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1.
Mol Psychiatry ; 20(11): 1420-7, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25560759

ABSTRACT

Antidepressant drugs are commonly prescribed treatments for anxiety disorders, and there is growing interest in understanding how these drugs impact fear extinction because extinction learning is pivotal to successful exposure-based therapy (EBT). A key objective within this domain is understanding how antidepressants alter the activation of specific elements of the limbic-based network that governs such fear processing. Chronic treatment with the antidepressant tianeptine has been shown to reduce the acquisition of extinction learning in rats, yet the drug's acute influence on activation in prefrontal and amygdalar regions, and on extinction learning are not well understood. To assess its influence on cellular activation, rats were injected with tianeptine and Fos immunoreactivity was measured in these regions. Acute tianeptine treatment selectively altered Fos expression within subdivisions of the central nucleus of the amygdala (CEA) in a bidirectional manner that varied in relation to ongoing activation within the capsular subdivision and its prefrontal and intra-amygdalar inputs. This pattern of results suggests that the drug can conditionally modulate the activation of CEA subdivisions, which contain microcircuits strongly implicated in fear processing. The effect of acute tianeptine was also examined with respect to the acquisition, consolidation and expression of fear extinction in rats. Acute tianeptine attenuated extinction learning as well as the recall of extinction memory, which underscores that acute dosing with the drug could alter learning during EBT. Together these findings provide a new perspective for understanding the mechanism supporting tianeptine's clinical efficacy, as well as its potential influence on CEA-based learning mechanisms.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Central Amygdaloid Nucleus/cytology , Extinction, Psychological/drug effects , Fear/drug effects , Neurons/drug effects , Thiazepines/pharmacology , Acoustic Stimulation/adverse effects , Analysis of Variance , Animals , Central Amygdaloid Nucleus/drug effects , Conditioning, Psychological/drug effects , Gene Expression Regulation/drug effects , Male , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Time Factors
2.
Br J Pharmacol ; 171(15): 3604-19, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24724693

ABSTRACT

Agomelatine behaves both as a potent agonist at melatonin MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic and 5-hydroxytryptaminergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in hippocampal proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodelling, glutamate signalling) and key targets (early genes, kinases). The present review focuses on the pharmacological properties of this novel antidepressant. Its mechanism of action, strikingly different from that of conventional classes of antidepressants, opens perspectives towards a better understanding of the physiopathological bases underlying depression.


Subject(s)
Acetamides/pharmacology , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Acetamides/therapeutic use , Animals , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Anxiety/drug therapy , Circadian Rhythm , Depression/drug therapy , Humans , Neurogenesis , Receptor, Melatonin, MT1/agonists , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/agonists , Receptor, Melatonin, MT2/metabolism , Serotonin 5-HT2 Receptor Antagonists/therapeutic use
3.
Mol Psychiatry ; 18(4): 471-84, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22733125

ABSTRACT

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Neuronal Plasticity/drug effects , Protein Transport/drug effects , Receptors, AMPA/metabolism , Synapses/drug effects , Thiazepines/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Benzylamines/pharmacology , Calcium Channels/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Corticosterone/pharmacology , Disks Large Homolog 4 Protein , Excitatory Postsynaptic Potentials/drug effects , Guanylate Kinases/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Membrane Proteins/metabolism , Mice , Neuronal Plasticity/physiology , Protein Kinase Inhibitors/pharmacology , Protein Transport/physiology , Signal Transduction/drug effects , Sulfonamides/pharmacology , Synapses/metabolism
4.
Psychopharmacology (Berl) ; 224(2): 313-25, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22707231

ABSTRACT

RATIONALE: Chronic social defeat stress (CSDS) has been proposed as a model of depression. However, most CSDS studies rely only on the analysis of stress-induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed, let alone its interaction with biological risk factors. OBJECTIVES: Here, we explore the validity of CSDS as a depression model. Further, the effect of decreased vesicular glutamate transporter 1 (VGLUT1), as a potential factor enhancing a depressive-like phenotype, was studied. METHODS: Mice were exposed to CSDS (10 days) followed by saline, venlafaxine, fluoxetine, or tianeptine treatment (30 days). The battery of behaviors included motor activity, memory, anxiety, social interaction, helplessness, and anhedonic-like behavior. Moreover, the behavioral effect of CSDS in VGLUT1 heterozygous (VGLUT1+/-) mice was studied, as well as the regulation of VGLUT1 mRNA. RESULTS: CSDS induced anhedonia, helplessness, hyperactivity, anxiety, social avoidance, and freezing, as well as downregulation of VGLUT1 mRNA in the amygdala. Repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. CSDS-induced social avoidance was reverted by tianeptine. Fluoxetine failed to revert most of the behavioral alterations. VGLUT1+/- mice showed an enhanced vulnerability to stress-induced social avoidance. CONCLUSION: We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role.


Subject(s)
Antidepressive Agents/pharmacology , Stress, Psychological/drug therapy , Stress, Psychological/genetics , Animals , Anxiety/drug therapy , Anxiety/genetics , Behavior, Animal , Cyclohexanols/pharmacology , Depression/drug therapy , Depression/genetics , Depressive Disorder/drug therapy , Depressive Disorder/genetics , Disease Models, Animal , Fluoxetine/pharmacology , Male , Mice , Mice, Inbred C57BL , RNA, Messenger/biosynthesis , Risk Factors , Social Behavior , Thiazepines/pharmacology , Venlafaxine Hydrochloride , Vesicular Glutamate Transport Protein 1
5.
J Neuroendocrinol ; 24(5): 798-808, 2012 May.
Article in English | MEDLINE | ID: mdl-22512326

ABSTRACT

GPR50, formerly known as melatonin-related receptor, is one of three subtypes of the melatonin receptor subfamily, together with the MT(1) and MT(2) receptors. By contrast to these two high-affinity receptor subtypes and despite its high identity with the melatonin receptor family, GPR50 does not bind melatonin or any other known ligand. Specific and reliable immunological tools are therefore needed to be able to elucidate the physiological functions of this orphan receptor that are still largely unknown. We have generated and validated a new specific GPR50 antibody against the ovine GPR50 and used it to analyse the neuroanatomical distribution of the GPR50 in sheep, rat and mouse whole brain. We demonstrated that GPR50-positive cells are widely distributed in various regions, including the hypothalamus and the pars tuberalis of the pituitary, in all the three species studied. GPR50 expressing cells are abundant in the dorsomedial nucleus of the hypothalamus, the periventricular nucleus and the median eminence. In rodents, immunohistochemical studies revealed a broader distribution pattern for the GPR50 protein. GPR50 immunoreactivity is found in the medial preoptic area (MPA), the lateral septum, the lateral hypothalamic area, the bed nucleus of the stria terminalis, the vascular organ of the laminae terminalis and several regions of the amygdala, including the medial nuclei of amygdala. Additionally, in the rat brain, GPR50 protein was localised in the CA1 pyramidal cell layer of the dorsal hippocampus. In mice, moderate to high numbers of GPR50-positive cells were also found in the subfornical organ. Taken together, these results provide an enlarged distribution of GPR50 protein, give further insight into the organisation of the melatoninergic system, and may lay the framework for future studies on the role of the GPR50 in the brain.


Subject(s)
Brain/metabolism , Nerve Tissue Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Rodentia/metabolism , Sheep/metabolism , Age Factors , Animals , Brain/anatomy & histology , Female , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Rabbits , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/physiology , Rodentia/anatomy & histology , Rodentia/genetics , Sheep/anatomy & histology , Sheep/genetics , Tissue Distribution
6.
Mol Psychiatry ; 17(2): 173-84, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21242991

ABSTRACT

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.


Subject(s)
AIDS-Related Complex/metabolism , Depression/complications , Emotions/physiology , MAP Kinase Signaling System/physiology , Memory Disorders/etiology , Receptors, Serotonin/metabolism , Analysis of Variance , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Benzopyrans/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Citalopram/therapeutic use , Depression/drug therapy , Depression/genetics , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Exploratory Behavior/drug effects , Gene Expression Regulation/drug effects , Hippocampus/metabolism , Immunoprecipitation , MAP Kinase Signaling System/genetics , Memory Disorders/drug therapy , Memory Disorders/pathology , Prefrontal Cortex/metabolism , Rats , Rats, Mutant Strains , Receptors, N-Methyl-D-Aspartate/metabolism , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/therapeutic use , Swimming/psychology
7.
Anim Reprod Sci ; 122(3-4): 328-34, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21075566

ABSTRACT

In seasonal breeding species, the gene encoding for the melatonin MT(1) receptor (oMT(1)) is highly polymorphic and numerous data have reported the existence of an association between an allele of the receptor and a marked expression of the seasonality of reproduction in ewes. This allele called "m" (previously named "-" allele) carries a mutation leading to the absence of a MnlI restriction site as opposed to the "M" allele (previously named "+" allele) carrying the MnlI restriction site (previously "+" allele). This allows the determination of the three genotypes "M/M" (+/+), "M/m" (+/-) and "m/m" (-/-). This mutation is conservative and could therefore not be causal. However, it is associated with another mutation introducing the change of a valine to an isoleucine in the fifth transmembrane domain of the receptor. Homozygous "M/M" and "m/m" animals consequently express structurally different receptors respectively named oMT(1) Val(220) and oMT(1) Ile(220). The objective of this study was to test whether these polymorphic variants are functionally different. To achieve this goal, we characterized the binding properties and the transduction pathways associated with both variants of the receptors. Using a pharmacological approach, no variation in binding parameters between the two receptors when transiently expressed in COS-7. In stably transfected HEK293 cells, significant differences were detected in the inhibition of cAMP production whereas receptors internalization processes were not different. In conclusion, the possibility that subtle alterations induced by the non conservative mutation in "m/m" animals might modify the perception of the melatoninergic signal is discussed in the context of melatonin action.


Subject(s)
Polymorphism, Genetic/physiology , Receptor, Melatonin, MT1/genetics , Reproduction/genetics , Seasons , Sheep/genetics , Sheep/physiology , Alleles , Animals , Breeding , COS Cells , Chlorocebus aethiops , Cyclic AMP/biosynthesis , Female , Gene Expression , Genotype , HEK293 Cells , Humans , Iodine Radioisotopes , Melatonin/metabolism , Receptor, Melatonin, MT1/metabolism , Transfection
8.
J Neuroendocrinol ; 22(11): 1148-56, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20819119

ABSTRACT

The master circadian pacemaker in the suprachiasmatic nuclei (SCN) regulates the nocturnal secretion of the pineal hormone melatonin. Melatonin, in turn, has feedback effects on SCN neuronal activity rhythms via high affinity G protein-coupled receptors (MT(1) and MT(2) ). However, the precise effects of melatonin on the electrical properties of individual SCN neurones are unclear. In the present study, we investigated the acute effects of exogenous melatonin on SCN neurones using whole-cell patch-clamp recordings in brain slices prepared from Per1::d2EGFP-expressing transgenic mice. In current-clamp mode, bath applied melatonin, at near-physiological concentrations (1 nM), hyperpolarised the majority (63.7%) of SCN neurones tested at all times of the projected light/dark cycle. In addition, melatonin depolarised a small proportion of cells (11.0%). No differences were observed for the effects of melatonin between Per1::GFP or non-Per1::GFP SCN neurones. Melatonin-induced effects were blocked by the MT(1)/MT(2) antagonist, luzindole (1 µM) and the proportion of SCN neurones responsive to melatonin was greatly reduced in the presence of either tetrodotoxin (200 or 500 nM) or gabazine (20 µM). In voltage-clamp recordings, 1 nM melatonin increased the frequency of GABA-mediated currents. These findings indicate, for the first time, that exogenous melatonin can alter neuronal excitability in the majority of SCN neurones, regardless of whether or not they overtly express the core clock gene Per1. The results also suggest that melatonin acts mainly by modulating inhibitory GABAergic transmission within the SCN. This may explain why exogenous application of melatonin has heterogenous effects on individual SCN neurones.


Subject(s)
Melatonin/pharmacology , Neurons/drug effects , Period Circadian Proteins/genetics , Suprachiasmatic Nucleus/drug effects , Animals , Cell Membrane/drug effects , Cell Membrane/ultrastructure , Electrophysiological Phenomena , Female , GABA Antagonists/pharmacology , Green Fluorescent Proteins , Hypothalamus/drug effects , Hypothalamus/metabolism , In Vitro Techniques , Male , Mice , Patch-Clamp Techniques , Pyridazines/pharmacology , Receptor, Melatonin, MT1/antagonists & inhibitors , Receptor, Melatonin, MT2/antagonists & inhibitors , Receptors, GABA-A/drug effects , Synaptic Transmission/drug effects , Tetrodotoxin/pharmacology , Tryptamines/pharmacology , gamma-Aminobutyric Acid/physiology
9.
Br J Pharmacol ; 158(5): 1248-62, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19814723

ABSTRACT

BACKGROUND AND PURPOSE: For many years, it was suspected that sheep expressed only one melatonin receptor (closely resembling MT(1) from other mammal species). Here we report the cloning of another melatonin receptor, MT(2), from sheep. EXPERIMENTAL APPROACH: Using a thermo-resistant reverse transcriptase and polymerase chain reaction primer set homologous to the bovine MT(2) mRNA sequence, we have cloned and characterized MT(2) receptors from sheep retina. KEY RESULTS: The ovine MT(2) receptor presents 96%, 72% and 67% identity with cattle, human and rat respectively. This MT(2) receptor stably expressed in CHO-K1 cells showed high-affinity 2[(125)I]-iodomelatonin binding (K(D)= 0.04 nM). The rank order of inhibition of 2[(125)I]-iodomelatonin binding by melatonin, 4-phenyl-2-propionamidotetralin and luzindole was similar to that exhibited by MT(2) receptors of other species (melatonin > 4-phenyl-2-propionamidotetralin > luzindole). However, its pharmacological profile was closer to that of rat, rather than human MT(2) receptors. Functionally, the ovine MT(2) receptors were coupled to G(i) proteins leading to inhibition of adenylyl cyclase, as the other melatonin receptors. In sheep brain, MT(2) mRNA was expressed in pars tuberalis, choroid plexus and retina, and moderately in mammillary bodies. Real-time polymerase chain reaction showed that in sheep pars tuberalis, premammillary hypothalamus and mammillary bodies, the temporal pattern of expression of MT(1) and MT(2) mRNA was not parallel in the three tissues. CONCLUSION AND IMPLICATIONS: Co-expression of MT(1) and MT(2) receptors in all analysed sheep brain tissues suggests that MT(2) receptors may participate in melatonin regulation of seasonal anovulatory activity in ewes by modulating MT(1) receptor action.


Subject(s)
Receptor, Melatonin, MT2/genetics , Amino Acid Sequence , Animals , Brain/metabolism , CHO Cells , Cattle , Cloning, Molecular , Cricetinae , Cricetulus , Female , GTP-Binding Proteins/metabolism , Humans , Molecular Sequence Data , Organ Specificity , RNA, Messenger/metabolism , Radioligand Assay , Rats , Receptor, Melatonin, MT1/antagonists & inhibitors , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/antagonists & inhibitors , Receptor, Melatonin, MT2/metabolism , Recombinant Proteins/metabolism , Retina/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Amino Acid , Sheep , Tetrahydronaphthalenes/pharmacology , Tryptamines/pharmacology
10.
Br J Pharmacol ; 154(6): 1182-95, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18493248

ABSTRACT

Melatonin is a neurohormone that has been claimed to be involved in a wide range of physiological functions. Nevertheless, for most of its effects, the mechanism of action is not really known. In mammals, two melatonin receptors, MT1 and MT2, have been cloned. They belong to the G-protein-coupled receptor (GPCR) superfamily. They share some specific short amino-acid sequences, which suggest that they represent a specific subfamily. Another receptor from the same subfamily, the melatonin-related receptor has been cloned in different species including humans. This orphan receptor also named GPR50 does not bind melatonin and its endogenous ligand is still unknown. Nevertheless, this receptor has been shown to behave as an antagonist of the MT1 receptor, which opens new pharmacological perspectives for GPR50 despite the lack of endogenous or synthetic ligands. Moreover, MT1 and MT2 interact together through the formation of heterodimers at least in cells transfected with the cDNA of these two receptors. Lastly, signalling complexes associated with MT1 and MT2 receptors are starting to be deciphered. A third melatonin-binding site has been purified and characterized as the enzyme quinone reductase 2 (QR2). Inhibition of QR2 by melatonin may explain melatonin's protective effect that has been reported in different animal models and that is generally associated with its well-documented antioxidant properties.


Subject(s)
Receptors, Melatonin/drug effects , Receptors, Melatonin/physiology , Signal Transduction/drug effects , Signal Transduction/physiology , Animals , Binding Sites/drug effects , Dimerization , Humans , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Receptor, Melatonin, MT1/drug effects , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/drug effects , Receptor, Melatonin, MT2/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/physiology , Receptors, Melatonin/metabolism , Tissue Distribution
11.
J Endocrinol ; 184(3): 505-13, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15749809

ABSTRACT

Glucagon-like peptide 1 (GLP-1) analogues are considered potential drugs for type 2 diabetes. We studied the effect of a novel GLP-1 analogue, S 23521 ([a8-des R36] GLP-1-[7-37]-NH2), on the metabolic state and beta-cell function, proliferation and survival in the Psammomys obesus model of diet-induced type 2 diabetes. Animals with marked hyperglycaemia after 6 days of high-energy diet were given twice-daily s.c. injection of 100 microg/kg S 23521 for 15 days. Food intake was significantly decreased in S 23251-treated P. obesus; however, there was no significant difference in body weight from controls. Progressive worsening of hyperglycaemia was noted in controls, as opposed to maintenance of pre-treatment glucose levels in the S 23521 group. Prevention of diabetes progression was associated with reduced mortality. In addition, the treated group had higher serum insulin, insulinogenic index and leptin, whereas plasma triglyceride and non-esterified fatty acid levels were decreased. S 23521 had pronounced effect on pancreatic insulin, which was 5-fold higher than the markedly depleted insulin reserve of control animals. Immunohistochemical analysis showed islet degranulation with disrupted morphology in untreated animals, whereas islets from S 23521-treated animals appeared intact and filled with insulin; beta-cell apoptosis was approximately 70% reduced, without a change in beta-cell proliferation. S 23521 treatment resulted in a 2-fold increase in relative beta-cell volume. Overall, S 23521 prevented the progression of diabetes in P. obesus with marked improvement of the metabolic profile, including increased pancreatic insulin reserve, beta-cell viability and mass. These effects are probably due to actions of S 23521 both directly on islets and via reduced food intake, and emphasize the feasibility of preventing blood glucose deterioration over time in type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucagon/therapeutic use , Hypoglycemic Agents/therapeutic use , Peptide Fragments/therapeutic use , Protein Precursors/therapeutic use , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diet , Female , Gerbillinae , Glucagon/blood , Insulin/blood , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Leptin/blood , Male , Models, Animal
12.
J Pineal Res ; 37(3): 176-84, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15357662

ABSTRACT

The ability of daily melatonin and the melatonin receptor antagonist, S22153, to entrain circadian system function was investigated in mice with atypical melatonin rhythm. B6D2F(1) mice were first synchronized to a LD 12:12 for approximately 2 wk, then exposed to continuous light (LL) until study completion. After 10-18 days of LL exposure, mice received daily subcutaneous (s.c.) melatonin at a dose of 0.1, 1 or 10 mg/kg/day (exp. 1) or daily intraperitoneal (i.p.) S22153 (20 mg/kg/day) with or without melatonin (1 mg/kg/day, exp. 2) at subjective zeitgeber time (ZT) 10 for 19 days. Then all the mice were exposed to LL for another 10 days. Spectral analysis showed that initial LL lengthened the period of both rhythms by approximately 1.5 hr as compared with LD 12:12. No entrainment of either rhythm was found in controls. Conversely, daily melatonin-only, S22153-only or their combination set the temperature and activity periods to approximately 24 hr and produced a significant increase of the circadian amplitude of both rhythms as compared with controls. However, after treatment withdrawal, the dominant period lengthened to approximately 25.5 hr in mice receiving either melatonin or S22153. On the contrary, the period remained close to 24 hr for the 10 days following withdrawal of combined S22153 and melatonin. Such sustained pharmacological resetting of circadian function could display therapeutic potential against external resynchronization resulting from defective photoperiodic entrainment.


Subject(s)
Circadian Rhythm/drug effects , Melatonin/pharmacology , Receptors, Melatonin/antagonists & inhibitors , Thiophenes/pharmacology , Animals , Body Temperature/drug effects , Drug Therapy, Combination , Injections, Intraperitoneal , Light , Male , Mice , Mice, Inbred Strains , Motor Activity/drug effects
13.
J Physiol Biochem ; 60(1): 61-72, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15352385

ABSTRACT

Melatonin is a lipophilic hormone, mainly produced and secreted at night by the pineal gland. Melatonin synthesis is under the control of postganglionic sympathetic fibers that innervates the pineal gland. Melatonin acts via high affinity G protein-coupled membrane receptors. To date, three different receptor subtypes have been identified in mammals: MT1 (Mel 1a) and MT2 (Mel 1b) and a putative binding site called MT3. The chronobiotic properties of the hormone for resynchronization of sleep and circadian rhythms disturbances has been demonstrated both in animal models or in clinical trials. Several other physiological effects of melatonin in different peripheral tissues have been described in the past years. In this way, it has been demonstrated that the hormone is involved in the regulation of seasonal reproduction, body weight and energy balance. This contribution has been focused to review some of the physiological functions of melatonin as well as the role of the hormone in the regulation of energy balance and its possible involvement in the development of obesity.


Subject(s)
Melatonin/physiology , Animals , Binding Sites , Melatonin/metabolism , Melatonin/pharmacology , Receptors, Melatonin/metabolism
14.
J Enzyme Inhib Med Chem ; 18(2): 119-25, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12943195

ABSTRACT

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is the penultimate enzyme in melatonin (5-methoxy-N-acetyltryptamine) biosynthesis. It is the key-enzyme responsible of the nocturnal rhythm of melatonin production in the pineal gland. Specific AANAT inhibitors could be useful for treatment of different physiopathological disorders encountered in diseases such as seasonal affective disorders or obesity. On the basis of previous works and 3D-QSAR studies carried out in our laboratory, we have synthesized and evaluated four novel benzo[b]thiophene derivatives designed as AANAT inhibitors. Compound 13 exhibited high inhibitory activity (IC50 = 1.4 microM) and low affinities for both MT, (1100 nM) and MT2 (1400 nM) receptors.


Subject(s)
Arylamine N-Acetyltransferase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors , Thiophenes , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Quantitative Structure-Activity Relationship , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacology
15.
J Neuroendocrinol ; 15(4): 442-8, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12622848

ABSTRACT

Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases.


Subject(s)
Circadian Rhythm/physiology , Melatonin/physiology , Melatonin/pharmacokinetics , Animals , Anxiety/metabolism , Body Weight/physiology , Brain/blood supply , Brain/metabolism , Cerebrovascular Circulation/physiology , Chronobiology Disorders/metabolism , Disease Models, Animal , Energy Metabolism/physiology , Gastrointestinal Motility/physiology , Melatonin/agonists , Melatonin/antagonists & inhibitors , Mice , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Cell Surface/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Melatonin
16.
Behav Brain Res ; 138(2): 145-52, 2003 Jan 22.
Article in English | MEDLINE | ID: mdl-12527445

ABSTRACT

In the Syrian hamster, short photoperiod (SP) induces changes in several physiological functions (body mass, reproduction, hibernation), and these responses involve the pineal hormone melatonin. The present study investigated the effects of a melatonin antagonist, S22153, on photoperiodic adaptation of male Syrian hamster. When constantly released from subcutaneous implants, S22153 had no effect on body or testes masses of animals kept in long photoperiod. S22153 decreased the total hibernation duration observed in animals exposed to SP and low temperature. The decrease in hibernation duration was due to a marked reduction in the number and duration of hypothermic bouts. Moreover, S22153 significantly inhibited the increase of interscapular brown adipose tissue (BAT) mass induced by SP. However, neither the gonadal atrophy nor the body mass increase induced by SP were affected by S22153. These results show that S22153 affects only part of the physiological changes controlled by SP and cold. Whether the decreases in BAT mass and hibernation duration are linked still remains an open question.


Subject(s)
Adipose Tissue, Brown/drug effects , Hibernation/drug effects , Melatonin/antagonists & inhibitors , Photoperiod , Seasons , Thiophenes/pharmacology , Adipose Tissue, Brown/physiology , Animals , Body Temperature Regulation/drug effects , Body Temperature Regulation/physiology , Body Weight/drug effects , Body Weight/physiology , Cricetinae , Hibernation/physiology , Male , Melatonin/physiology , Mesocricetus , Testis/drug effects , Testis/physiology
17.
Ann N Y Acad Sci ; 1009: 175-9, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15028584

ABSTRACT

This study investigates the binding of [(3)H]harmane to rat whole brain homogenates. Saturation studies revealed [(3)H]harmane labels a single, saturable, high-capacity population with high affinity. All the test compounds displaced [(3)H]harmane completely and in an apparently monophasic manner. The displacement profile of the test ligands indicated labeling of MAO-A. Given the high level of MAO-A binding, it is unlikely that a low-capacity I(2) site would be distinguishable from the total [(3)H]harmane population.


Subject(s)
Brain/metabolism , Cell Membrane/metabolism , Harmine/analogs & derivatives , Harmine/metabolism , Animals , Binding Sites , Brain/cytology , Brain Chemistry , Harmine/chemistry , Radioligand Assay , Rats , Tritium/chemistry , Tritium/metabolism
18.
Minerva Endocrinol ; 28(4): 313-20, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14752401

ABSTRACT

Melatonin, the hormone of darkness, has been known for a long time to be a major regulator of energy homeostasis in hibernating animals. Much less is known about the role of melatonin in energy homeostasis in non-hibernating animals, including humans. In mammals, two specific melatonin receptor subtypes, MT1 and MT2, have been cloned and are known to be expressed at central and peripheral sites. Although a central regulation of energy homeostasis has been widely accepted for hibernating animals, the exact site of melatonin action remains still poorly defined. Central effects appear to be predominantly mediated by the MT1 subtype. Recently, several groups showed that melatonin may also have a direct effect on peripheral tissues involved in energy homeostasis such as pancreatic beta cell, hepatocytes and adipocytes. Both, the MT1 and MT2 subtypes appear to be involved. The respective contribution of central and peripheral effects of melatonin on energy homeostasis in vivo must be established in future studies.


Subject(s)
Hibernation/physiology , Homeostasis/physiology , Melatonin/physiology , Animals
19.
Cell Mol Life Sci ; 59(8): 1395-405, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12363042

ABSTRACT

Current melatonin research is essentially based on the finding of new molecular tools, including synthetic or natural agonists and antagonists for the melatonin receptors and synthetic inhibitors of the enzymes involved in its biosynthesis. Indeed, the use of these compounds will improve our understanding of some of the numerous mechanisms of action of melatonin. The present report deals with the establishment and description of a new cell line expressing in a stable manner human arylalkylamine-N-acetyltransferase (AANAT, E.C.2.3.1.87). This new cellular system permits one to check the capacity of newly discovered inhibitors to penetrate the cell and reach their target. Some emphasis is put on inhibitors of the bromoacetyltryptamine family since these precursor compounds form in situ bisubstrate inhibitors with strong affinity for the human enzyme. AANAT is known to undergo complex and rapid regulation by a subtle balance between extremely fast catabolism and protection against it, both due to serine phosphorylation. In the present report, this phosphorylation is shown to occur in vitro after incubation with several kinases (rho-kinase, chk-1, protein kinase A) but not with protein kinase C. Phosphorylation enhances the specific activity of the enzyme by a factor of two to five. This phosphorylation is also shown to occur after treatment of the cell with compounds such as forskolin and rolipram that enhance or protect the intracellular pool of cAMP or the cell-permeable cAMP analogue, dioctanoyl-cAMP. The specificity of the cellular model was assessed using a series of substrates and inhibitors of AANAT already described in the literature, and the characteristics of this cellular system are shown to correspond with those reported for the purified enzyme. This cell line was used to screen libraries of compounds in a living system and led to the discovery of several potent specific and non-toxic AANAT inhibitors.


Subject(s)
Arylamine N-Acetyltransferase/genetics , CHO Cells/metabolism , 5-Methoxytryptamine/metabolism , Animals , Arylamine N-Acetyltransferase/antagonists & inhibitors , Arylamine N-Acetyltransferase/metabolism , Caco-2 Cells , Chromatography, High Pressure Liquid , Colforsin/metabolism , Cricetinae , Enzyme Inhibitors/pharmacology , Humans , Phenethylamines/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Serotonin/metabolism , Tetradecanoylphorbol Acetate/metabolism , Transgenes , Tritium/metabolism
20.
J Enzyme Inhib Med Chem ; 17(6): 409-14, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12683677

ABSTRACT

Serotonin N-acetyltransferase (arylalkylamine N-acetyl-transferase, AANAT) is an enzyme that catalyses the first rate limiting step in the biosynthesis of melatonin (5-methoxy-N-acetyltryptamine). Different physiopathological disorders in human may be due to abnormal secretion of melatonin leading to an inappropriate exposure of melatonin receptors to melatonin. For that reason, we have designed, synthesized and evaluated as inhibitors of human serotonin N-acetyltransferase, a series of compounds that were able to react with coenzyme A to give a bisubstrate analog inhibitor. Compound 12d was found to be a potent AANAT inhibitor (IC50 = 0.18 microM).


Subject(s)
Arylamine N-Acetyltransferase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Databases, Factual , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship
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