Identifying biological markers predicting vulnerability to develop excessive alcohol consumption may lead to a real improvement of clinical care. With converging evidence suggesting that gut ...microbiome is capable of influencing brain and behavior, this study aimed at investigating whether changes in gut microbiome composition is associated with conditioned responses to alcohol. We trained Wistar rats to self-administer alcohol for a prolonged period before screening those exhibiting uncontrolled alcohol seeking and taking by modeling diagnostic criteria for AUD: inability to abstain during a signaled period of reward unavailability, increased motivation assessed in a progressive effortful task and persistent alcohol intake despite aversive foot shocks. Based on addiction criteria scores, rats were assigned to either Vulnerable or Resilient groups. Vulnerable rats not only displayed increased impulsive and compulsive behaviors, but also displayed increased relapse after abstinence and increased sensitivity to baclofen treatments compared to resilient animals. Then, rats underwent a 3-month wash out period before sacrifice. Dorsal striatum was collected to assess dopamine receptor mRNA expression, and 16S microbiome sequencing was performed on caecal contents. Multiple significant correlations were found between gut microbiome and impulsivity measures, as well as augmentations in striatal Dopamine 1 receptor (D1R) and reductions in D2R as vulnerability to AUD increased. Therefore, using a singular translational approach based on biobehavioral dispositions to excessive alcohol seeking without heavy intoxication, our observations suggests an association between gut microbiome composition and these specific “at risk” behavioral traits observed in our translationally relevant model.
•Less than 15% of rats display diagnostic criteria of uncontrolled alcohol seeking.•These vulnerable rats have reduced striatal dopamine 2 receptor expression.•And increased striatal dopamine 1 receptor expression.•Significant correlations were observed between microbiome and dopamine receptors.
Introduction
Currently, alcohol dependence is characterized by immediate onset of dipsomania states (code F10.26, ICD-10) interpreted in clinical addictology as reliable diagnostic signs of morbid ...alcohol dependence. These are classified clinically by rate, severity, therapeutically resistant post alcohol comorbidities (alcohol-induced polyneuropathy, hepatic dysfunctions, etc.), and by the presence of “lucid spaces”, when patients, depleted physically and mentally by hypertoxic alcohol abuse states, periodically (after binge drinking) intake no alcohol.
Objectives
Effectiveness improvement and reducing time of treatment for hypertoxic alcohol abuse states by reasonable pathogenetic use of highly effective drugs, wide polymodality and synergistic pharmacological range, with few side effects, potential for inclusion to the conventional standard treatment patterns according to thiamine concepts.
Methods
Valid clinical-diagnostic, laboratory, biochemical, electrophysiological, psychological (scaling, testing), statistical methods for identification of alcohol dependence complicated by hypertoxic alcohol abuse states.
Results
A new method of alleviating the hypertoxic intoxication in alcohol dependence has been developed on representative clinical material, which involves conventional pharmacological and drug-free symptomatic remedies and methods. Along with psychotherapeutic potentiation, a therapeutically targeted pharmacological complex was prescribed: intramuscular Vitaxon № 10 per course; Sibazon 0.5% solution, 2 ml intramuscular, 3-5 injections per course; oral Phenazepam, one tablet (0.001g) twice a day for 10-14 days; Cocarnit one ampoule daily intramuscular injection, for a course of 3-10 injections.
Conclusions
The effectiveness of the proposed pharmacological complex has been proven by the statistical reliability method and illustrated by clinical examples of patient-specific research.
Relevance. In case of developed alcoholic disease, under conditions of alcoholic hypoglycemia, ketone bodies act as an energy substrate for the brain. However, the role of ketone hunger for ...maintaining the craving for alcohol has not been established. The assumption of such a connection has a right to exist, since it is alcohol that stimulates the formation of ketone bodies. Therefore, with developed alcoholism, the desire to consume alcohol (and, in fact, "saturate" the brain with ketone bodies) can be considered as a consequence of hypoketonemia. Accordingly, the hunger of the alcoholic is the result of hypoketonemia, but not hypoglycemia. Therefore, it is relevant to conduct a study in which the given variables (controlled by us) were the level of glycemia and the level of ketonemia, and the amount of alcohol consumed voluntarily (under conditions of free choice) was a derivative and dependent value.
Objective: to study the relationship between craving for alcohol, and levels of glycemia and ketonemia in alcoholized rats.
Materials and methods. Male white rats (n = 40) were forcibly alcoholized with 10% ethanol in 16 weeks. After that, for 30 days, they had a free choice of three types of drinking: clean water, 5% glucose, and 10% ethanol. The volume of consumed liquids was recorded. The criterion for the developed alcohol dependence was the preference of ethanol. At this stage, the animals were divided into 4 groups. Rats were injected per os with 0.8-1.5 ml of: 1.4% unitiol (3.5 mg / kg) to suppress ketonemia – group 1 (n = 10); 40% starch (1.0 g / kg) to eliminate hypoglycemia – group 2 (n = 10); 2.8% unitiol and 80% starch to suppress ketonemia and eliminate hypoglycemia – group 3 (n = 10); 0.9% NaCl as a control – group 4 (n = 10). Blood glucose (from the tail vein) and urine ketone bodies were monitored. The glucose level was determined with a glucometer. Test strips were used to detect ketone bodies in urine. The results were processed with MedStat software. To measure the strength of the correlation between the indicators, Spearman and Pearson tests were used.
Results. No ketone bodies were found in the urine of healthy animals; however, after the end of forced alcoholization, varying levels of ketonuria were recorded in all rats: from 0.5 to 10 mmol / L (Spearman's rank correlation test was 0.8). Glycemia in healthy rats was 7.0 ± 1.4 mmol / L. After alcoholization, it decreased (p <0.001) to 3.0 ± 0.7 mmol / l. Ethanol consumption during first 10 days of forced alcoholization was 3.2 ± 0.7 ml per 100 g of animal weight; by the end of the third week - 4.9 ± 1.1 ml; by the end of the sixth week - 6.4 ± 1.4 ml (this was a climax of consumption, since consumption did not increase up to the 16th week).
After a 30-day correction, the level of glycemia (mmol / L) was as follows: animals of the 1st group (unitiol) - 4.0 ± 0.8; animals of the 2nd group (enhanced carbohydrate diet) - 7.1 ± 1.2; animals of the 3rd group (unitiol + enhanced carbohydrate diet) - 7.1 ± 1.1; animals of the 4th group (0.9% NaCl) - 3.5 ± 0.8.
Alcohol consumption (ml per 100 g of animal weight) after 30-day correction was as follows: in group 1 (unitiol) - 5.1 ± 0.9; in group 2 (enhanced carbohydrate diet) - 2.7 ± 1; in group 3 (unitiol + enhanced carbohydrate diet) - 3.5 ± 1.5; in group 4 (0.9% NaCl) - 4.5 ± 1.2.
A positive strong correlation was found between ethanol consumption and a decrease in glycemia (Pearson's test – 0.8).
Conclusion. In alcoholized animals with severe hypoglycemia and ketosis, drug suppression of ketosis does not reduce the craving for ethanol. Metabolic correction, aimed at eliminating hypoglycemia, helps to reduce alcohol consumption and reduce the severity of ketosis. The reason for maintaining a stable craving for alcohol is the metabolic demand of the brain for ketone bodies, as alternative food sources in conditions of alcoholic hypoglycemia, and the synthesis of which is stimulated by alcohol intake.
Animal models of addiction Spanagel, Rainer
Dialogues in clinical neuroscience,
09/2017, Volume:
19, Issue:
3
Journal Article
Open access
In recent years, animal models in psychiatric research have been criticized for their limited translational value to the clinical situation. Failures in clinical trials have thus often been ...attributed to the lack of predictive power of preclinical animal models. Here, I argue that animal models of voluntary drug intake-under nonoperant and operant conditions-and addiction models based on the Diagnostic and Statistical Manual of Mental Disorders are crucial and informative tools for the identification of pathological mechanisms, target identification, and drug development. These models provide excellent face validity, and it is assumed that the neurochemical and neuroanatomical substrates involved in drug-intake behavior are similar in laboratory rodents and humans. Consequently, animal models of drug consumption and addiction provide predictive validity. This predictive power is best illustrated in alcohol research, in which three approved medications-acamprosate, naltrexone, and nalmefene-were developed by means of animal models and then successfully translated into the clinical situation.
Background
The free‐access (FA) intravenous alcohol self‐administration (IV‐ASA) paradigm is an experimental approach that can identify modulators of alcohol consumption in humans. Moreover, the ...outcome measures of IV‐ASA paradigms are associated with self‐reported alcohol intake using the timeline follow‐back method (TLFB). To evaluate how FA IV‐ASA reflects drinking in real life, we examined the relationship between an objective marker of recent alcohol intake, phosphatidylethanol in blood (B‐PEth), and TLFB and measures obtained during IV‐ASA in individuals with alcohol use disorder (AUD) and social drinkers (SD). We also explored the associations between these measures and gut‐brain peptides involved in AUD pathophysiology.
Methods
Thirty‐eight participants completed a laboratory session in which they self‐administered alcohol intravenously. The safety limit was 200 mg%, and main outcomes were mean and peak breath alcohol concentrations (BrAC). Blood samples were drawn prior to IV‐ASA and subjective alcohol effects were rated during the experiment.
Results
The study sample comprised 24 SD and 14 participants with DSM‐5 mild AUD. Although BrACs were not associated with B‐PEth or TLFB in the full sample or AUD subgroup, there was an association with TLFB in SD. In both subgroups, BrACs were associated with alcohol craving but with differential timing. Total ghrelin levels were higher in AUD participants than in SD.
Conclusions
No associations between B‐PEth levels and achieved BrACs were observed in the mild AUD group, the SD group, or the full sample. The ability for FA IV‐ASA to reflect recent drinking was confirmed only for TLFB in SD, whereas there were no associations within the smaller subsample of participants with mild AUD or in the full sample. Further studies that include a larger AUD sample are warranted. The association of BrACs with craving for alcohol suggests that the IV‐ASA method may be useful for assessing interventions that target craving. This could be explored by using the FA IV‐ASA model to evaluate the effects on craving of approved pharmacotherapies for AUD.
This study examined how well the experimental method free access intravenous alcohol self‐administration (IV‐ASA) reflects real‐life drinking as measured by an objective alcohol marker (B‐PEth) and self‐reported recent drinking history (TLFB) in participants with AUD and in social drinkers (SD). No associations were identified for IV‐ASA and B‐PEth, whereas IV‐ASA and TLFB were associated in SD but not in AUD or in the full sample. In both subgroups, IV‐ASA measures were associated with alcohol craving, but with differential timing.
•Oxytocin administration (24 IU) versus placebo attenuated Nucleus accumbens connectivity during processing of alcohol stimuli in social drinkers during an fMRI alcohol cue-reactivity paradigm.•The ...effect of oxytocin was only observed during alcohol picture trials and not during neutral picture trials.•Nucleus accumbens connectivity during processing of alcohol stimuli correlated with subjective craving for alcohol.
The brain oxytocin system is involved in a wide range of addictive behaviors, inhibiting prime- and cue-induced relapse in preclinical models of substance use disorders. Especially the ability of oxytocin to modulate connectivity between the nucleus accumbens (NAc) and cortical regions has been identified as a factor likely to be critical to its effects on relapse. We thus investigated the effect of oxytocin on NAc functional connectivity during an alcohol cue-reactivity task.
Thirteen male social drinkers participated in a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging (fMRI) alcohol cue-reactivity task with and without prior intranasal application of 24 IU oxytocin. Effects of oxytocin and functional connectivity during presentation of alcohol cues were assessed using ROI-to-ROI generalized psychophysiological interaction analyses.
Oxytocin application significantly reduced NAc connectivity with the cuneus and thalamo-occipital connectivity, while enhancing connectivity between the paracingulate gyrus and precentral gyrus. This effect was specific to the alcohol presentation and was not found during processing of neutral pictures. In addition, the NAc-cuneus connectivity significantly correlated with alcohol cue-induced craving during the scanning session.
For the first time, we could show that oxytocin selectively attenuates NAc connectivity during an alcohol cue-reactivity task which was related to changes in subjective craving for alcohol. This might reflect an attenuation of alcohol-cue saliency by oxytocin, which improves inhibitory control over craving and cue reactivity.
Limited data exist on the association between
alcohol consumption and incidence of alcohol related liver disease (ARLD). The aims were to analyse this relationship and assess prevalence of ARLD in ...Iceland and among patients treated for alcohol use disorder (AUD) and its impact on outcomes.
A retrospective study on all patients diagnosed with severe ARLD: alcohol related cirrhosis (ARC) and alcohol related hepatitis (ARH) in Iceland 1984-2020. Medical records were scrutinized for clinical features, severity of ARLD, proportion undergoing treatment for AUD, data on abstinence and long-term outcomes.
A total of 314 patients, males 76%, median age 56 years, fulfilled the predetermined criteria for ARLD. Median MELD was 17, 73% with Child-Pugh B/C and 70/314 (22%) who had ARH. Incidence of ARLD increased from 0.77 cases per 100 000 inhabitants annually 1984-2000 to 6.1 per 100 000 in 2016-2020.
alcohol consumption increased from 4.3 Liters to 7.5 L in in the same time periods. Overall 220/314 (70%) with ARLD had undergone treatment for AUD. Of all individuals who had AUD treatment during the study period (
= 21.845), 1% were diagnosed with ARLD. Patients who underwent treatment for AUD after the ARLD diagnosis had better prognosis than those who had treatment prior to ARLD diagnosis (hazard ratio 2.5 95% CI 1.3-5.0).
The incidence of ARLD increased 8-fold during the study period coinciding with 74% increase in
alcohol consumption. Patients with prior diagnosis of AUD had worse prognosis that needs special attention.
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