5-HT and NA Reuptake Inhibitors and Appetite Regulation: The Role of the Central 5-HT Network

Author(s): Katsunori Nonogaki.

Journal Name: Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Under Re-organization)

Volume 8 , Issue 4 , 2008

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Abstract:

Brain serotonin (5-hydroxytryptamine; 5-HT) systems have been implicated in the leptin-independent neural regulation of appetite, as indicated by the anorectic effects of drugs that directly or indirectly stimulate postsynaptic 5-HT receptors. The identification of 5-HT subtype receptor functions in the regulation of feeding behavior and energy balance using genetic models has shed new light on the poorly understood area of leptin-independent appetite regulation. With the voluntary withdrawal of d-fenfluramine, which inhibits serotonin (5-HT) uptake and induces 5-HT release, due to primary pulmonary hypertension, research attention has been focused on the downstream pathways of central 5-HT subtype receptors, especially 5-HT2C receptors (5-HT2CRs), in the regulation of satiety. Central 5-HT systems which operate via 5- HT2CRs have a complex neural network, with certain neurons in the hypothalamus harboring appetite regulatory neuropeptides such as proopiomelanocortin (POMC) and corticosterone releasing hormone (CRH). The 5-HT drugs, which enhance 5-HT release via 5-HT2CR in the hypothalamus, induce the activation of hypothalamus-pituitary adrenal (HPA) axis as well as satiety. On the other hand, the selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and noradrenalin reuptake inhibitors (SNRIs) induce satiety without stimulating the HPA axis. 5-HT2CR and 5-HT1BR substantially contribute to the anorexic effects of fenfluramine, whereas inactivation of 5-HT2CR enhances the effects of SSRIs so as to increase extracellular 5-HT in the brain and induce the appetite suppressing effects via 5-HT1BR. Moreover, SNRIs induce satiety independently of 5-HT2CRs and 5-HT1BRs. alpha-1 Adrenoceptors likely contribute to the appetite suppressing effects of SNRIs. Thus, the complex 5-HT network systems orchestrate leptin-independent central appetite regulation.

Keywords: Inhibitors, Brain serotonin, 5-HT receptors, hypothalamus, fenfluramine, appetite regulation

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Article Details

VOLUME: 8
ISSUE: 4
Year: 2008
Page: [303 - 310]
Pages: 8
DOI: 10.2174/187152208787169198
Price: $58