GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality

Jan 3, 2016Psychoneuroendocrinology

GLP-1 may increase anxiety but also reduce depression, with different effects from short-term and long-term exposure

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Abstract

GLP-1 and its analog, Exendin-4, have contrasting effects on anxiety and depression-like behaviors in rats.

Acute administration of GLP-1 and Exendin-4 increased anxiety-like behavior in multiple behavioral tests.
Acute stimulation of GLP-1 receptors affected serotonin signaling in the amygdala.
Chronic administration of Exendin-4 did not change anxiety-like behavior but significantly decreased depression-like behavior in the forced swim test.
The antidepressant effect of Exendin-4 was not linked to body weight loss or reduced food intake.
Central GLP-1 activation has distinct impacts on emotionality, which vary between acute and chronic conditions.

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Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression.

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GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality

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