ABSTRACT
The growth hormone secretagogue receptor (GHS-R) is expressed in several tissues and seems to mediate the different actions of the synthetic growth hormone secretagogues (GHS) and the endogenous ligand of this receptor, ghrelin. The GHS-R belongs to the family of G-protein coupled receptors (GPCR). Two different receptor variants, type 1a and 1b, have been described and they seem to mediate different actions in different tissues. In addition to their functions on growth hormone (GH) secretion and food intake, ghrelin and its receptor are involved in several cardiovascular mechanisms, pancreatic functions, adipogenesis, gonadal function, immune system actions or tumoral cells. This review will summarize data regarding the structure of the GHS-R gene, reports investigating the expression, control and functions of the GHS-R in various tissues, and studies of the underlying transcriptional mechanisms and the genetic manipulation of both ghrelin and GHS-R. Thus, it seems clear the possibility that ghrelin and/or GHS analogs, acting as either agonists or antagonists on different activities, might have clinical impact.
Subject(s)
Body Weight/physiology , Drug Delivery Systems/methods , Receptors, G-Protein-Coupled/physiology , Animals , Body Weight/drug effects , Humans , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, GhrelinABSTRACT
1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.
Subject(s)
Appetite Depressants/pharmacology , Cyclobutanes/pharmacology , Frontal Lobe/drug effects , Hypothalamus/drug effects , Norepinephrine/metabolism , Receptors, Adrenergic, alpha-2/physiology , Adrenergic alpha-Antagonists/pharmacology , Animals , Dialysis , Frontal Lobe/metabolism , Hypothalamus/metabolism , Idazoxan/analogs & derivatives , Idazoxan/pharmacology , Imidazoles/pharmacology , Male , Rats , Rats, Sprague-DawleyABSTRACT
1. The effects of sibutramine (0.25 - 10 mg kg-1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane-anaesthetized rats were compared with those of d-amphetamine (1 - 3 mg kg-1, i.p.) using in vivo microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective alpha2-adrenoceptor antagonist, RX821002. 2. Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose-response relationship was described by a bell-shaped curve with a maximum effect at 0.5 mg kg-1. In contrast, d-amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose. 3. Pretreatment with the alpha2-adrenoceptor antagonist, RX821002 (dose 3 mg kg-1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg-1) and reduced the latency of sibutramine to reach its maximum effect from 144 - 56 min. 4. RX821002-pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d-amphetamine alone (10 mg kg-1) and had no effect on the latency to reach maximum. 5. These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic alpha2-adreno-ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d-amphetamine is consistent with this being mainly due to an increase in Ca2+-independent release of noradrenaline.
