Recent functional, autoradiographic, and molecular investigations have shown that the pineal secretory product melatonin reduces the forskolin-stimulated insulin secretion from isolated pancreatic islets of neonate rats. Autoradiographic and binding studies as well as reverse transcriptase-polymerase chain reaction (RT-PCR) experiments proved that these effects are mediated through specific, high-affinity pertussis-toxin-sensitive Gi-protein-coupled MT(1) receptors and subsequent inhibition of the adenylyl cyclase/cyclic adenosine monophosphate (cAMP) system. This hypothesis was proved by blocking the intracellular signal transduction pathway using the non-hydrolyzable guanosine triphosphate analog guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) or the competitive melatonin receptor antagonist luzindole. Both GTPgammaS and luzindole diminished the melatonin effect. We have published these prior results elsewhere. So far, however, no information is available on both whether the MT1 receptors are located on the beta-cells and whether the consecutive functional reactions are based on a direct influence of melatonin on the insulin producing beta-cells. In order to examine this question, we used a glucose responsive insulin producing insulinoma cell line INS-1 isolated from rats. Comparable with the results of islets the competitive receptor antagonist luzindole diminished the insulin-decreasing effect of melatonin. In addition, our RT-PCR experiments, using specific primers for the rat melatonin receptor MT(1) showed that this melatonin receptor mRNA is also expressed in the INS-1 cells. Furthermore we radioimmunologically analyzed the forskolin-stimulated cAMP concentration in the superfusate. Similar to insulin secretion, the cAMP concentration was significantly reduced by melatonin. Following the hypothesis that cAMP is actively secreted from INS-1 cells by an energy-dependent mechanism based on either a OAT1/ROAT1 like anion exchanger or MDR-like transport systems, we used probenecid (p-[dipropylsulfamoyl] benzoic acid), a known inhibitor of cAMP extrusion. Probenecid blocks the export of cAMP by acting on transport mechanisms which are as yet not completely understood. Consistently, insulin secretion was increased and cAMP concentration diminished. The application of the phosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine) caused a marked rise of insulin secretion as well as cAMP concentration in the perifusate. From these data we conclude that the MT1 receptor is located on the INS-1 cell and therefore in general on pancreatic beta-cells.

Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the ␤-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence.antidepressant ͉ chronic depression ͉ osteoporosis ͉ bone formation ͉ adrenergic signaling

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Insulin plays a key role in the control of glucose homeostasis in mammals. Insulin secretion is regulated by a coordinated interplay of several factors. The role of the indoleamines in the control of insulin secretion has not been fully elucidated yet. The present study was addressed to investigate the function of melatonin and serotonin in the direct control of insulin secretion from the pancreatic islets. Explanted rat Langerhans' islets were treated with melatonin or serotonin while also being exposed to specific (glucose) or non-specific (KCl) stimulus either in a pulsatile or long-term manner in a perifusion system. Insulin content from the effluent tissue culture media was analyzed with RIA. Pulsatile administration of melatonin and serotonin alone did not alter the basal insulin secretion from the explanted islets even at pharmacological (5 microM) level. However, insulin response to specific (glucose) or non-specific (KCl) stimulus was significantly reduced while the islets were treated with melatonin (3 to 12 hr, 10 nM to 5 microM). This effect was reversible and repeatable. Both the start and end of the effect was rapid, evolving and disappearing within 10 min. On the other hand, under similar experimental protocol, serotonin (at 5 microM concentration) significantly enhanced both glucose and KCl stimulated insulin release. Since the effect of the non-specific stimulation (with KCl) was also altered, melatonin and serotonin seem to alter not only the release but also the synthesis of the insulin. Our data show that melatonin and serotonin have a direct effect on the insulin secretion from the pancreatic islets.

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