Dataset Information

The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation.

ABSTRACT: The valine 66 to methionine (Met) polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders.We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDNF) and used alcohol-drinking paradigms in combination with viral-mediated gene delivery and pharmacology.We found that Met68BDNF mice consumed excessive amounts of alcohol and continued to drink despite negative consequences, a hallmark of addiction. Importantly, compulsive alcohol intake was reversed by overexpression of the wild-type valine68BDNF allele in the ventromedial prefrontal cortex of the Met68BDNF mice or by systemic administration of the tropomyosin receptor kinase B agonist, LM22A-4.Our findings suggest that carrying this BDNF allele increases the risk of developing uncontrolled and excessive alcohol drinking that can be reversed by directly activating the BDNF receptor, tropomyosin receptor kinase B. Importantly, this work identifies a potential therapeutic strategy for the treatment of compulsive alcohol drinking in humans carrying the Met66BDNF allele.

SUBMITTER: Warnault V

PROVIDER: S-EPMC4676961 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation.

Warnault Vincent V Darcq Emmanuel E Morisot Nadege N Phamluong Khanhky K Wilbrecht Linda L Massa Stephen M SM Longo Frank M FM Ron Dorit D

Biological psychiatry 20150612 6

<h4>Background</h4>The valine 66 to methionine (Met) polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders.<h4>Methods</h4>We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDN ...[more]

PMID: 26204799

Similar Datasets

Project description:Aims:Implicit measures of alcohol associations (i.e. measures designed to assess associations that are fast/reflexive/impulsive) have received substantial research attention. Alcohol associations related to the self (drinking identity), the effects of alcohol (alcohol excite) and appetitive inclinations (alcohol approach) have been found to predict drinking cross-sectionally and over time. A critical next step in this line of research and the goal of this study is to evaluate whether increases in the strength of these associations predict increases in drinking and vice versa. These hypotheses were tested in a sample of first- and second-year US university students: a sample selected because this time period is associated with initiation and escalation of drinking, peak levels of alcohol consumption and severe alcohol-related negative consequences. Short summary:This study's purpose was to evaluate whether increases in the strength of alcohol associations with the self (drinking identity), excitement (alcohol excite) and approach (alcohol approach) as assessed by implicit measures predicted subsequent increases in drinking risk and vice versa using a longitudinal, university student sample. Results were consistent with hypotheses. Methods:A sample of 506 students' (57% women) alcohol associations and alcohol consumption were assessed every 3 months over a 2-year period. Participants' consumption was converted to risk categories based on NIAAA's criteria: non-drinkers, low-risk drinkers and high-risk drinkers. A series of cross-lagged panel models tested whether changes in alcohol associations predicted subsequent change in drinking risk (and vice versa). Results:Across all three measures of alcohol associations, increases in the strength of alcohol associations were associated with subsequent increases in drinking risk and vice versa. Conclusion:Results from this study indicate bi-directional relationships between increases in alcohol associations (drinking identity, alcohol excite and alcohol approach) and subsequent increases in drinking risk. Intervention and prevention efforts may benefit from targeting these associations.

Project description:BackgroundMost physiological studies interested in alcohol-dependence examined ethanol as a pharmacological agent rather than a nutrient. We conducted two studies, which assessed the metabolic and endocrine factors involved in the regulation of alcohol and nutrient intake in alcohol-dependent (AD) subjects. We also examined the potential role of a disruption in energy balance in alcohol-dependence.Methods and resultsIn Study-1, quantitative dietetic interviews of eating and drinking habits were conducted with 97 AD subjects. The population was split around a median alcohol intake value of 12.5 kcal/kg/day. The results showed that the "low alcohol" drinking AD subjects had high Body Mass Index (BMI) and Fat Mass (FM) and alcohol intake was compensated for by a decrease in non-alcoholic intakes. "High alcohol" drinking AD subjects, on the other hand, had low BMI and FM and the total caloric intakes were largely above norms. In Study-2, 24 AD inpatients were submitted to dietetic interviews, calorimetry and blood samplings for the measurement of biomarkers of the regulation of metabolism and satiety, on day 2, 5 and 16 of abstinence. These patients were compared with 20 controls matched for age and gender. We observed in AD patients an increase in cortisol, leptin and PYY plasma levels and a decrease in ghrelin, which might explain the observed decrease in non-alcoholic intakes. However, alcoholic and non-alcoholic intakes correlated positively with basal metabolism and negatively with leptin and leptin/BMI.ConclusionFor individuals consuming below 12.5 kcal/kg/day of alcohol, alcohol intake is compensated for by a decrease in non-alcoholic nutrient intakes, probably due to changes in metabolic and satiety factors. For individuals consuming above 12.5 kcal/kg/day of alcohol, alcohol accelerates metabolism and decreases fat mass and leptin levels, and the total caloric intake largely exceeds norms. A dual model for regulation of energy intake in AD subjects is proposed.

Dataset Information

The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation.

Publications

The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets