Dataset Information

Greater inhibition of female rat binge alcohol intake by adrenergic receptor blockers using a novel Two-Shot rat binge drinking model.

ABSTRACT: Binge drinking (BD) contributes strongly to the harms of alcohol use disorder. Most rodent models do not result in binge-level blood alcohol concentrations (BACs), and to better understand individual and sex differences in neurobiological mechanisms related to BD, the use of outbred rat strains would be valuable. Here, we developed a novel BD model where after 3+ months of intermittent access to 20% alcohol Wistar rats drank, twice a week, with two 5-min intake (what we called Two-shot) separated by a 10-min break. Our findings showed during Two-Shot that most animals reached ≥ 80 mg% BAC levels (when briefly food-restricted). However, when increasing alcohol concentrations from 20 to 30%, 40%, or 50%, rats titrated to similar intake levels, suggesting rapid sensing of alcohol effects even when front-loading. Two-Shot drinking was reduced in both sexes by naltrexone (1 mg/kg), validating intake suppression by a clinical therapeutic agent for human problem drinking. Further, both propranolol (β-adrenergic receptor antagonist) and prazosin (α1-adrenergic receptor antagonist) reduced female but not male BD at the lower dose. Thus, our results provide a novel model for BD in outbred rats and suggest that female binging is more sensitive to adrenergic modulation than males, perhaps providing a novel sex-related therapy.

SUBMITTER: De Oliveira Sergio T

PROVIDER: S-EPMC11189554 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Greater inhibition of female rat binge alcohol intake by adrenergic receptor blockers using a novel Two-Shot rat binge drinking model.

De Oliveira Sergio Thatiane T Jane Smith Rebecca R Wean Sarah E SE Engleman Eric A EA Hopf Frederic W FW

Scientific reports 20240618 1

Binge drinking (BD) contributes strongly to the harms of alcohol use disorder. Most rodent models do not result in binge-level blood alcohol concentrations (BACs), and to better understand individual and sex differences in neurobiological mechanisms related to BD, the use of outbred rat strains would be valuable. Here, we developed a novel BD model where after 3+ months of intermittent access to 20% alcohol Wistar rats drank, twice a week, with two 5-min intake (what we called Two-shot) separate ...[more]

PMID: 38890353

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Project description:BackgroundGlucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.MethodsIn the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.FindingsIn male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.InterpretationAltogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.FundingSwedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.

Project description:BackgroundAlcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α2-subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α2-containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking.MethodsMale wild-type (Wt) C57BL/6J and point-mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α2-containing GABAA receptors were assessed for their binge-like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH-naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.).ResultsMice with BZD-insensitive α2-containing GABAA receptors (H101R) escalated their binge-like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild-types, they did not show forced abstinence-induced social deficits.ConclusionsThese findings suggest a role for: (i) H101 in species-typical binge-like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence-associated social deficits. Clinical findings report reduced BZD-binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD-sensitive α2-containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABAA receptors by ALLO and THDOC; we postulate that neurosteroid action on α2-containing receptor may be necessary for escalated chronic EtOH intake.

Project description:BackgroundBinge drinking (BD) refers to a pattern of alcohol consumption characterized by the consumption of large amounts of alcohol in a short period of time followed by periods of abstinence. This drinking pattern is prevalent worldwide, mainly among young people. Excessive alcohol consumption is the spectrum of consumption patterns that may have or have had health consequences, and includes the concepts of risky alcohol use, harmful alcohol use and alcohol dependence according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), the latter two are currently grouped into alcohol use disorder (AUD) according to the fifth edition of the DSM (DSM-5). Due to the high prevalence of BD among young people, especially university students, as well as the important consequences of its practice, a study was conducted to evaluate excessive alcohol consumption and its relationship with the practice of BD in university students.MethodsA cross-sectional study was conducted among students (aged 18-30 years) enrolled in the academic year 2018-2019 at the Faculty of Nursing at a university in northern Spain. Data collection included sociodemographic information, and alcohol use information, collected using a semi-structured questionnaire. To measure the excessive alcohol consumption, this study used the Alcohol Use Disorders Identification Test (AUDIT).ResultsA total of 142 participants were included, of which 88.03% were women. Up to 38.03% were classified as BD. Up to 14.77% of non-BD participants and 66.67% of BD participants were classified as risky drinkers (AUDIT Total geq 8 in men or geq 6 in women) (p < 0.001). Up to 3.41% of the non-BD and 24.07% of the BD were drinkers with harmful alcohol use and probable alcohol dependence (AUDIT Total geq 13) (p < 0.001). A total of 5.68% of non-BD and 42.59% of BD were AUD drinkers (AUDIT Total geq 9 in males or geq 8 in females) (p < 0.001). In addition, statistically significant differences were found between the BD and non-BD groups in the responses to each of the AUDIT items, as well as in the total score and also in the scores of the three domains of the questionnaire.ConclusionsExcessive alcohol consumption is frequent among university students, especially among those who practice BD.

Dataset Information

Greater inhibition of female rat binge alcohol intake by adrenergic receptor blockers using a novel Two-Shot rat binge drinking model.

Publications

Greater inhibition of female rat binge alcohol intake by adrenergic receptor blockers using a novel Two-Shot rat binge drinking model.

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