The effects of low-dose ketamine and (2R,6R)-Hydroxynorketamine on affective behaviors associated with protracted oxycodone withdrawal.

The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement

BackgroundPreclinical studies have indicated that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is a rapid-acting antidepressant drug with limited dissociation properties and low abuse potential. However, its effects and molecular mechanisms remain unclear. In this work, we examined the involvement of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and Narp in the antidepressant-like actions of (2R,6R)-HNK in a chronic restraint stress (CRS) mouse model.MethodsC57BL/6 male mice were subjected to CRS for 8 h per day for 14 consecutive days. Open field, forced swimming, novelty suppressed feeding, and tail suspension tests were performed after administering (2R,6R)-HNK (10 mg/kg), a combination of (2R,6R)-HNK and NBQX (an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist; 10 mg/kg), or a combination of (2R,6R)-HNK and ANA-12 (a TrkB receptor antagonist; 0.5 mg/kg). The mRNA levels of Bdnf and Narp in the hippocampus were determined by quantitative reverse transcription-PCR (qRT–PCR). Western blotting was used to determine the hippocampal protein levels of GluA1, GluA2, BDNF, Narp, PSD95, and synaptophysin, as well as the p-TrkB/TrkB protein ratio.Results(2R,6R)-HNK had rapid antidepressant-like effects in CRS mice. Furthermore, (2R,6R)-HNK significantly ameliorated CRS-induced downregulation of GluA1, GluA2, BDNF, Narp, PSD95, and the p-TrkB/TrkB protein ratio in the hippocampus. The effects of (2R,6R)-HNK were blocked by combinations with NBQX or ANA-12.ConclusionBDNF-TrkB signaling-mediated upregulation of Narp in the hippocampus may play a key role in the antidepressant-like effect of (2R,6R)-HNK in the CRS model of depression.

The impact of long-term soy peptide consumption on mood-related behavior in adult male mice was studied under normal housing conditions. Male C57BL/6J mice were fed a modified AIN-93M diet containing 7% soy peptide for 70 d. Sucrose preference and tail suspension tests were conducted to evaluate anhedonia and despair, respectively. Mice fed soy peptide consumed more sucrose than those in the control group fed AIN-93M in the sucrose preference test. However, no significant difference was observed in the total immobility time between the two groups in the tail suspension test. These findings suggest that chronic soy peptide intake may attenuate anhedonia, a hallmark symptom of major depressive disorder characterized by decreased sensitivity to reward and pleasure.

BACKGROUNDThe association between hypothyroidism and depression is well established, but the underlying mechanisms remain unclear.AIMTo explore the potential role of the gut microbiota in depressive-like behaviors in a mouse model of hypothyroidism, with a focus on bacterial composition.METHODSHypothyroidism was induced in mice using propylthiouracil. Depressive-like behaviors were assessed using the sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT). Inflammatory cytokines, including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α, and IL-10, were quantified, together with colon histopathology scores, brain-derived neurotrophic factor, nuclear factor κB, inhibitor of nuclear factor κB, and tight junction proteins (occludin, claudin-1, zonula occludens-1). Gut microbial composition was determined by 16S rRNA gene sequencing of fecal samples.RESULTSPropylthiouracil-treated mice exhibited pronounced depressive-like behaviors, intestinal barrier dysfunction, elevated peripheral and central inflammation, and gut microbiota dysbiosis. Pearson correlation analysis showed that Bilophila and Psychrobacter abundance positively correlated with sucrose preference in the SPT and locomotor activity in the OFT, and negatively correlated with immobility times in the FST and TST. Gordonibacter abundance was positively correlated with locomotion in the OFT and negatively correlated with immobility in the FST and TST. Prevotellaceae_UCG_001 was inversely correlated with immobility in the FST and TST. Streptococcus was positively associated with sucrose preference in the SPT.CONCLUSIONThe observed associations between specific bacterial taxa and behavioral indices support a potential connection between gut microbiota composition and depressive symptoms in mice with hypothyroidism.

Effects of alpha-7 nicotinic allosteric modulator PNU 120596 on depressive-like behavior after lipopolysaccharide administration in mice

Chronic pain can be challenging to treat and increases the risk of developing psychological disorders such as depression. Identifying novel treatment modalities that effectively alleviate pain is essential to improve clinical treatment and rehabilitation for patients with pain conditions. Ketamine is an effective analgesic for many types of pain. However, its widespread use is limited by its side effect profile and requirement for intranasal/intravenous administration under medical supervision. (2R,6R)‐hydroxynorketamine (HNK) is a ketamine metabolite that lacks the psychotomimetic effects of its parent drug but retains ketamine’s anti‐stress effects. Therefore, it is natural to question whether (2R,6R)‐HNK may also possess analgesic activity.Administration of (2R,6R)‐HNK produced antinociception in healthy mice exposed to a noxious, painful stimulus 24 hours after injection. The dose response for the delayed‐yet‐persistent antinociception revealed an inverted U shape with significant antinociception at doses of 10‐18 mg/kg for both sexes and 30 mg/kg in female mice. Mice pretreated with different receptor antagonists to examine the potential mechanism for (2R,6R)‐HNK mediated antinociception revealed a mechanism dependent on AMPA receptors and not opioid receptors. In contrast, ketamine antinociception was not dependent on AMPA receptors and partially dependent on opioid receptors. These results demonstrate that both (2R,6R)‐HNK and the parent drug ketamine produce antinociception but work via different neural mechanisms.In separate studies, (2R,6R)‐HNK administration reversed mechanical allodynia associated with localized inflammatory pain induced in mice by injecting λ‐carrageenan into the hind paw. The onset for this analgesia‐like activity was less than 1 hour with a duration greater than 24 hours following a single administration. (2R,6R)‐HNK was effective at reversing mechanical allodynia at doses of 10 & 30 mg/kg in both male and female animals. These results demonstrate (2R,6R)‐HNK exhibits great promise for treating inflammatory pain in addition to other pain types. Overall, these data suggest that (2R,6R)‐HNK may be a safe alternative therapy for pain that could be made widely available to patients and support the need for continued investigation and development of (2R,6R)‐HNK as a novel non‐opioid pain treatment.

This study aims to explore the effects and potential mechanisms of Modified Shuyu Pills in ameliorating depressive behaviors in the mouse model of vascular dementia(VaD). Seventy-two three-month-old male C57BL/6 mice were assigned into six groups: sham, model, low-, medium-, and high-dose Modified Shuyu Pills, and fluoxetine. The other five groups except the sham group underwent bilateral common carotid artery stenosis combined with chronic unpredictable stress. Depressive behaviors were assessed by the sucrose preference test and tail suspension test. Cerebral blood flow was measured by laser speckle imaging. Protein levels of low density lipoprotein receptor(LDLR), mitogen-activated protein kinase kinase(MEK), phosphorylated(p)-MEK, extracellular signal-regulated kinase(ERK), and p-ERK in the ventral tegmental area(VTA) and nucleus accumbens(NAc) were determined by Western blot. The fluorescence intensity of myelin basic protein(MBP) in the VTA and NAc were measured by immunofluorescence. Myelin sheath morphology in the VTA and NAc was observed by luxol fast blue staining, and the ultrastructure of myelin sheath in the VTA and NAc was examined by transmission electron microscopy. In the tail suspension test, the immobility time of the model group was longer than that of the sham group(P<0.01). In the sucrose preference test, the sucrose preference rate of the model group was lower than that of the sham group(P<0.01). After intervention with Modified Shuyu Pills, the immobility time in the tail suspension test was shortened(P<0.01), and the sucrose preference rate increased(P<0.01). Laser speckle imaging results showed that compared with the sham group, the model group showed reduced cerebral blood flow(P<0.01), and the reduction was reversed by medium-and high-dose Modified Shuyu Pills(P<0.01). Western blot results indicated that the relative expression levels of LDLR, p-MEK/MEK, and p-ERK/ERK in the VTA and NAc of the model group were lower than those in the sham group(P<0.01). Medium-and high-dose Modified Shuyu Pills reversed this trend(P<0.01). Immunofluorescence results showed that the fluorescence intensity of MBP in the VTA and NAc of the model group was lower than that of the sham group(P<0.01). The medium-and high-dose Modified Shuyu Pills groups showed increased fluorescence intensity of MBP in the VTA compared with the model group(P<0.01). In the NAc, the fluorescence intensity of MBP in all the groups of Modified Shuyu Pills increased to varying degrees compared with that in the model group(P<0.01). Luxol fast blue staining results showed that the model group presented lighter staining intensity and looser arrangement of myelin fibers than the sham group, indicating significant demyelination in the model group. However, after intervention with medium-and high-dose Modified Shuyu Pills, the staining intensity and myelin sheath structure in the VTA and NAc were improved. Transmission electron microscopy results revealed that the myelin sheath in the VTA and NAc of the sham group was intact and dense, while the model group exhibited extensive myelin loss, with myelin sheath degeneration and disintegration. After intervention with Modified Shuyu Pills, the myelin sheath loss in the VTA and NAc of mice was reduced, and the proportion of myelinated tissue increased. In summary, Modified Shuyu Pills may promote myelination via the VTA-NAc circuit by upregulating the LDLR/MEK/ERK signaling pathway, thereby ameliorating depressive-like behaviors in VaD mice.

Valsartan reverses depressive/anxiety-like behavior and induces hippocampal neurogenesis and expression of BDNF protein in unpredictable chronic mild stress mice

Ketamine metabolite (2R,6R)-hydroxynorketamine enhances aggression via periaqueductal gray glutamatergic transmission

Brain functional changes following electroacupuncture in a mouse model of comorbid pain and depression: A resting-state functional magnetic resonance imaging study.

IntroductionDepression is one of the common comorbidities seen in chronic alcohol use disorder. Also, alcohol withdrawal induces depression and anxiety, which is associated with relapse in alcohol consumption. Minocycline, a tetracycline derivative, has shown an antidepressant effect in preclinical models. However, their effect on alcohol withdrawal-induced depression has not been studied. Therefore, the current study has been undertaken to evaluate the effect of minocycline on alcohol abstinence-induced depression models in mice.MethodWe conducted the study in two models. C57bl/6 mice were given a two-bottle choice (alcohol + water) for 28 days. During alcohol abstinence of 14 days, mice were treated with 10 mg/kg, 30 mg/kg, and 50 mg/kg of minocycline and were evaluated for behavioral changes using the forced swim test (FST) and tail suspension test (TST). A sucrose preference test was carried out where mice were exposed to binge alcohol drinking protocol for 12 days, where a two-bottle choice (alcohol or water) was given. This was followed by exposing the mice to a two-bottle choice paradigm (alcohol + sucrose) and they were divided into groups - no treatment group, vehicle-treated, minocycline 30 mg/kg or minocycline 50 mg/kg treated - and consumption of sucrose was assessed.ResultIn the forced swim test, a significant decrease in immobility time (p<0.05) was observed in the high-dose minocycline group (82.75±19.09) as compared to the vehicle control group (128.12±35.44). In the tail suspension test also, a significant decrease in immobility time (p<0.05) was seen in the high-dose minocycline group (83.75±18.61) as compared to the vehicle control group (122.25±18.51). The water and alcohol intake were comparable among all groups. In the sucrose preference test, it was found that the minocycline 50 mg/kg group had the highest sucrose preference (55%) followed by the minocycline 30 mg/kg group (50%) as compared to 42% in the vehicle control group. Significant reduction in brain-derived neurotrophic factor (BDNF) levels was seen with minocycline 50 mg/kg (p<0.05) and minocycline 30 mg/kg group (p<0.05) in BDNF levels when compared to the normal control group.ConclusionMinocycline in a higher dose (50 mg/kg) has shown an effect in alcohol withdrawal-induced depression in the abstinence-induced two-bottle choice model in mice. Both doses of minocycline have shown an effect in the sucrose preference test in the alcohol withdrawal-induced depression model.

Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive–compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.

Background: Fast-onset antidepressants are urgently needed. Chaihu-jia-Longgu-Muli-tang (CLM), a classic Chinese herbal medicine, has been used for antidepressant treatment with long history. Olfactory bulbectomization (OB) model is validated for identification of rapid antidepressant efficacy. Here we used OB model for investigating the rapid onset activity of CLM in mice, and also tested the involvement of prefrontal Akt-mTOR and associated AMPA/NMDA receptors as well as hippocampal BDNF in the rapid antidepressant-like effect of CLM.Methods: The OB model was first characterized with depression-like behaviors and the time course changes of the behaviors. The fast onset of antidepressant effect of CLM was evaluated using sucrose preference test, tail suspension test and forced swim test in OB mice after a single administration. The expression of synaptic proteins of AMPA and NMDA subunits as well as Akt/mTOR signaling in the prefrontal cortex, and hippocampal BDNF was evaluated with the immunoblotting method.Results: A single dose of CLM significantly improved the deficiency in the sucrose preference and decreased the immobility time in the tail suspension test in OB mice. In the prefrontal cortex (PFC) in OB mice, there was lower expression level of the AMPA receptor subunit GluR1, rescued by a single dose of CLM. Additionally, the expression of NMDA subunit NR1 was up-regulated in OB mice, whereas mTOR and its upstream Akt signalings were both down-regulated. These deficiencies were reversed by a single dose of CLM. The CLM treatment also attenuated the expressions of NMDA receptor subunits NR2A and NR2B, which did not change in OB mice. In the hippocampus, expressions of GluR1 and brain derived neurotrophic factor (BDNF) were both up-regulated in OB mice, although CLM increased GluR1, but not BDNF.Conclusion: CLM elicited rapid antidepressant-like effects in the OB model mice, and CLM reversal of the abnormality in PFC expression of AMPA and NMDA receptors and associated Akt-mTOR signaling may underlie the effects.

Inhibition of activated astrocyte ameliorates lipopolysaccharide- induced depressive-like behaviors

In recent years, the number of patients with depression disorders has increased. New stratagem should be established for the recovery of depression. The gene encoding Teneurin-4 (Tenm-4), ODZ4, has been identified as a risk gene for many psychiatric disorders1,2,3. However, it is still unclear how Tenm-4 affects the pathogenesis of psychiatric disorders. Prefrontal cortex (PFC) contributes emotion regulation, cognitive function, and social behaviors4,5. Importantly, a reduced volume of the PFC region has been reported in depressed patients6. Therefore, the PFC is thought to be involved in the pathogenesis of depression. We hypothesized that Tenm-4 in the PFC influences depression and other psychiatric disorders. In this study, we generated mice with Tenm-4 knockdown specifically in the PFC of mice, to clarify the involvement of Tenm-4 in psychiatric disorders in the PFC, We investigated their behavioral phenotype by conducting various behavioral experiments. Mice with reduced Tenm-4 expression in the PFC were generated using genetic modification technology incorporating the CRISPER- Cas9 system in an adeno-associated virus vector (AAV)(Tenm-4 KD, and Mock as control), and we used these mice for the behavioral experiments. We performed various behavioral experiments by using the mice. In the forced swimming test and tail suspension test, Tenm-4 KD mice group showed significantly increased immobility time compared with Mock mice group. In the sucrose preference test, Tenm-4 KD mice group showed significantly decreased sucrose preference compared with Mock mice group.Furthermore, a single intraperitoneal dose of aripiprazole significantly decreased immobility time in the tail suspension test and restored sucrose preference in the sucrose preference test in mice accompanied with reducion Tenm-4 expression. These results suggest that reduction of Tenm-4 in the PFC would cause depression-like behaviors. Further, we revealed that depression-like behaviors induced by reduction of the Tenm-4 in the PFC was recovered by the administration of aripiprazole. Aripiprazole functions as a partial agonist of dopamine D2,3 receptors, a partial agonist of serotonin 5-HT1A receptors, and an antagonist of serotonin 5-HT2Areceptors. Therefore, this result suggests that the dopaminergic and/or Serotonergic neurons, especially in the PFC, would be involved in depression-like behaviors induced by reduction of the Tenm-4 in the PFC. The relationship between depression and Tenm-4 is still not well understood. However, we have successfully generated a new mouse model of depression induced by decreased Tenm-4 in the PFC. These results could provide a pathomechanism involving Tenm-4 in depression. Our study successfully identified a new therapeutic target for depressed patients.