Compensatory effect by sigma1 (σ1) receptor stimulation during alcohol withdrawal in mice performing an object recognition task

Chronic alcohol consumption (CAC) provokes intense neurobiological alterations, which lead, notably, to an important abstinence syndrome upon withdrawal with deleterious cognitive consequences. We here examined the effect of activation or inactivation of the σ1 receptor during CAC withdrawal on the cognitive abilities of Swiss mice. Animals consumed an alcohol 10%/sucrose 30 g/l solution during 4 months. Control groups consumed only the sucrose vehicle solution. Then, animals experienced a progressive, 16 days long, CAC withdrawal, during which they were administered once daily with saline, igmesine (10 mg/kg i.p.), a σ1 receptor agonist, or BD1047 (10 mg/kg i.p.), a σ1 antagonist. Mice were then tested using an object exploration task, to evaluate their locomotor and exploratory activities and reactions to object habituation, spatial change or novel object presentation. CAC-treated animals showed augmentation of locomotion, anxiety and object exploration, which impeded correct reaction to object habituation, spatial change or novelty. Treatment with the σ1 ligands, ineffective in control groups, resulted in decrease of the hyper-responsiveness and restored habituation. However, correct reactions to spatial change and novelty were only produced by the σ1 agonist treatment. Moreover, the σ1 receptor hippocampal expression was increased in CAC-treated mice. Treatments with both σ1 ligands regulated its expression, but subcellular fractionation experiments revealed that the agonist treatment increased [3H](+)-pentazocine binding to σ1 sites in the plasma membrane fraction, while the antagonist maintained it only in the microsomal, putatively endoplasmic reticulum, fraction. In conclusion, CAC increased the σ1 receptor expression in the hippocampus of mice. Regulation of its expression during withdrawal, notably using a selective agonist, allowed not only to attenuate the CAC-induced hyper-responsiveness, but also to restore correct cognitive abilities.