Effects of metabotropic 2/3-glutamate receptor agonism and antagonism on activity-based anorexia model in mice

Neuropharmacology. 2026 Oct 6:111217. doi: 10.1016/j.neuropharm.2026.111217. Online ahead of print.

ABSTRACT

Anorexia nervosa is an eating disorder disproportionately found in female teens and young adults. It is often resistant to treatment, has a significant chance of relapse and is more lethal than other eating disorders, such as bulimia nervosa or Avoidant/Restrictive Food Intake Disorder (ARFID). There is no specific medication for the treatment of anorexia nervosa. Treatment consists of psychosocial means, psychotherapy, psychoeducation, and nutritional counseling. Medication is usually used for treating comorbidities such as anxiety or to decrease obsessive-compulsive tendencies. These medications cannot help the patient regain weight or treat core symptoms. Metabotropic 2/3-glutamate (mGluR2/3) receptor agonist (LY379268) and antagonist (LY341495) are promising pharmacological agents to treat psychiatric disorders. Both have been reported to be anxiolytic, while antagonists have shown antidepressant-like effects in preclinical studies. The activity-based anorexia (ABA) paradigm is used to study mechanisms related to anorexia nervosa. It consists of giving mice access to a running wheel and restricting their feeding time. This causes mice to exercise more than mice without feeding time restriction and to eat less than mice without access to a moving running wheel. In this study, we subcutaneously injected female ABA model mice with a metabotropic 2/3-glutamate receptor agonist (LY379268) and antagonist (LY341495) in two experiments. Both compounds exacerbated weight loss by decreasing food intake as well as increasing physical activity. It can be concluded that the pharmacological manipulation of mGluR2/3 receptors is detrimental for the female ABA model and, therefore, might be potentially harmful for anorexia nervosa as well.

PMID:42838416 | DOI:10.1016/j.neuropharm.2026.111217