs and high for observational studies.<div class="boxTitle">Conclusions</div>The review confirmed a significant association between the addition of intervention-based advice in routine care to the reduction of harmful alcohol consumption, GGT and alcohol-related mortality. The findings support the inclusion of this type of advice in routine alcohol care.</span>

Targeting the Opioid Receptors: A Promising Therapeutic Avenue for Treatment in “Heavy Drinking Smokers”
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>Despite a general decline in tobacco use in the last decades, the prevalence of tobacco smoking in individuals with alcohol use disorder (AUD) remains substantial (45–50%). Importantly, the co-use of both substances potentiates the adverse effects, making it a significant public health problem. Substantial evidence suggests that AUD and Tobacco use disorder (TUD) may share common mechanisms. Targeting these mechanisms may therefore provide more effective therapy. Numerous studies describe a potential role of the endogenous opioid system in both AUD and TUD. Reviewing this literature, we aim to evaluate the efficacy of molecules that target the opioid system as promising therapeutic interventions for treating alcohol and tobacco co-use disorders.<div class="boxTitle">Methods</div>We provide a synthesis of the current epidemiological knowledge of alcohol and tobacco co-use disorders. We evaluate clinical and preclinical research that focuses on the regulation of the endogenous opioid system in alcohol, nicotine, and their interactions.<div class="boxTitle">Results</div>The epidemiological data confirm that smoking stimulates heavy drinking and facilitates alcohol craving. Pharmacological findings suggest that treatments that are efficacious in the dual addiction provide a beneficial treatment outcome in comorbid AUD and TUD. In this regard, MOP, DOP and NOP-receptor antagonists show promising results, while the findings prompt caution when considering KOP-receptor antagonists as a treatment option in alcohol and tobacco co-use disorders.<div class="boxTitle">Conclusions</div>Existing literature suggests a role of the opioid system in sustaining the high comorbidity rates of AUD and TUD. Molecules targeting opioid receptors may therefore represent promising therapeutic interventions in ‘heavy drinking smokers.’</span>

Startrek: The Next Generation of Alcohol Researchers. A Perspective from Markus Heilig, 2019 Recipient of the ESBRA Manfred Lautenschläger—European Alcohol Research Award
<span class="paragraphSection">This present issue of <span style="font-style:italic;">Alcohol and Alcoholism</span>, the official Journal of the European Society for Biomedical Research on Alcoholism (ESBRA), features a special section on the Young Investigator Award symposium held during the 2019 ESBRA meeting in Lille, France. The four papers in this section describe work by promising young European scientists, including two basic scientists, a clinical researcher and a physician scientist. Individually, each of the papers reports important advances in the understanding of alcohol addiction. Jointly, they highlight the interdisciplinary nature of alcohol research, and point to the importance of investing in coming generations of investigators who can pursue this research, in a manner that harnesses the full armamentarium of modern neuroscience, and beyond.</span>

Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background and aims</div><span style="font-style:italic;">Andrographis paniculata</span> is an annual herbaceous plant which belongs to the Acanthaceae family<span style="font-style:italic;">.</span> Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats.<div class="boxTitle">Methods</div>The present study evaluated whether <span style="font-style:italic;">A. paniculata</span> reduces alcohol drinking and relapse in msP rats by activating PPARγ.<div class="boxTitle">Results</div>Oral administration of an <span style="font-style:italic;">A. paniculata</span> dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of <span style="font-style:italic;">A. paniculata</span>, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of <span style="font-style:italic;">A. paniculata</span> (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking.<div class="boxTitle">Conclusions</div>Results point to <span style="font-style:italic;">A. paniculata</span>-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.</span>

CB1R Promotes Chronic Alcohol-Induced Neuronal Necroptosis in Mice Prefrontal Cortex
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>Alcohol abuse induces multiple neuropathology and causes global burden to human health. Prefrontal cortex (PFC) is one of the most susceptible regions to alcohol-induced neuropathology. However, precise mechanisms underlying these effects on PFC remain to be elucidated. Herein, we investigated whether RIP1/RIP3/MLKL-mediated necroptosis was involved in the alcohol-induced PFC injury, and explored the effect that cannabinoid receptors (CBRs) exerted on the neurotoxicity of alcohol.<div class="boxTitle">Methods</div>In this study, dynamic development of neuronal necroptosis in the PFC region was monitored after 95% (v/v) alcohol vapor administration for 15 and 30 days, respectively. Selective CBRs agonists or inverse agonists were pretreated according to the experimental design. All the PFC tissues were isolated and further examined by biochemical and histopathological analyses.<div class="boxTitle">Results</div>It was found that chronic alcohol exposure increased the protein level of MLKL and also the phosphorylated levels of RIP1, RIP3 and MLKL in a time-dependent manner, all of which indicated the activation of necroptosis signaling. Particularly, compared to astrocytes, neurons from the PFC showed more prototypical necrotic morphology in response to alcohol insults. In parallel, an increased protein level of CB1R was also found after 15 and 30 days alcohol exposure. Administration of specific inverse agonists of CB1R (AM251 and AM281), but not its agonists or CB2R modulators, significantly alleviated the RIP1/RIP3/MLKL-mediated neuronal necroptosis.<div class="boxTitle">Conclusion</div>We reported the involvement of RIP1/RIP3/MLKL-mediated necroptosis in alcohol-induced PFC neurotoxicity, and identified CB1R as a critical regulator of neuronal necroptosis that enhanced our understanding of alcohol-induced neuropathology in the PFC.</span>

Retrospective Hair Cortisol Concentrations from Pretreatment to Early Recovery in Alcohol Use Disorder
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Cortisol profiles are known to vary across phases of alcohol use disorder (AUD; e.g. chronic use, withdrawal and early/sustained recovery). These patterns have largely been established through between-subjects contrasts. Using a segmental hair cortisol concentrations (HCC) approach, retrospective longitudinal analyses are feasible. Here, we examine monthly cortisol secretion in treatment-seekers with AUD from alcohol use to abstinence. At ~6 weeks of recovery we collected hair samples from individuals with moderate-to-severe AUD. We examined HCC from three consecutive segments; proximal to the scalp representing the most recent month (sustained abstinence from alcohol), the midsegment representing the previous month in which abstinence was attained, and the distal segment representing 2 months prior during active drinking. Analyses examined main and interactive effects of segment and sex, controlling for monthly alcohol consumption. Best fit by a quadratic shape, within-subject change was significant (<span style="font-style:italic;">F1,15</span> = 5.27, <span style="font-style:italic;">P</span> = 0.04, <span style="font-style:italic;">ηpartial2</span> = 0.26). The distal and midsegments did not differ from one another (<span style="font-style:italic;">P</span> = 0.51). The proximal segment was significantly lower than both the distal (<span style="font-style:italic;">M∆</span> = 0.200, <span style="font-style:italic;">P</span> = 0.004) and mid (<span style="font-style:italic;">M∆</span> = 0.175, <span style="font-style:italic;">P</span> &lt; 0.001) segments. An effect of sex approached significance suggesting women had modestly higher HCC than men (<span style="font-style:italic;">MWOMEN</span> = 1.37 vs. <span style="font-style:italic;">MMEN</span> = 1.02, <span style="font-style:italic;">P</span> = 0.10). Consistent with previous cross-sectional reports, these data confirm nonlinear patterns of cortisol accumulation with elevations apparent during periods of alcohol consumption and a decrease in abstinence. Capturing these within-subject patterns via HCC trajectories may serve as a valuable resource in identifying profiles associated with increased risk and post-treatment outcomes.</span>

Gamma-Glutamyl Transferase: A Useful Marker of Habitual Drinking in Cases of Alcohol-Associated Osteonecrosis of the Femoral Head
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>Alcohol intake is one of the factors associated with the occurrence of osteonecrosis of the femoral head (ONFH), and its epidemiological information regarding alcohol intake depends on patients’ self-reports. Therefore, we analysed the efficacy of laboratory tests as an objective diagnostic tool to indicate habitual drinking in patients with alcohol-associated ONFH.<div class="boxTitle">Methods</div>This study included 109 consecutive patients diagnosed with ONFH who underwent primary hip surgery in our institution between 2010 and 2018. The patients were classified into group AL (alcohol-associated ONFH; <span style="font-style:italic;">n</span> = 26) and group NO (alcohol-unassociated ONFH; <span style="font-style:italic;">n</span> = 83), based on their self-reported information. Serum levels of gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol and triglycerides were compared between both groups. The sensitivities and specificities with the optimal cut-off values for detecting alcohol-associated ONFH were compared among these markers.<div class="boxTitle">Results</div>The median serum levels of GGT, AST and ALT were significantly higher in the AL group than in the NO group. The receiver operating characteristic curve analysis demonstrated an area under the curve of 0.795 for GGT, 0.731 for AST and 0.709 for ALT. The optimal cut-off level of GGT as a marker for alcohol-associated ONFH was 36.5 units/L, with a sensitivity of 76% and specificity of 80%, and it was found to be the best marker among the other examined laboratory markers.<div class="boxTitle">Conclusion</div>Serum GGT level is a useful laboratory marker with moderate accuracy that indicates habitual drinking in patients with alcohol-associated ONFH.</span>

Ethyl Glucuronide and Ethyl Sulphate in Urine: Caution in their use as markers of recent alcohol use
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aim</div>To clarify the role of the ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), in monitoring alcohol consumption.<div class="boxTitle">Method</div>We recruited 7 female and 17 male volunteers who were instructed to consume a quantity of beer (containing 48 gm ethanol) with food in one session. We examined urinary excretion of EtG and EtS over time and looked for correlations between the concentrations of the metabolites EtG and EtS.<div class="boxTitle">Results</div>EtG concentrations in urine varied between 0.026 and 430.372 μg/ml with average values between 11.85 μg/ml (SD 19.75), 30 min after alcohol intake, and 100.39 μg/ml (SD 101.34), 4.5 h after alcohol intake. EtS urinary concentration ranged from 0.006 to 101.432 μg/ml with average values between 4.77 μg/ml (SD 5.42), 30 min after alcohol intake, and 30.14 μg/ml (SD 27.20), 4.5 h after alcohol intake. Spearman’s test showed that urinary EtG and EtS correlated significantly at several time points.<div class="boxTitle">Conclusion</div>The great interindividual variability in their excretion suggests caution in the use of urinary measurement of these metabolites in forensic investigations.</span>

Ethanol-Induced Neuronal and Cognitive/Emotional Impairments are Accompanied by Down-Regulated NT3-TrkC-ERK in Hippocampus
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>Ethanol ingestion affects cognition and emotion, which have been attributed to the dysfunction of specific brain structures. Studies of alcoholic patients and animal models consistently identify reduced hippocampal mass as a key ethanol-induced brain adaptation. This study evaluated how neuroadaptation in the hippocampus (Hip) produced by ethanol contributed to related behavioral deficits in male and female rats.<div class="boxTitle">Methods</div>Effects of acute, short-term and long-term ethanol exposure on the anxiety-like behavior and recognition memory on adult male and female Sprague–Dawley rats were assessed using elevated plus maze test and novel object recognition test, respectively. In addition, in order to investigate the direct effect of ethanol on hippocampal neurons, primary culture of hippocampal neurons was exposed to ethanol (10, 30 and 90 mM; 1, 24 and 48 h), and viability (CCK-8) and morphology (immunocytochemistry) were analyzed at structural levels. Western blot assays were used to assess protein levels of NT3-TrkC-ERK.<div class="boxTitle">Results</div>Acute and short-term ethanol exposure exerted anxiolytic effects, whereas long-term ethanol exposure induced anxiogenic responses in both sexes. Short-term ethanol exposure impaired spatial memory only in female rats, whereas long-term ethanol exposure impaired spatial and recognition memory in both sexes. These behavioral impairments and ethanol-induced loss of hippocampal neurons and decreased cell viability were accompanied by downregulated NT3-TrkC-ERK pathway.<div class="boxTitle">Conclusion</div>These results indicate that NT3-TrkC-ERK signaling in the Hip may play an important role in ethanol-induced structural and behavioral impairments.</span>

Neural Responses to the Implicit Processing of Emotional Facial Expressions in Binge Drinking
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>Emotional processing is a crucial ability in human and impairments in the processing of emotions are considered as transdiagnostic processes in psychopathology. In alcohol use disorder, numerous studies have investigated emotional processing and showed emotional deficits related to the perpetuation of alcohol use. Recent studies have also explored this topic in binge drinking, but few studies are available. In this paper, we explored whether emotional difficulties in binge drinking may be extended to implicit emotion processing.<div class="boxTitle">Methods</div>We compared 39 binge drinkers (BD) and 40 non-binge drinkers who performed a gender categorization task while faces represented emotional expressions of anger, fear, happiness and sadness. Emotional brain responses were assessed thanks to functional magnetic resonance imaging. Emotional versus non-emotional conditions were first contrasted in the whole sample and groups were then compared.<div class="boxTitle">Results</div>Emotional condition led to differential activations than non-emotional condition, supporting the validity of the paradigm. Regarding group comparisons, BD exhibited higher activations in the left posterior cerebellum (anger processing) and the right anterior cingulate (fear processing) as well as lower activations in the left insula (happiness), the right post-central gyrus, the right cingulate gyrus and the right medial frontal gyrus (sadness processing).<div class="boxTitle">Conclusions</div>Beyond emotional identification, BD presented differential brain responses following the implicit processing of emotions. Emotional difficulties in binge drinking might be related to a more automatic/unconscious processing of emotions.</span>

Effect of Modulation of the Astrocytic Glutamate Transporters’ Expression on Cocaine-Induced Reinstatement in Male P Rats Exposed to Ethanol
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aim</div>Reinforcing properties of ethanol and cocaine are mediated in part through the glutamatergic system. Extracellular glutamate concentration is strictly maintained through several glutamate transporters, such as glutamate transporter 1 (GLT-1), cystine/glutamate transporter (xCT) and glutamate aspartate transporter (GLAST). Previous findings revealed that cocaine and ethanol exposure downregulated GLT-1 and xCT, and that β-lactam antibiotics restored their expression.<div class="boxTitle">Methods</div>In this study, we investigated the effect of ampicillin/sulbactam (AMP/SUL) (200 mg/kg, i.p.), a β-lactam antibiotic, on cocaine-induced reinstatement and locomotor activity in male alcohol preferring (P) rats using free choice ethanol (15 and 30%, v/v) and water. We also investigated the effect of co-exposure to ethanol and cocaine (20 mg/kg, i.p.) on GLT-1, xCT and GLAST expression in the nucleus accumbens (NAc) core, NAc shell and dorsomedial prefrontal cortex (dmPFC).<div class="boxTitle">Results</div>Cocaine exposure decreased ethanol intake and preference. Cocaine and ethanol co-exposure acquired place preference and increased locomotor activity compared to ethanol-exposed rats. GLT-1 and xCT expression were downregulated after cocaine and ethanol co-exposure in the NAc core and shell, but not in dmPFC. AMP/SUL attenuated reinstatement to cocaine as well attenuated the decrease in locomotor activity and ethanol intake and preference. These effects were associated with upregulation of GLT-1 and xCT expression in the NAc core/shell and dmPFC. GLAST expression was not affected after ethanol and cocaine co-exposure or AMP/SUL treatment.<div class="boxTitle">Conclusion</div>Our findings demonstrate that astrocytic glutamate transporters within the mesocorticolimbic area are critical targets in modulating cocaine-seeking behavior while being consuming ethanol.</span>

The Impact of Appetite-Regulating Neuropeptide Leptin on Alcohol Use, Alcohol Craving and Addictive Behavior: A Systematic Review of Preclinical and Clinical Data
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Aims</div>The appetite regulating hormone leptin, which is mainly secreted from adipose tissue, is an important regulator of food intake and modulator of reward-driven behavior. Leptin exerts its biological actions via binding to the leptin receptor, which is expressed in the hypothalamus, but also in the hippocampus, the amygdala and the substantia nigra. In the ventral tegmental area (VTA), leptin attenuates the firing rate of dopaminergic neurons that project to the Nucleus accumbens (NAc), which serves as relay to other brain areas of the “addiction network”, such as the prefrontal cortex. This suggests that leptin plays a role in the processing of rewards in the context of substance use disorders such as alcohol use disorder, especially through attenuation of dopaminergic activity in the mesolimbic reward system. This supports the plausibility of leptin’s potential effects in alcohol use disorder.<div class="boxTitle">Methods</div>We searched MEDLINE from 1990 to February 2020. All abstracts were screened for relevance and we only included publications reporting original data with a full text available in English language. Studies that did not report leptin-data, reviews or case reports/series were not included.<div class="boxTitle">Results</div>We identified a total of N=293 studies of whom a total of N=55 preclinical and clinical studies met the specified criteria. N=40 studies investigated the effects of alcohol on leptin plasma levels, N=9 studies investigated the effects of leptin on alcohol craving and N=6 studies investigated the effects of leptin on relapse and alcohol consumption.<div class="boxTitle">Conclusions</div>In this review of preclinical and clinical data, we assess the role of leptin in alcohol use and the development and maintenance of an alcohol use disorder, alcohol craving and relapse. Integrating the existing preclinical and clinical data on leptin may reveal new and innovative targets for the treatment of substance use disorders in the future.</span>