Béatrice Botia1, Rémi Legastelois, Hakim Houchi, Mickaël Naassila. 1. INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, UFR de Pharmacie, Amiens, France; Structure Fédérative de Recherche CAP-Santé, Université de Picardie Jules Verne, Amiens, France.
Abstract
BACKGROUND: Anxiety disorders predispose individuals to the development of alcohol dependence in humans. Surprisingly, whether anxiety is a trait influencing the development of alcohol-related behaviors in rodents remains controversial. Here, we addressed the hypothesis of a relationship between basal anxiety levels and the development of ethanol (EtOH)-induced behavioral sensitization (EIBS), a model of neuroadaptations occurring after repeated EtOH exposure which is proposed to play a role in early and recurring steps of addiction. METHODS: EtOH-naïve DBA/2J mice were submitted to the elevated plus maze and light/dark box tests to evaluate their basal anxiety levels. Then, mice received daily intraperitoneal injection of saline or 2 g/kg EtOH for 10 days and locomotor activity was immediately monitored. Mice were then split into resistant and sensitized phenotypes based on their increase in locomotion. The relationship between basal anxiety and the development of sensitization was investigated. In addition, we tested the effect of an 8-day-long treatment with 4 mg/kg diazepam, a broad-spectrum benzodiazepine anxiolytic, on the expression of sensitization in both resistant and sensitized mice. RESULTS: For the first time, we showed that vulnerability to EIBS is negatively correlated with basal anxiety. Moreover, a diazepam treatment during EIBS procedure increased EtOH-induced hyperlocomotion of resistant mice after 1 week of withdrawal (but not immediately after) without any effect in the group of sensitized mice. CONCLUSIONS: This study shows that, in mice, basal anxiety predicts the vulnerability to EIBS. Mice exhibiting low basal anxiety will develop higher EIBS than mice with elevated anxiety levels. Modulation of anxiety by a diazepam treatment during the development of EIBS enhances its expression after 1 week postinduction. Altogether, we demonstrated an inverse relationship between basal anxiety-like behaviors and EIBS vulnerability and that resistance to EIBS vanishes after anxiolytic treatment.
BACKGROUND:Anxiety disorders predispose individuals to the development of alcohol dependence in humans. Surprisingly, whether anxiety is a trait influencing the development of alcohol-related behaviors in rodents remains controversial. Here, we addressed the hypothesis of a relationship between basal anxiety levels and the development of ethanol (EtOH)-induced behavioral sensitization (EIBS), a model of neuroadaptations occurring after repeated EtOH exposure which is proposed to play a role in early and recurring steps of addiction. METHODS:EtOH-naïve DBA/2J mice were submitted to the elevated plus maze and light/dark box tests to evaluate their basal anxiety levels. Then, mice received daily intraperitoneal injection of saline or 2 g/kg EtOH for 10 days and locomotor activity was immediately monitored. Mice were then split into resistant and sensitized phenotypes based on their increase in locomotion. The relationship between basal anxiety and the development of sensitization was investigated. In addition, we tested the effect of an 8-day-long treatment with 4 mg/kg diazepam, a broad-spectrum benzodiazepine anxiolytic, on the expression of sensitization in both resistant and sensitized mice. RESULTS: For the first time, we showed that vulnerability to EIBS is negatively correlated with basal anxiety. Moreover, a diazepam treatment during EIBS procedure increased EtOH-induced hyperlocomotion of resistant mice after 1 week of withdrawal (but not immediately after) without any effect in the group of sensitized mice. CONCLUSIONS: This study shows that, in mice, basal anxiety predicts the vulnerability to EIBS. Mice exhibiting low basal anxiety will develop higher EIBS than mice with elevated anxiety levels. Modulation of anxiety by a diazepam treatment during the development of EIBS enhances its expression after 1 week postinduction. Altogether, we demonstrated an inverse relationship between basal anxiety-like behaviors and EIBS vulnerability and that resistance to EIBS vanishes after anxiolytic treatment.