Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine.

BACKGROUND AND PURPOSE: The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear. EXPERIMENTAL APPROACH: The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain. KEY RESULTS: 60 min after injection, ketamine (10 mg·kg-1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg-1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice. CONCLUSION AND IMPLICATIONS: This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) via regulating the synaptic plasticity in hippocampus.

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.

Gamma oscillations in the mPFC: A potential predictive biomarker of depression and antidepressant effects.

Gamma oscillations have attracted much attention in the field of mood disorders, but their role in depression remains poorly understood. This study aimed to investigate whether gamma oscillations in the medial prefrontal cortex (mPFC) could serve as a predictive biomarker of depression. Chronic restraint stress (CRS) or lipopolysaccharide (LPS) were used to induce depression-like behaviors in mice; local field potentials (LFPs) in the mPFC were recorded by electrophysiological techniques; We found that both CRS and LPS induced significant depression-like behaviors in mice, including increasing immobility durations in the forced swimming test (FST) and tail suspension test (TST) and increasing the latency to feed in the novelty-suppressed feeding test (NSFT). Electrophysiological results suggested that CRS and LPS significantly reduced low and high gamma oscillations in the mPFC. Furthermore, a single injection of ketamine or scopolamine for 24 h significantly increased gamma oscillations and elicited rapid-acting antidepressant-like effects. In addition, fluoxetine treatment for 21 days significantly increased gamma oscillations and elicited antidepressant-like effects. Taken together, our findings suggest that gamma oscillations are strongly associated with depression, yielding new insights into investigating the predictive biomarkers of depression and the time course of antidepressant effects.

A rate-limiting step in antidepressants onset: Excitation of glutamatergic pyramidal neurons in medial prefrontal cortex of rodents.

Although clinical antidepressants have varied mechanisms of action, it remains unclear whether they may have a common mechanism underlying their antidepressant effects. We investigated the behavioral effects of five different antidepressants (differing in target, chemical structure, and rate of onset) and their effects on the firing activities of glutamatergic pyramidal neurons in the medial prefrontal cortex (mPFC) using the forced swimming test (FST) and electrophysiological techniques (in vivo). We employed fiber photometry recordings to validate the effects of antidepressants on the firing activity of pyramidal neurons. Additionally, multichannel electrophysiological recordings were conducted in mice exhibiting depressive-like behaviors induced by chronic restraint stress (CRS) to investigate whether antidepressants exert similar effects on pyramidal neurons in depressed mice. Behavioral tests were utilized for evaluating the depression model. We found that fluoxetine, duloxetine, vilazodone, YL-0919, and ketamine all increase the firing activities of glutamatergic pyramidal neurons (at least 57%) while exerting their initial onset of antidepressant effects. Fiber photometry revealed an increase in the calcium activity of pyramidal neurons in the mPFC at the onset of antidepressant effects. Furthermore, a significant reduction was observed in the firing activity of pyramidal neurons in the mPFC of CRS-exposed mice, which was reversed by antidepressants. Taken together, our findings suggested that five pharmacologically distinct classes of antidepressants share the common ability to increase the firing activity of pyramidal neurons, just different time, which might be a rate-limiting step in antidepressants onset. The study contributes to the body of knowledge of the mechanisms underlying antidepressant effects and paves the way for developing rapid-acting antidepressants.

Inulin-type oligosaccharides of Morinda officinalis exerted antidepressant effects by reducing hippocampal inflammation.

Neuroinflammation contributes to the pathogenesis of depression. Inulin-type oligosaccharides of Morinda officinalis (IOMO) exert antidepressant-like effects in rodents and patients with depression, while the underlying mechanisms remain unclear. This study used chronic restraint stress (CRS) and lipopolysaccharide (LPS) to induce depression-like behaviors in mice. Western blotting and ELISA analysis were used to investigate the effects of IOMO on inflammatory cytokine levels. Immunofluorescence analysis was used to investigate the effects of IOMO on hippocampal NLRP3 inflammasome and microglial cells. The results suggested that 6 weeks of CRS induced significant depression-like behaviors based on the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST), which were accompanied by increases in the expression of IL-6 and the activation of hippocampal microglial cells. Chronic treatment with IOMO (25 mg/kg, i.g.) for 28 days significantly reversed these depression-like behaviors and inhibited the activation of microglial cells. Furthermore, LPS (0.5 mg/kg, i.p.) also significantly induced depression-like behaviors in the TST, FST, and novelty-suppressed feeding test (NSFT), as well as increased the expression of IL-1ß and caspase-1, and activated the microglial cells and the NLRP3 inflammasome in the hippocampus. Treatment with IOMO for 9 days significantly reversed these depression-like behaviors and normalized the LPS-induced activation of the microglial cells and NLRP3 inflammasome. Taken together, these results suggested that IOMO exerted antidepressant-like effects via hippocampal microglial NLRP3 inflammasome mediation followed by caspase-1 inhibition and the production of IL-1ß. These findings provide a basis for developing new antidepressants targeting the microglial NLRP3 inflammasome.

The interaction between social hierarchy and depression/anxiety: Involvement of glutamatergic pyramidal neurons in the medial prefrontal cortex (mPFC).

Social hierarchy greatly impacts physical and mental health, but the relationship between social hierarchy and depression/anxiety and the underlying neural mechanism remain unclear. The present study used the tube test to determine the social hierarchy status of mice and then performed several behavioral tests to evaluate depression-like and anxiety-like behaviors. Electrophysiological techniques were used to record the firing activities of glutamatergic pyramidal neurons and local field potentials in the medial prefrontal cortex (mPFC). The results suggested that the mice in each cage (4 per cage) established a stable social hierarchy after 2 weeks. Subordinate mice displayed significantly fewer pushing and advancing behaviors, and more retreat behaviors compared with dominant mice. Furthermore, subordinate mice had significantly more immobility durations in the TST, but significantly fewer distances, entries, and time into the center in the OFT, as well as significantly less percent of distances, entries, and time into the open arms in the EPMT, compared with dominant mice, which indicated that subordinate mice displayed depression- and anxiety-like behaviors. In addition, chronic restraint stress (CRS) significantly induced depression- and anxiety-like behaviors in mice and altered social dominance behaviors in the tube test. CRS mice displayed significantly fewer pushing and advancing behaviors, and more retreat behaviors compared with control mice. Furthermore, low social rank and CRS significantly decreased the firing of pyramidal neurons and γ-oscillation activity in the mPFC. Taken together, the present study revealed an inverse relationship between social hierarchy and depression/anxiety, and the neural basis underlying this association might be the excitability of pyramidal neurons and γ oscillation in the mPFC. These findings established an important foundation for a depression/anxiety model based on social hierarchy and provided a new avenue for the development of therapies for stress-related mood disorders.

The role of the excitation:inhibition functional balance in the mPFC in the onset of antidepressants.

Currently available antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), generally require weeks to months to produce a therapeutic response, but the mechanism of action underlying the delayed onset of antidepressant-like action remains to be elucidated. The balance between excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons, i.e., the excitation:inhibition functional (E:I) balance, in the medial prefrontal cortex (mPFC) is critical in regulating several behaviors and might play an important mediating role in the mechanism of rapid antidepressant-like action reported by several studies. In the present study, the multichannel electrophysiological technique was used to record the firing activities of pyramidal neurons and interneurons and investigate the effects of a single dose of fluoxetine and ketamine (both 10 mg/kg, i.p.) on the E:I functional balance in the rat mPFC after 90 min or 24 h, and the forced swimming test (FST) was used to evaluate the antidepressant-like effects of fluoxetine and ketamine. The present study also explored the effects of chronic treatment with fluoxetine (10 mg/kg, i.g.) for 7 d or 21 d on the E:I functional balance in the mPFC. The present results suggested that a single dose of ketamine could both significantly increase the firing activities of pyramidal neurons and significantly decrease the firing activities of interneurons in the mPFC and exerted significant antidepressant-like action on the FST after 90 min and 24 h, but fluoxetine had no such effects under the same conditions. However, chronic treatment with fluoxetine for 21 d (but not 7 d) could significantly affect the firing activities of pyramidal neurons and interneurons in the mPFC. Taken together, the present results indicated that rapid regulation of the E:I functional balance in the mPFC might be an important common mechanism of rapid-acting antidepressants and the delayed onset of SSRIs might be partly attributed to their inability to rapidly regulate the E:I functional balance in the mPFC. The present study provided a new entry point to the development of rapid-acting antidepressants.

Anti-PTSD Effects of Hypidone Hydrochloride (YL-0919): A Novel Combined Selective 5-HT Reuptake Inhibitor/5-HT1A Receptor Partial Agonist/5-HT6 Receptor Full Agonist.

Posttraumatic stress disorder (PTSD) is a debilitating trauma and stressor-related disorder that has become a major neuropsychiatric problem, leading to substantial disruptions in individual health and societal costs. Our previous studies have demonstrated that hypidone hydrochloride (YL-0919), a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist, exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 exerts anti-PTSD effects and its underlying mechanisms are still unclear. In the present study, we showed that repeated treatment with YL-0919 caused significant suppression of contextual fear, enhanced anxiety and cognitive dysfunction induced by the time-dependent sensitization (TDS) procedure in rats and by inescapable electric foot-shock in a mouse model of PTSD. Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC.

The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress.

Given the limited monkey models of depression available to date, as well as the procedural complexity and time investments that they involve, the ability to test the efficacy and time course of antidepressants in monkey models is greatly restricted. The present study attempted to build a simple and feasible monkey model of depression with chronic unpredictable stress (CUS) and evaluate the antidepressant effect and onset time of fluoxetine hydrochloride (FLX) and the new drug hypidone hydrochloride (YL-0919), a potent and selective 5-HT reuptake inhibitor, 5-HT1A receptor partial agonist and 5-HT6 receptor full agonist. Female cynomolgus monkeys with low social status in their colonies were selected and subjected to CUS for 8 weeks by means of food and water deprivation, space restriction, loud noise, strobe light, and intimidation with fake snakes. Huddling, self-clasping, locomotion and environmental exploration were monitored to evaluate behavioral changes. In addition, the window-opening test was used to evaluate the exploratory interest of the monkeys. The present results revealed that CUS-exposed monkeys displayed significant depression-like behaviors, including significant decreases in exploratory interest, locomotion, and exploration as well as significant increases in huddling and self-clasping behavior and the level of fecal cortisol after 8 weeks of CUS. Treatment with FLX (2.4 mg/kg, i. g.) or YL-0919 (1.2 mg/kg, i. g.) markedly reversed the depression-like behaviors caused by CUS, producing significant antidepressant effects. YL-0919 (once daily for 9 days) had a faster-onset antidepressant effect, compared with FLX (once daily for 17 days). In summary, the present study first established a CUS model using female cynomolgus monkeys with low social status and then successfully evaluated the onset time of 5-HTergic antidepressants. The results suggested that monkeys exposed to CUS displayed significant depression-like behaviors, and both FLX and YL-0919 produced antidepressant effects in this model. Moreover, YL-0919 appeared to act faster than FLX. The present study provides a promising prospect for the evaluation of fast-onset antidepressant drugs based on a CUS monkey model.

Serotonergic transmission is required for the anxiolytic-like behavioral effects of YL-IPA08, a selective ligand targeting TSPO.

Anxiety disorders are the most prevalent group of mental disorders globally, leading to considerable losses in health, functioning and increase of medical costs. Till now, the search for novel pharmacological treatments is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. In central nervous system, the mitochondrially located translocator protein (18 kDa, TSPO) serves as the rate-limiting step for neurosteroidogenesis and influences GABAergic transmission. Since 5-HT is one of the most comprehensively studied neurotransmitter systems in the anxiety field, in the present study, we want to investigate whether 5-HT system is involved in the anxiolytic-like effects of YL-IPA08, a novel TSPO ligand designed and synthesized at our institute. Our data showed that YL-IPA08 could potentiate the 5-HTP-induced head-twitch response, and the anxiolytic-like effect of YL-IPA08 was abolished by pCPA or 5,7-DHT pretreatment in mice. Furthermore, we found that YL-IPA08 increased the extracellular levels of 5-HT in the rat ventral hippocampus in freely moving rat using the rapid and validated HPLC coupled with microdialysis. In addition, 5-HT level was positively correlated with the level of allopregnanolone. The above results suggest that 5-HT neurotransmission may play a critical role in the anxiolytic-like effects of YL-IPA08.