Abstract
The hypothalamus in the brain is the main center for appetite control and integrates signals from adipose tissue and the gastrointestinal tract. Antidepressants are known to modulate the activities of hypothalamic neurons and affect food intake, but the cellular and molecular mechanisms by which antidepressants modulate hypothalamic function remain unclear. Here we have investigated how hypothalamic neurons respond to treatment with antidepressants, including desipramine and sibutramine. In primary cultured rat hypothalamic cells, desipramine markedly suppressed the elevation of intracellular Ca2+ evoked by histamine H1 receptor activation. Desipramine also inhibited the histamine-induced Ca2+ increase and the expression of corticotrophin-releasing hormone in hypothalamic GT1-1 cells. The effect of desipramine was not affected by pretreatment with prazosin or propranolol, excluding catecholamine reuptake activity of desipramine as an underlying mechanism. Sibutramine which is also an antidepressant but decreases food intake, had little effect on the histamine-induced Ca2+ increase or AMP-activated protein kinase activity. Our results reveal that desipramine and sibutramine have different effects on histamine H1 receptor signaling in hypothalamic cells and suggest that distinct regulation of hypothalamic histamine signaling might underlie the differential regulation of food intake between antidepressants.
Highlights
Appetite is subjected to multiple layers of regulation by several neuropeptides and neuromodulators in a number of regions of the hypothalamus, including the arcuate nucleus, paraventricular nucleus, and lateral hypothalamic area
Desipramine inhibits the increase in cytosolic Ca2+ concentration ([Ca2+]i) induced by histamine in rat hypothalamic cells To investigate neurotransmitter receptor-mediated signaling in the hypothalamus, we prepared primary cultures of rat hypothalamic cells, including cells from the paraventricular nucleus, an appetite modulation center
We reveal that desipramine, but not sibutramine, inhibits histamine signaling in both primary rat hypothalamic cells and GT1-1 cells
Summary
Appetite is subjected to multiple layers of regulation by several neuropeptides and neuromodulators in a number of regions of the hypothalamus, including the arcuate nucleus, paraventricular nucleus, and lateral hypothalamic area. Neuropeptide Y and alpha-melanocortin are released from the arcuate nucleus to modulate neuronal activity in the paraventricular nucleus and lateral hypothalamus [1]. Numerous intrinsic and extrinsic factors that modulate hypothalamic neuronal activity are known to affect food intake. Drugs affecting adrenergic and serotonergic signaling (such as phentermine, phenylpropanolamine, amphetamine, and fenfluramine) have been shown to either decrease appetite or increase satiety [2,3]. Food intake behavior is influenced by chemicals or drugs that block the reuptake or enhance the release of neurotransmitters, such as serotonin or catecholamines [4,5]
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