Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression

作者：Nollet Mathieu; Gaillard Philippe; Minier Frederic; Tanti Arnaud; Belzung Catherine; Leman Samuel^*

来源：Neuropharmacology, 2011, 61(1-2): 336-346.

DOI：10.1016/j.neuropharm.2011.04.022

• Depression
• Orexin/hypocretin
• Melanin-concentrating hormone
• Antidepressant
• Dorsomedial/perifornical hypothalamic area
• Dual orexin receptor antagonist

Chronic stressful life events are risk factors for depression often accompanied by homeostatic disturbances. Hypothalamic neuropeptides, such as orexins (OXs) and melanin-concentrating hormone (MCH), are involved in regulation of several autonomic functions that are altered in depression. However, little is known about the link between orexinergic or MCH-ergic systems and depression. Using double immunohistochemical labeling for OX- or MCH-containing neurons and Fos protein, we studied the effects of a chronic selective serotonin reuptake inhibitor antidepressant treatment (fluoxetine) on the OX and MCH neuronal activation in mice exposed to unpredictable chronic mild stress (UCMS), a rodent model of depression. Western blot was also performed to assess OX and MCH receptor expression in various brain areas. Finally, almorexant, a dual OX receptor antagonist, was assessed in the tail suspension test. UCMS induced physical and behavioral disturbances in mice reversed by 6-week fluoxetine treatment. Orexinergic neurons were more activated in the dorsomedial and perifornical hypothalamic area (DMH-PFA) of UCMS-subjected mice compared to the lateral hypothalamus (LH), and this increase was reversed by 6-week fluoxetine treatment. UCMS also reduced expression of OX-receptor 2 in the thalamus and hypothalamus, but not in animals chronically treated with fluoxetine. MCH neurons were neither affected by UCMS nor by antidepressant treatment, while UCMS modulated MCH receptor 1 expression in thalamus and hippocampus. Finally, chronic but not acute administration of almorexant, induced antidepressant-like effect in the tail suspension test. These data suggest that OX neurons in the DMH-PFA and MCH-ergic system may contribute to the pathophysiology of depressive disorders.

• 出版日期2011-8