Leptin: A potential novel antidepressant

Abstract

Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedoniclike deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders.depression ͉ hippocampus ͉ stress ͉ forced swim test ͉ social defeat

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

“…Rats or mice exposed to chronic unpredictable stress or chronic social defeat stress develop behavioral deficits and endocrine abnormalities, mimicking the symptoms of human depression. While acute stress had no effect on levels of leptin, rats exposed to chronic unpredictable stress or chronic social defeat stress showed decreased basal levels of leptin in plasma [7]. This decrease in chronically stressed animals was independent of body weight alterations but correlated with behavioral changes.…”

“…One of the depression-like behaviors in chronically stressed animals is reduction of sucrose preference, which is regarded as an analog of anhedonia, a key symptom of depression in human [12,13]. Systemic administration of leptin can reverse the chronic stress-induced decrease in sucrose preference [7]. Sucrose preference in non-stressed rats, however, was not affected by leptin treatment, suggesting that leptin does not have hedonic-like effects in the absence of a hedonic deficit.…”

“…Immobility can be reduced by acute or chronic administration of various existing antidepressant drugs [14,15]. Systemic leptin administration was found to produce a dose-dependent reduction of the duration of immobility in both tests [7,16]. Locomotor activity was not affected by leptin treatment as compared with controls, suggesting that the immobility-antagonizing effects of leptin in the FST and TST are not due to nonspecific stimulation of locomotion [7].…”

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

“…The CUS procedure is a modification of published procedures (Katz et al, 1981;Lu et al, 2006;Willner et al, 1987). One day before beginning the chronic unpredictable stress, rats were housed individually, and the CUS procedure was then applied for 14 consecutive days, as outlined in Table 1.…”

“…However, although many pre-clinical studies attempting to model aspects of depression have focused on behaviors thought to represent anhedonia, reduced locomotor activity or behavioral despair (eg, Lu et al, 2006;Rygula et al, 2005;Willner, 1997;Willner and Mitchell, 2002), relatively few have attempted to model cognitive impairments or state anxiety associated with depression.…”