Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats.

RATIONALE AND OBJECTIVES: The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT(2c) serotonin receptor antagonist. RESULTS: Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40-50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a "disease-dependent" drug. CONCLUSIONS: These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.

High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease.

Chronic high frequency stimulation of the subthalamic nucleus (STN-HFS) efficiently alleviates motor symptoms of advanced Parkinson's disease (PD). Here, we looked for possible STN-HFS-induced changes on adult brain neurogenesis in the hippocampus and olfactory bulb that may be related to non-motor deficits associated to PD, such as mood disorders and olfaction deficits. Cell proliferation (Ki-67 immuno-positive-cells) and survival (bromodeoxyuridine (BrdU)-immuno-positive cells) were assessed in the subventricular zone-olfactory bulb continuum and the dentate gyrus of the hippocampus of hemiparkinsonian rats with or without continuous STN-HFS for 8 days. Dopamine lesion impaired cell proliferation and survival through different mechanisms, the effect on proliferation being correlated to the level of dopamine depletion whereas the effect on survival was not. Prolonged STN-HFS did not affect cell proliferation, but increased cell survival bilaterally. In these regions of constitutive neurogenesis, the percentage of new neuroblasts (BrdU-doublecortin-positive cells) was unchanged, suggesting that STN-HFS can lead to a net increase in newly formed neurons later on. STN-HFS also increased new cell survival in the striatum and promoted dopamine system recovery detected by tyrosine hydroxylase immunostaining. These data provide the first evidence that prolonged STN-HFS has a neurorestorative action and support the view that the action of this neurosurgical treatment can bypass the cortico-basal ganglia-thalamocortical loop circuits and largely impinge neuroplasticity and brain function.

Region- and phase-dependent effects of 5-HT(1A) and 5-HT(2C) receptor activation on adult neurogenesis.

Adult neurogenesis and serotoninergic transmission are associated to mood disorders and their treatments. The present study focused on the effects of chronic activation of 5-HT(1A) and 5-HT(2C) receptors on newborn cell survival in the dentate gyrus (DG) and olfactory bulb (OB), and examined whether potential neurogenic zones as the prefrontal cortex (PFC) and striatum (ST) are reactive to these treatments. Administration of 8-OH-DPAT, but not RO600,175 increases neurogenesis and survival of late differentiating cells (15-21days) in the DG. Both 8-OH-DPAT and RO600,175 increase neurogenesis in the OB, but only 8-OH-DPAT affected cell survival, inducing a parallel decrease in the number of BrdU cells in the OB and increase in the SVZ, which suggests an impaired migration. In the PFC and ST, 8-OH-DPAT and R0600,175 increase gliogenesis (NG2-labeled cells). This study provides new insights on the serotonergic regulation of critical phases of neurogenesis helpful to understand the neurogenic and gliogenic effects of antidepressant treatments in different brain regions.

Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus.

Agomelatine is a novel antidepressant acting as a melatonergic receptor agonist and serotonergic (5-HT(2C)) receptor antagonist. In adult rats, chronic agomelatine treatment enhanced cell proliferation and neurogenesis in the ventral hippocampus (VH), a region pertinent to mood disorders. This study compared the effects of agomelatine on cell proliferation, maturation, and survival and investigated the cellular mechanisms underlying these effects. Agomelatine increased the ratio of mature vs immature neurons and enhanced neurite outgrowth of granular cells, suggesting an acceleration of maturation. The influence of agomelatine on maturation and survival was accompanied by a selective increase in the levels of BDNF (brain-derived neurotrophic factor) vs those of VEGF (vascular endothelial factor) and IGF-1 (insulin-like growth factor 1), which were not affected. Agomelatine also activated several cellular signals (extracellular signal-regulated kinase1/2, protein kinase B, and glycogen synthase kinase 3beta) known to be modulated by antidepressants and implicated in the control of proliferation/survival. Furthermore, as agomelatine possesses both melatonergic agonist and serotonergic (5-HT(2C)) antagonist properties, we determined whether melatonin and 5-HT(2C) receptor antagonists similarly influence cell proliferation and survival. Only the 5-HT(2C) receptor antagonists, SB243,213 or S32006, but not melatonin, mimicked the effects of agomelatine on cell proliferation in VH. The promoting effect of agomelatine on survival was not reproduced by the 5-HT(2C) receptor antagonists or melatonin alone. However, it was blocked by a melatonin antagonist, S22153. These results show that agomelatine treatment facilitates all stages of neurogenesis and suggest that a joint effect of melatonin agonism and 5HT(2C) antagonism may be involved in promotion by agomelatine of survival in the hippocampus.

S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models.

RATIONALE: Serotonin (5-HT)(2C) receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states. OBJECTIVES: Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006. MATERIALS AND METHODS: Standard cellular, electrophysiological, neurochemical, and behavioral procedures were used. RESULTS: S32006 displayed high affinity for human (h)5-HT(2C) and h5-HT(2B) receptors (pK (i)s, 8.4 and 8.0, respectively). By contrast, it had negligible (100-fold lower) affinity for h5-HT(2A) receptors and all other sites examined. In measures of Gq-protein coupling/phospholipase C activation, S32006 displayed potent antagonist properties at h5-HT(2C) receptors (pK (B) values, 8.8/8.2) and h5-HT(2B) receptors (7.8/7.7). In vivo, S32006 dose-dependently (2.5-40.0 mg/kg, i.p. and p.o.) abolished the induction of penile erections and a discriminative stimulus by the 5-HT(2C) receptor agonist, Ro60,0175, in rats. It elevated dialysis levels of noradrenaline and dopamine in the frontal cortex of freely moving rats, and accelerated the firing rate of ventrotegmental dopaminergic and locus ceruleus adrenergic neurons. At similar doses, S32006 decreased immobility in a forced-swim test in rats, reduced the motor depression elicited by 5-HT(2C) and alpha(2)-adrenoceptor agonists, and inhibited both aggressive and marble-burying behavior in mice. Supporting antidepressant properties, chronic (2-5 weeks) administration of S32006 suppressed "anhedonia" in a chronic mild stress procedure and increased both expression of BDNF and cell proliferation in rat dentate gyrus. Finally, S32006 (0.63-40 mg/kg, i.p. and p.o) displayed anxiolytic properties in Vogel conflict and social interaction tests in rats. CONCLUSION: S32006 is a potent 5-HT(2C) receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models.

Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knock-out mouse.

Decreased serotonin (5-HT) transmission is thought to underlie several mental diseases, including depression and feeding disorders. However, whether deficits in genes encoding G protein-coupled receptors may down-regulate the activity of 5-HT neurons is unknown currently. Based on recent evidence that stress-induced anorexia may involve 5-HT(4)receptors (5-HT(4)R), we measured various aspects of 5-HT function in 5-HT(4)R knock-out (KO) mice. When compared to dorsal raphe nucleus (DRN) 5-HT neurons from wild-type mice, those from 5-HT(4)R KO mice exhibited reduced spontaneous electrical activity. This reduced activity was associated with diminished tissue levels of 5-HT and its main metabolite, 5-hydroxyindole acetic acid (5-HIAA). Cumulative, systemic doses of the 5-HT uptake blocker citalopram, that reduced 5-HT cell firing by 30% in wild-type animals, completely inhibited 5-HT neuron firing in the KO mice. This effect was reversed by administration of the 5-HT(1A) receptor (5-HT(1A)R) antagonist, WAY100635, in mice of both genotypes. Other changes in DRN of the KO mice included increases in the levels of 5-HT plasma membrane transporter sites and mRNA, as well as a decrease in the density of 5-HT(1A)R sites without any change in 5-HT(1A) mRNA content. With the exception of increased 5-HT turnover index in the hypothalamus and nucleus accumbens and a decreased density of 5-HT(1A)R sites in the dorsal hippocampus (CA1) and septum, no major changes were detected in 5-HT territories of projection, suggesting region-specific adaptive changes. The mechanisms whereby 5-HT(4)R mediate a tonic positive influence on the firing activity of DRN 5-HT neurons and 5-HT content remain to be determined.

Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis.

BACKGROUND: Antidepressant treatments increase neural plasticity and adult neurogenesis, especially in the hippocampus. Here, we determined the effects of agomelatine (S-20098), a new antidepressant, on various phases of neurogenesis in the dentate gyrus of adult rat. METHODS: Animals were injected with agomelatine for different time periods. Immunostaining for bromodeoxyuridine, neuron specific nuclear protein, and glial fibrillary acid protein, as well as for the highly polysialylated form of neuronal cell adhesion molecule and doublecortin, was used to detect changes in cell proliferation, neurogenesis, and survival. Cell death was estimated by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling and cresyl violet staining. RESULTS: Chronic (3 weeks) but not acute (4 hours) or subchronic (1 week) administration of agomelatine increased cell proliferation and neurogenesis in the ventral dentate gyrus, a region notably implicated in response to emotion, which is consistent with the antidepressant-anxiolytic properties of the drug. Extending agomelatine treatment over several weeks, however, increases survival of newly formed neurons in the entire dentate gyrus. Finally, agomelatine treatment does not affect mature granule cells. CONCLUSIONS: This study shows that an antidepressant can affect differentially various stages of neurogenesis in the dorsal and ventral hippocampus. Altogether, these changes lead to a pronounced augmentation in the total number of new granule cells.

[Depression and neuroplasticity: implication of serotoninergic systems]. / Dépression et neuroplasticité : implication des systèmes sérotoninergiques.

Neuroplasticity contributes to both normal and pathological brain function. A recent hypothesis links depression to lack of adaptive responses to stress or other aversive stimuli, and effects of antidepressant treatments on adult neurogenesis are more and more extensively studied because of the structural changes involved in the pathophysiology of depression. Indeed, neuronal remodelling in hippocampal formation is associated with chronic stress and is reversed by antidepressant treatments in animals. Decrease in hippocampal volume has also been associated to cognitive deficits in patients with major depression. Interestingly, serotonergic (5-HT) systems play a major role both as antidepressants and by increasing hippocampal neurogenesis through various receptor subtypes. Recently, we have also demonstrated that agomelatine, a new antidepressant drug having serotonergic and melatonergic properties, can increase proliferation and survival of newly formed hippocampal cells. Although the mechanisms underlying such effects are still unknown, these data reinforce the view that changes in hippocampal neurogenesis might belong to the cellular correlates of mood disorders.

[Feeding disorders in 5-HT4 receptor knockout mice]. / Anomalies de la prise alimentaire chez la souris dépourvue de récepteur 5-HT4.

To study the functional contributions of the 5-HT4 receptor subtype of serotonin (5-HT), we have generated knockout mice lacking the 5-HT4 receptor gene. The male mutant mice exhibit a hyposensitivity to anorexic stress. Our recent data indicate that the pharmacological inactivation, using a systemic injection of the 5-HT4 receptor antagonist RS39604 (0.5 mg/kg), suppressed restraint stress-induced anorexia in wild-type female mice. In parallel, the same treatment reduced the 3,4-N-methylenedioxymethamphetamine (" ecstasy", 10 mg/kg)-induced anorexia in male wild-type mice. Our neurochemical analyses suggest that the mechanisms underlying feeding disorders in 5-HT4 receptor knockout mice are related to a lesser efficacy of 5-HT (hypothalamus, nucleus accumbens), leptin and the cocaine-amphetamine related transcript to reduce food intake following stress.

Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone.

Increase in serotonin (5-HT) transmission has profound antidepressant effects and has been associated with an increase in adult neurogenesis. The present study was aimed at screening the 5-HT receptor subtypes involved in the regulation of cell proliferation in the subgranular layer (SGL) of the dentate gyrus (DG) and the subventricular zone (SVZ) and to determine the long-term changes in adult neurogenesis. The 5-HT1A, 5-HT1B, and 5-HT2 receptor subtypes were chosen for their implication in depression and their location in/or next to these regions. Using systemic administration of various agonists and antagonists, we show that the activation of 5-HT1A heteroreceptors produces similar increases in the number of bromodeoxyuridine-labeled cells in the SGL and the SVZ (about 50% over control), whereas 5-HT2A and 5-HT2C receptor subtypes are selectively involved in the regulation of cell proliferation in each of these regions. The activation of 5-HT2C receptors, largely expressed by the choroid plexus, produces a 56% increase in the SVZ, while blockade of 5-HT2A receptors produces a 63% decrease in the number of proliferating cells in the SGL. In addition to the influence of 5-HT1B autoreceptors on 5-HT terminals in the hippocampus and ventricles, 5-HT1B heteroreceptors also regulate cell proliferation in the SGL. These data indicate that multiple receptor subtypes mediate the potent, partly selective of each neurogenic zone, stimulatory action of 5-HT on adult brain cell proliferation. Furthermore, both acute and chronic administration of selective 5-HT1A and 5-HT2C receptor agonists produce consistent increases in the number of newly formed neurons in the DG and/or olfactory bulb, underscoring the beneficial effects of 5-HT on adult neurogenesis.

Serotonergic regulation of the GABAergic transmission in the rat basal ganglia.

The GABAergic neurons represent a major neuronal population in the basal ganglia. Although alterations in serotonin (5-HT) transmission are associated with neurodegenerative diseases involving these regions, the influence exerted by 5-HT afferents on GABAergic populations remains poorly understood. Here, we examined the consequences of 5,7-dihydroxytryptamine-induced lesion of 5-HT neurons on glutamic acid decarboxylase (GAD) activity, mRNA expression of the two isoforms of the enzyme, GAD65 and GAD67, GABA uptake, and extracellular GABA levels in the striatum. The 5-HT depletion produced an increase in GAD activity without modifying GAD65 and GAD67 mRNA levels, suggesting that 5-HT acts at the posttranscriptional level to regulate striatal GABA synthesis. No change in GAD activity was measured in the main striatal target structures, the globus pallidus and substantia nigra. Striatal GABA uptake and extracellular levels of GABA measured under basal conditions in freely moving rats were maintained in a normal range following 5-HT deprivation. By contrast, depolarization-induced increases in extracellular levels of GABA were larger in the striatum of 5-HT-deprived rats than in controls, which may be accounted for by an increase in a releasable pool of GABA due to increased synthesis rate. Together, these results suggest that 5-HT afferents may exert a phasic inhibitory control on striatal GABA transmission. Therefore, a decrease in striatal 5-HT transmission in disease states, such as Parkinson's disease, may contribute to pathological changes in striatal GABA neuron activity by increasing their reactivity to depolarizing stimuli.

Serotonin Reinnervation of the Suprachiasmatic Nucleus by Intrahypothalamic Fetal Raphe Transplants, with Special Reference to Possible Influences of the Target.

Survival and development of fetal serotonin (5-HT) neurons grafted to various brain areas in adult mammals have been suggested to be under host influences. The aim of this study was to determine whether the suprachiasmatic nucleus of the hypothalamus (SCN), a region receiving a 5-HT input which is one of the densest and the most heavily synaptic in the brain, can actually support the development of transplanted 5-HT neurons. The time course and extent of 5-HT reinnervation were therefore investigated with 5-HT immunocytochemistry in adult rats subjected to intraventricular injection of 5,7-dihydroxytryptamine and subsequent grafting of fetal cell suspension of mesencephalic raphe neurons. The ultrastructural features of the newly formed 5-HT terminal plexa were also examined. Serotonin reinnervation of the SCN remained partial up to 4 months post-transplantation, with no apparent predilection of the reinnervating fibres for any particular portion of the nucleus, thus differing from the normal 5-HT innervation of the SCN both quantitatively and qualitatively. This was in sharp contrast to the 5-HT hyperinnervation observed in neighbouring areas such as the supraoptic nucleus, a structure normally provided with only few 5-HT fibres, and the ventral wall of the third ventricle. The graft-derived 5-HT axons, however, displayed ultrastructural features that did not appear different from those of their normal counterparts; in particular they re-established defined synaptic contacts with the host population. These results may indicate that the mature SCN specifically lacks a trophic factor necessary for the ingrowth of graft-derived 5-HT fibres, or that it represents an inhibitory environment for such an ingrowth. The limited ability of regrowing 5-HT axons to restore a normal density of 5-HT innervation could also be related to the fact that these neurons normally establish a relatively high number of synaptic contacts in the target region.