International Journal of Neuropsychopharmacology最新文献

Insomnia is a serious public health concern. As the widely prescribed hypnotics that positively modulate gamma-aminobutyric acid (GABA)A receptor activity have various safety concerns, there is a growing demand for the development of novel hypnotics that act on targets other than GABAA receptor signaling to overcome the drawbacks of current medications. As an alternative target to generate novel hypnotics, the orexin system has recently gained much attention, and 3 dual orexin receptor antagonists (DORAs)-suvorexant, lemborexant, and daridorexant-were launched. However, some doses of these DORAs are associated with a higher incidence of somnolence compared to placebo. Vornorexant is a novel DORA designed to have an improved pharmacokinetic profile-rapid absorption and the shortest half-life among existing DORAs to reduce the risk of residual activity, which has been confirmed in humans. Indeed, it has shown rapid sleep-promoting effects in patients with insomnia, maintaining its activity throughout the night but having a low incidence of next-day residual effects. In this review, we first provide an overview of the role of the orexin system in sleep/wake balance and then describe the profile of a newly developed DORA, vornorexant, from drug discovery to clinical results.

Background: Ethanol consumption disrupts glutamate homeostasis in several brain regions. The uptake of extracellular glutamate is regulated in the majority by the astrocytic glutamate transporter 1 (GLT-1), and cystine-glutamate exchanger (xCT) contributes to this regulatory effect. Chronic ethanol consumption is well known to downregulate GLT-1 expression in several reward brain regions, including the nucleus accumbens (NAc).

Objectives: Recently, we reported that a novel beta-lactam, MC-100093, attenuated ethanol consumption and normalized the expression of GLT-1 in the subregions of the NAc. Based on these findings, we aimed in this study to determine the dose-dependent effect of MC-100093 in attenuating ethanol consumption and whether this attenuating effect is associated with restoration of glutamate uptake. In addition, we focused on whether the effects of MC-100093 on GLT-1 are mediated through the mammalian target of rapamycin (mTOR), protein kinase B (Akt), and nuclear factor-kappa B (NF-κB) signaling pathways.

Methods: Male and female alcohol-preferring (P) rats are grouped into 4 groups. Other than control groups all the 3 groups had free access to ethanol (15% and 30% v/v), and water for 5 weeks. On week 6, rats received intraperitoneal injection (i.p.) of MC-100093 at a dosage of 100 or 150 mg/kg, or saline, for 5 days. The Na+ dependent and Na+ independent glutamate uptake is measured by radioactive glutamate uptake assay. The expression of GLT-1, xCT, mTOR, phospho-Akt (p-Akt), kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBa), and NF-κB are determined by Western blot analysis.

Results: MC-100093 treatment reduced ethanol drinking in male and female P rats. MC-100093 was associated with an increase in Na+-dependent and Na+-independent glutamate uptake. Furthermore, MC-100093 treatment attenuated ethanol-induced decrease in GLT-1, xCT, NF-κB, and p-Akt expression in the NAc.

Conclusions: These findings demonstrate that MC-100093 attenuated ethanol consumption and regulated glutamate uptake through normalizing GLT-1 expression.

Background: High trait anhedonia and low trait extraversion have both been previously related to not only low state positive affect but also depressive disorders, disrupted reward processing, and altered mesolimbic dopaminergic signaling. Research on placebo responses suggests that treatment expectations may alter dopamine signaling, elevate positive affect, and reduce depressive symptoms in anhedonic individuals. However, it remains unclear whether such antidepressant placebo responses depend on putative low baseline dopaminergic functioning in high anhedonia and low extraversion. The present study investigates how interindividual differences in these traits influence positive affective responses under manipulation of dopamine and treatment expectations.

Methods: In a randomized, double-blind 2 × 2 design (N = 297), we administered either placebo or the dopamine D2 receptor antagonist sulpiride (400 mg), and manipulated treatment expectations by telling participants that they received either a mood-elevating drug or an inactive substance. Moreover, we assessed trait anhedonia and extraversion, and had participants rate their state positive affect at 6 different time points before and after treatment.

Results: Trait anhedonia and extraversion, as well as a broad trait positive affectivity factor, predicted state positive affect across time points. Importantly, the effects of sulpiride and antidepressant treatment expectations on positive affect were moderated by dopaminergic traits such that sulpiride increased state positive affect in high anhedonia but decreased it in low anhedonia. Similarly, antidepressant treatment expectations raised positive affect in low extraversion but reduced it in high extraversion.

Conclusions: This study demonstrates that dopamine-related individual differences moderate the effects of both sulpiride and a placebo intervention on positive affective state. Significance Statement In one of the first pharmacological studies examining the effects of treatment expectations and dopamine on mood in a large, healthy sample, we observed that lower baseline positive affectivity was linked to stronger mood-elevating treatment responses to both a placebo and a dopamine-related drug over time. This highlights how individual differences in relevant traits can influence treatment effectiveness, offering valuable insights for tailoring personalized approaches to depression care.

Objective: Postoperative cognitive dysfunction (POCD) is a prevalent complication in older patients who undergo surgery that requires anesthesia. This study explored the role of the adenosine monophosphate-activated protein kinase (AMPK)/silent information regulator factor 2-related enzyme 1 (SIRT1) pathway in gut dysbiosis-mediated POCD in aged mice.

Methods: POCD was induced in aged male mice via open tibial fracture surgery under isoflurane anesthesia. Mice then received the probiotic VSL#3, the SIRT1 inhibitor EX527, and the AMPK/SIRT1 activator resveratrol. Fecal microbiota transplantation was conducted in aged POCD mice. Mouse cognitive function was assessed using the Morris water maze and novel object recognition tests. Mouse histopathological changes were observed via hematoxylin-eosin staining. Iba1+/GFAP+ activation was assessed via immunofluorescence, and proinflammatory cytokines (tumor necrosis factor alpha, interleukin [IL]-1β, and IL-6) in the hippocampus were determined via enzyme-linked immunosorbent assay. Gut microbiota compositions were detected via 16S rRNA sequencing. Hippocampal pAMPK/AMPK and SIRT1 levels were assessed by western blot.

Results: Aged POCD mice exhibited prolonged escape latency, reduced platform crossings, and an impaired object discrimination rate on postoperative day 7. Severe hippocampal CA1 damage, increased Iba1+/GFAP+ cell numbers, elevated proinflammatory cytokines, and gut dysbiosis were also observed. The probiotic VSL#3 ameliorated gut dysbiosis, alleviated POCD, and reduced neuroinflammation. Gut microbiota from POCD mice exacerbated cognitive deficits and neuroinflammation in aged mice, while clearance of the gut microbiota improved outcomes. VSL#3 improved POCD in aged mice by balancing the gut microbiota through the AMPK/SIRT1 pathway. The AMPK/SIRT1 pathway activation mitigated POCD.

Conclusion: VSL#3 balanced the gut microbiota and suppressed neuroinflammation in the hippocampal CA1 region by activating the AMPK/SIRT1 pathway, thereby alleviating POCD in aged mice. Significance Statement Postoperative cognitive dysfunction (POCD) is a common complication in older adults after surgery, causing memory loss and difficulty thinking. In this study, using aged male mice (Mus musculus) we found that an imbalance in gut bacteria can worsen POCD by increasing brain inflammation. Treatment with the probiotic VSL#3 restored healthy gut bacteria, reduced brain inflammation, and improved memory through the AMPK/SIRT1 pathway. These findings suggest that targeting the gut-brain connection may help prevent POCD in older surgical patients.

Background: The hippocampal dentate gyrus (DG) is a critical region that contributes to recent and remote memory. Granule cells within this region, in which adult neurogenesis occurs, undergo dynamic and reversible maturation via genetic and environmental factors during adulthood. A pseudo-immature state of DG granule cells, called immature DG (iDG), has been observed in the adult mice of certain mutant strains, which are considered animal models of neuropsychiatric and neurodegenerative disorders, such as intellectual disability, schizophrenia, autism, and Alzheimer's disease. However, the association between the iDG phenotype and recent and remote memories in the mouse models remains unclear.

Methods: We assessed spatial memory in the Barnes circular maze task in five mutant mouse models of the disorders with the iDG phenotype, including Camk2a heterozygous knockout (HET KO), forebrain-specific Calcineurin (Cn) conditional KO (cKO), Neurogranin (Nrgn) KO, and Hivep2 (Schnurri-2) KO, and hAPP-J20 transgenic mice.

Results: Camk2a HET KO mice and J20 mice spent less time around the target than their wild-type control mice in the memory retention tests 1 day and 4 weeks after the last training session. Cn cKO, Nrgn KO, and Schnurri-2 KO mice showed no significant differences in the time spent around the target from wild-type mice in the retention test 1 day after the training session, but those mutants spent less time around the target than their wild-type mice in the retest conducted 4 weeks later.

Conclusions: These results indicated that mouse models of neuropsychiatric and neurodegenerative disorders exhibiting the iDG phenotype demonstrate a common behavioral characteristic of remote spatial memory deficits, suggesting the potential involvement of the pseudo-immature state of DG granule cells in remote memory dysfunction. Significance Statement A pseudo-immature state of granule cells in the hippocampal dentate gyrus (DG), called immature DG (iDG), has been observed in several mutant strains of mice considered as animal models of neuropsychiatric and neurodegenerative disorders. Thus, the iDG phenotype is proposed as one of the characteristic features of some types of the disorders. However, the impacts of iDG phenotype on hippocampal functions remains unclear. This study demonstrated that two of the five genetically modified mouse strains with iDG phenotype exhibited deficits in both recent and remote memory, with the impairments being more pronounced at the remote delay. The other three strains showed selective deficits in remote memory. These observations suggest that the pseudo-immature state of DG is associated with remote memory dysfunction, although further studies are needed to determine the causality and elucidate the underlying mechanisms.

Background: Hyperprolactinemia and altered prolactin (PRL) levels are well-documented in schizophrenia. However, very few studies have investigated sex-specific differences in the prevalence of PRL disturbances in first-episode patients with schizophrenia. This cross-sectional study investigated sex-specific PRL dysregulation and its interplay with gonadal hormones in first-episode schizophrenia (FES) patients.

Methods: One hundred eighty-nine first-episode patients (96 males, 93 females) with minimally treated (≤2 weeks) were recruited. PRL levels and gonadal hormones were measured in all participants.

Results: We found a significantly higher prevalence of abnormal PRL levels in males compared to females (32.3% vs 8.6%, χ2 = 16.2, P < .001). Comparative analysis of gonadal hormones between elevated PRL (n = 39) and normal PRL (n = 150) groups demonstrated elevated follicle-stimulating hormone (Z = 2.7, P = .007) and testosterone (Z = 3.7, P < .001) in the hyperprolactinemic group. In the elevated PRL group, PRL positively correlated with progesterone and testosterone, whereas in the normal PRL group, PRL showed positive associations with estradiol and luteinizing hormone, but negative correlations with progesterone.

Conclusions: Our findings underscore the complex and sex-specific nature of PRL dysregulation and its association with gonadal hormones in FES patients. Significance Statement This work analyses the sex-specific pattern of prolactin (PRL) disturbance in antipsychotic-naïve or minimally treated first-episode schizophrenia (FES), the earliest clinical manifestation of the disorder. While hyperprolactinemia is well documented, its sex-stratified links to gonadal hormones at illness onset remain unclear. We therefore reassessed PRL and gonadal hormone levels in 189 drug-naïve or minimally treated FES patients. Results showed that abnormal PRL levels were almost four times more common in males than in females. Hyperprolactinemic patients displayed elevated testosterone and follicle-stimulating hormone, whereas normal-PRL patients exhibited inverse PRL-progesterone relationships. These findings reveal a sex-divergent neuroendocrine signature at psychosis onset, underscoring the need for sex-specific endocrine monitoring and personalized early intervention strategies that target PRL-gonadal hormone pathways.

Importance: Bipolar disorder (BD) is mainly treated with mood stabilizers, among which lithium represents the gold standard. Despite its high clinical efficacy, the molecular players involved in lithium response and nonresponse remain partly unclear. Therefore, the identification of peripheral biomarkers would significantly improve the management of pharmacological interventions in BD.

Objective and design: In this study, we sought to investigate the blood metabolome in patients with BD to identify biosignatures of treatment with different mood stabilizers as well as possible biomarkers of response to lithium.

Setting and participants: The blood metabolome was measured in a sample of 89 patients with BD either under prophylactic lithium treatment (n = 47), and characterized as responders or nonresponders, or with other mood stabilizers (MS, n = 42). For each patient the plasma metabolome was measured with hydrogen nuclear magnetic resonance (1H-NMR) and gas chromatography-mass spectrometry (GC-MS). Data were investigated with multivariate analyses accounting for covariates.

Results: Patients exposed to lithium or to other MS showed different, specific metabolic signatures, with different levels of metabolites belonging to pathways involved in glucose, pyruvate, and glutamate metabolism, which were previously suggested to be implicated in BD and to be regulated by lithium. On the other hand, we were not able to identify significant differences in the metabolomic profile between responders and nonresponders to lithium.

Conclusions and relevance: The findings from this exploratory study suggest that patients treated with lithium show distinctive metabolomic biosignatures, specifically pointing to energy metabolism and mitochondria functioning, thus potentially suggesting possible biosignatures of mood-stabilizing treatments.