Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT 7 ) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT 7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT 7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT 7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

Background:Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania.Methods:Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control.Results:We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD.Conclusions:Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties.

The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT(3) and 5-HT(7) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT(3) receptor agonist, SR57227 or the selective 5-HT(1A) receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT(3) receptor antagonism of vortioxetine in association with its reduced SERT occupancy.

Serotonin (5-HT)3 receptors are the only ligand-gated ion channel of the 5-HT receptors family. They are present both in the peripheral and central nervous system and are localized in several areas involved in mood regulation (e.g., hippocampus or prefrontal cortex). Moreover, they are involved in regulation of neurotransmitter systems implicated in the pathophysiology of major depression (e.g., dopamine or GABA). Clinical and preclinical studies have suggested that 5-HT3 receptors may be a relevant target in the treatment of affective disorders. 5-HT3 receptor agonists seem to counteract the effects of antidepressants in non-clinical models, whereas 5-HT3 receptor antagonists, such as ondansetron, present antidepressant-like activities. In addition, several antidepressants, such as mirtazapine, also target 5-HT3 receptors. In this review, we will report major advances in the research of 5-HT3 receptor's roles in neuropsychiatric disorders, with special emphasis on mood and anxiety disorders.

Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K+ buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal–glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.

No abstract

No abstract

Discontinuation of drug intake in cocaine abusers commonly produces a variety of adverse withdrawal symptoms among which anxiety and depression-related behavior are prevailing during the initial period of abstinence. The aim of this study was to provide further insight into the neurobiological dysregulations that might contribute to these pathological states. Rats were treated with cocaine or saline for 14 days (20 mg/kg; i.p) and anxiety-related behavior was assessed in different paradigms (elevated plus-maze (EPM), confinement to an open arm of the EPM and shock-probe burying tests) for up to 4 weeks after withdrawal. Depression-like behavior was assessed by the forced swim test and sucrose preference test. Altogether our results demonstrated that cocaine withdrawal induced persistent heightened levels of anxiety that last for at least 28 days but did not affect depression-like behavior. We then used Fos immunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm of an EPM, and a double labeling procedure using Fos immunohistochemistry and in situ hybridization of glutamic acid decarboxylase or vesicular glutamate transporter mRNAs to identify the phenotype of the activated neurons. Our data showed that the exacerbated anxiety observed in cocaine withdrawn rats exposed to an elevated open arm was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex (anterior cingulate and dorsal prelimbic cortices), the paraventricular thalamic nucleus and the lateral and anterior areas of the hypothalamus. In the medial prefrontal cortex, we evidenced a negative correlation between Fos expression in its dorsal part and open arm-induced freezing in NaCl-treated rats but not in cocaine withdrawn rats. We also found that more than 65% of activated neurons were glutamatergic projection neurons. The present study provides new insights into the neuroanatomical regions and neuronal cell types that may underlie pathological anxiety during cocaine withdrawal.