ABSTRACT
Orexins (hypocretins) are peptides that have been shown to regulate behavioral arousal and wakefulness. Recent evidence indicates that orexin neurons are activated by stress and that orexins play a role in anxiety. The present paper describes a series of experiments that examined whether orexins are involved in the anxiety that resulted from exposing rats to an acute episode of footshocks (5 × 2 s of 1.5 mA shocks). We found that prepro-orexin (ppOX) mRNA was elevated in rats at 6 and 14 days after exposure to footshock and that ppOX mRNA levels were correlated with fear at 14 days post-shock. Systemic injections of the non-selective dual orexin receptor antagonist TCS-1102 (10 and 20 mg/kg, i.p.) were found to decrease fear and anxiety in rats 14 days after exposure to footshock. We also found that rats that exhibited a high level of immobility to a novel tone the day after the footshock episode (high responders, HR) showed significantly elevated levels of ppOX mRNA at 14 days post-shock compared to control rats. Furthermore, TCS-1102 (10 mg/kg, i.p.) was found to have anxiolytic effects that were specific for HR when tested in the elevated T-maze. This study provides evidence linking the orexin system to the anxiety produced by exposure of rats to a single episode of footshocks. It also provides preclinical evidence in support of the use of orexin antagonists for the treatment of anxiety in response to an acute episode of stress.
Subject(s)
Avoidance Learning/physiology , Benzimidazoles/pharmacology , Fear/physiology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/physiology , Neuropeptides/antagonists & inhibitors , Neuropeptides/physiology , Proline/analogs & derivatives , Stress, Psychological/physiopathology , Animals , Anxiety/physiopathology , Avoidance Learning/drug effects , Electric Stimulation , Fear/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Male , Neuropeptides/metabolism , Orexins , Proline/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
The central melanocortin system regulates hepatic lipid metabolism. Hepatic lipogenic gene expression is regulated by transcription factors including sterol regulatory element-binding protein 1c (SREBP-1c), carbohydrate responsive element-binding protein (ChREBP), and peroxisome proliferator-activated receptor gamma2 (PPARgamma2). However, it is unclear if central melanocortin signaling regulates hepatic lipogenic gene expression through the activation of these transcription factors. To delineate the molecular mechanisms by which the melanocortin system regulates hepatic lipid metabolism, we examined the effect of intracerebroventricular injection of SHU9119, a melanocortin receptor antagonist, on hepatic expression levels of genes involved in lipid metabolism in mice. SHU9119 treatment increased hepatic triglyceride content and mRNA levels of lipogenic genes, SREBP-1c, and PPARgamma2, whereas it did not cause any changes in hepatic ChREBP mRNA levels. These findings suggest that reduced central melanocortin signaling increases hepatic lipid deposition by stimulating hepatic lipogenic gene expression at least partly through the activation of SREBP-1c and PPARgamma2.
Subject(s)
Gene Expression Regulation , Lipogenesis/genetics , Liver/metabolism , Melanocortins/metabolism , PPAR gamma/genetics , Adipose Tissue, White/metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Lipogenesis/drug effects , Liver/drug effects , Male , Melanocyte-Stimulating Hormones/pharmacology , Mice , Mice, Inbred C57BL , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Receptors, Melanocortin/antagonists & inhibitors , Receptors, Melanocortin/metabolism , Signal Transduction , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , TriglyceridesABSTRACT
Galanin is a biologically active neuropeptide, widely distributed in the central and peripheral nervous systems and the endocrine system. The amino acid sequence of galanin is very conserved (almost 90% among species), indicating the importance of the molecule. Galanin has multiple biological effects. In the central nervous system, galanin alters the release of several neurotransmitters. In particular the ability of galanin to inhibit acetylcholine release, along with the observation of hyperinervation of galanin fibres in the human basal forebrain of Alzheimer's disease patients, suggest a possible role for galanin in the cholinergic dysfunction, characteristic of the disease. Moreover, galanin has been suggested to be involved in other neuronal functions, such as learning and memory, epileptic activity, nociception, spinal reflexes and feeding. Galanin has also been shown to increase the levels of growth hormone, prolactin and luteinizing hormone, to inhibit glucose induced insulin release and to affect gastrointestinal motility. The expression of galanin (mRNA and peptide levels) is elevated following estrogen administration, neuronal activation, denervation and/or nerve injury, as well as during development. The spectrum of galanin's activities indicates that galanin is an important messenger for intercellular communication within the nervous system and the neuroendocrine axis. Galanin acts at specific membrane receptors to exert its effects; so far three human and rodent galanin receptor subtypes have been cloned. Galanin agonists have been shown to have therapeutic application in treatment of chronic pain; galanin antagonists have therapeutic potential in treatment of Alzheimer's disease, depression, and feeding disorders.
