Background: Most antidepressant medications target central monoamine systems and are often characterized by limited efficacies and unwanted side effects. Thus, significant efforts are ongoing to identify novel targets for the treatment of depression. Growing evidence suggests that neuropeptides play a role in the pathophysiology of depression. The melanin-concentrating hormone (MCH) is one such neuropeptide, implicated in the modulation of many physiological responses.
Methods: We utilized an array of techniques including chronic mild stress (CMS) as a depression paradigm, neurobehavior, gene expression analysis, and knockout genetics to investigate the role of MCH receptor subtype 1 (MCHR1) in murine models of depression.
Results: We report here that following a 5-week exposure to repeated chronic mild stress (an ethologically relevant animal model of depression), C57Bl/6J mice have increased hippocampal gene expression of MCH receptor subtype 1 (MCHR1), the cognate melanin concentrating hormone receptor in mice. This increased gene expression is reversed by chronic fluoxetine hydrochloride (Prozac) treatment. Additionally, while female and male mice carrying a null mutation of the MCHR1 gene show comparable anxiolytic-like behavior on the open field, only female knockout mice exhibit antidepressant-like behavior, when tested on the forced swim and tail suspension tests.
Conclusion: Taken together, we suggest that antagonism of the MCHR1 receptor may provide a novel approach for the treatment of affective disorders, including depression, with a potentially increased efficacy in women.