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BACKGROUND AND PURPOSE The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients. EXPERIMENTAL APPROACH Mice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies. KEY RESULTS The increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogenic-like/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted. CONCLUSIONS AND IMPLICATIONS Our data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity.

Background: Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain. Method: Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively. Results: InvivomicrodialysisexperimentsshowedthateachMRIincreased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXAinduced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXAinducedmechano-hypersensitivityandcoldallodynia.Venlafaxine(16 mg/ kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechanohypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice. Conclusions: Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.

An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice. Htr2a knock-out mice (Htr2a(-/-)) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a(-/-)mice), were studied in a sample of 485 Caucasian patients with MDD. In response to chronic corticosterone exposure, Htr2a(-/-) mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher "emotionality score" (p0.01). In patients, the C allele of rs6313 was more frequent in depressed patients (p=0.019) and was also associated with a more severe major depressive episode (p=0.03). This translational and ecological study involving constitutive Htr2a(-/-) knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission.

Antidepressant drugs such as the serotonin (5-HT)/norepinephrine (NE) and dopamine (DA) reuptake inhibitors activate monoaminergic neurotransmission in various brain regions, such as the amygdala, the frontal cortex or the hippocampus. Although this property is well established, the post-synaptic mechanisms by which these pharmacological agents exert therapeutic activity in major depressive disorders (MDD) is not fully understood. Recent clinical and preclinical studies have indicated that the density and reactivity of glia and more particularly of astrocytes are reduced in MDD patients. These data along with the fact that astrocytes express monoaminergic transporters and receptors make these cells putative targets for antidepressant treatments. Accordingly, in vitro evidence has demonstrated that the application of various classes of antidepressant drugs on rodent primary astrocyte cultures elicits a wide spectrum of responses, from the rise in cytosolic calcium concentrations, as a marker of cellular activity, to the release of glucose metabolites, gliotransmitters and neurotrophic factors. Remarkably, antidepressant drugs also attenuate the release of inflammatory molecules from reactive astrocytes or microglia, suggesting that part of the beneficial effects in depressed patients or animal models of depression might result from the ability of antidepressants to regulate the synthesis and release of psychoactive substances acting on both pre- and post-synaptic neurons. Among the many long-term targets of antidepressant drugs, brainderived neurotrophic factor (BDNF) has been well studied because of the positive influence on adult hippocampal neurogenesis, synaptogenesis and the local serotonergic tone. This review will illustrate how the concept of the tripartite synapse, which is classically associated with different forms of plasticity involving glutamate, could be expanded to the monoaminergic systems to regulate antidepressant drug responses. The recent in vivo data supporting that hippocampal astrocytes act in concert with neurons to release BDNF under pharmacological conditions and thereby regulate different facets of anxiolytic-/antidepressant-like activities through neurogenesis-dependent and independent mechanisms will be emphasized.

One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT(2) receptor subtypes represent promising targets but their precise roles have yet to be determined.The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT(2A) and/or 5-HT(2C) receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT(2) receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis.Although studies support the hypothesis that the inactivation of 5-HT(2A) and/or 5-HT(2C) receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT(2B) receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.

Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT(1A)) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT(1A) autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT(1A) autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle- and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.