Effect of mineralocorticoid receptor blockade on hippocampal-dependent memory in adults with obesity

Abstract

Objective The hippocampus is crucial for paired-associate learning. Obesity is associated with increased mineralocorticoid receptor (MR) activity in peripheral and possibly central tissues, decreased hippocampal size in humans, and impaired hippocampal learning in rodents. The MR is expressed in hippocampal neurons, and MR blockade improves hippocampal learning in obese animals. The goal of the study was to determine whether MR blockade would modulate paired-associate learning in men and women with obesity. Methods Men and women ages 20-61 years with BMI between 30-45 kg/m2 were randomly assigned to placebo (n=11; 7 women) or 50 mg spironolactone daily (n=12; 7 women) for six weeks. At baseline and post-treatment, subjects underwent a clinical and hormonal evaluation. They also underwent a computerized task that assesses paired-associate learning and has been shown by functional magnetic resonance imaging to activate the hippocampus. Results In an ANCOVA model that adjusted for baseline paired-associate learning, age, and race, spironolactone treatment was associated with a significant (P=0.043) improvement in hippocampal memory as compared to placebo treatment. Conclusions Our findings demonstrate, for the first time, that blocking MR with chronic, low-dose spironolactone treatment improves paired-associate learning in individuals with obesity, suggesting that MR activation contributes to hippocampal memory modulation in humans.