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Frontiers in Behavioral Neuroscience 2023The dopaminergic system plays a key role in the appropriate functioning of the central nervous system, where it is essential for emotional balance, arousal, reward, and...
INTRODUCTION
The dopaminergic system plays a key role in the appropriate functioning of the central nervous system, where it is essential for emotional balance, arousal, reward, and motor control. The cell adhesion molecule close homolog of L1 (CHL1) contributes to dopaminergic system development, and CHL1 and the dopamine receptor D2 (D2R) are associated with mental disorders like schizophrenia, addiction, autism spectrum disorder and depression.
METHODS
Here, we investigated how the interplay between CHL1 and D2R affects the behavior of young adult male and female wild-type (CHL+/+) and CHL1-deficient (CHL1-/-) mice, when D2R agonist quinpirole and antagonist sulpiride are applied.
RESULTS
Low doses of quinpirole (0.02 mg/kg body weight) induced hypolocomotion of CHL1+/+ and CHL1-/- males and females, but led to a delayed response in CHL1-/- mice. Sulpiride (1 mg/kg body weight) affected locomotion of CHL1-/- females and social interaction of CHL1+/+ females as well as social interactions of CHL1-/- and CHL1+/+ males. Quinpirole increased novelty-seeking behavior of CHL1-/- males compared to CHL1+/+ males. Vehicle-treated CHL1-/- males and females showed enhanced working memory and reduced stress-related behavior.
DISCUSSION
We propose that CHL1 regulates D2R-dependent functions . Deficiency of CHL1 leads to abnormal locomotor activity and emotionality, and to sex-dependent behavioral differences.
PubMed: 38025382
DOI: 10.3389/fnbeh.2023.1288509 -
Molecules (Basel, Switzerland) Oct 2023Icariin, a major bioactive compound found in the genus, has been reported to exert protective effects against neurodegenerative disorders. In the current study, we...
Icariin, a major bioactive compound found in the genus, has been reported to exert protective effects against neurodegenerative disorders. In the current study, we aimed to investigate the regulatory effect of icariin and its active metabolites (icariside II and icaritin) against prime G-protein-coupled receptor targets, considering their association with neuronal disorders. Icariside II exhibited selective agonist activity towards the dopamine D3 receptor (DR), with half-maximal effective concentrations of 13.29 μM. Additionally, they effectively inhibited the specific binding of radioligands to DR. Molecular docking analysis revealed that icariside II potentially exerts its agonistic effect through hydrogen-bonding interaction with Asp110 of the DR, accompanied by negative binding energy. Conversely, icaritin demonstrated selective antagonist effects on the muscarinic acetylcholine M2 receptor (MR). Radioligand binding assay and molecular docking analysis identified icaritin as an orthosteric ligand for MR. Furthermore, all three compounds, icariin and its two metabolites, successfully mitigated MK-801-induced schizophrenia-like symptoms, including deficits in prepulse inhibition and social interaction, in mice. In summary, these findings highlight the potential of icariin and its metabolites as promising lead structures for the discovery of new drugs targeting cognitive and neurodegenerative disorders.
Topics: Mice; Animals; Dizocilpine Maleate; Molecular Docking Simulation; Schizophrenia; Flavonoids; Neurodegenerative Diseases
PubMed: 37959720
DOI: 10.3390/molecules28217300 -
International Journal of Molecular... Aug 2023Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however,...
Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [H]dopamine release without influencing the resting [H]dopamine release from rat striatal slices in 10-10 mol/L concentrations. Rasagiline added in 10 to 10 mol/L concentrations did not alter the resting or electrically stimulated [H]dopamine release. Rasagiline (10 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10-10 mol/L) also inhibited the stimulatory effect of selegiline on [H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (-)methamphetamine (10 mol/L) also exhibited enhancer activity on [H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.
Topics: Animals; Rats; Selegiline; Dopamine; Indans; Monoamine Oxidase
PubMed: 37686140
DOI: 10.3390/ijms241713334 -
Neuropsychopharmacology : Official... Oct 2023NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a... (Randomized Controlled Trial)
Randomized Controlled Trial
NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (-0.33, sd = 0.13, 95%HDI [-0.56,-0.04]) and hippocampus (-0.3 (sd = 0.19), 95%HDI [-0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (-0.28, sd = 0.11, 95%HDI [-0.46, -0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: -0.01108, 95% HDI [-0.0184,-0.003]; follow-up: -0.0183, 95% HDI [-0.02719,-0.0107]; left: post-treatment: -0.019, 95% HDI [-0.028,-0.011]; follow-up: -0.017, 95% HDI [-0.026,-0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.
Topics: Humans; Extinction, Psychological; Ketamine; Midazolam; Pilot Projects; Psychotherapy; Stress Disorders, Post-Traumatic
PubMed: 37270621
DOI: 10.1038/s41386-023-01606-3 -
Translational Neurodegeneration Apr 2024The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs,... (Review)
Review
The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
Topics: Animals; Humans; Angiotensin Receptor Antagonists; Angiotensins; Blood Pressure; Brain; Dopamine; Parkinson Disease; Receptor, Angiotensin, Type 1; Renin-Angiotensin System
PubMed: 38622720
DOI: 10.1186/s40035-024-00410-3 -
Intensive Care Medicine Jan 2024We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo.
METHODS
We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values.
RESULTS
At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS.
CONCLUSIONS
In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.
Topics: Adult; Humans; Delirium; Haloperidol; Hospitalization; Intensive Care Units; Quality of Life
PubMed: 38170227
DOI: 10.1007/s00134-023-07282-7 -
Molecular Psychiatry Sep 2023This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia...
This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015-December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18-34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = -0.19, -0.26 and -0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = -0.20, -0.24, -0.21, respectively) and ED admissions (SMD = -0.15, -0.13, -0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.
Topics: Male; Humans; Female; Antipsychotic Agents; Schizophrenia; Risperidone; Paliperidone Palmitate; Aripiprazole; Injections; Administration, Oral
PubMed: 37479781
DOI: 10.1038/s41380-023-02175-z -
European Psychiatry : the Journal of... Mar 2024We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics... (Meta-Analysis)
Meta-Analysis Review
We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or ≤ 10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.
Topics: United States; Humans; Antipsychotic Agents; Bipolar Disorder; Quetiapine Fumarate; Olanzapine; Lurasidone Hydrochloride; Network Meta-Analysis; United States Food and Drug Administration; Bayes Theorem; Treatment Outcome
PubMed: 38487836
DOI: 10.1192/j.eurpsy.2024.25 -
Journal of Affective Disorders Sep 2023The efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated.
METHODS
We performed subgroup analysis (rapid cycling/non-rapid cycling) of pooled data from two 6-week, randomized, double-blind, placebo-controlled trials of lurasidone monotherapy (20-60 mg/day or 80-120 mg/day). Analyses included mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Safety assessments included the number of treatment-emergent adverse events (TEAEs) and laboratory assessments.
RESULTS
Of 1024 patients randomized, 85 were rapid cycling. Mean change in MADRS total score in patients with non-rapid cycling and rapid cycling, respectively, was -14.8 (effect size = 0.47) and - 12.8 (effect size = 0.04) in the lurasidone 20-60 mg/day group, -14.3 (effect size = 0.41) and - 13.0 (effect size = 0.02) in the lurasidone 80-120 mg/day group and -10.6 and -13.3 in the placebo group. The most common TEAE in each subgroup was akathisia in both lurasidone groups. Treatment-emergent mania was reported only in a small number of rapid cycling and non-rapid cycling patients.
LIMITATIONS
This was a post-hoc analysis of a short-term study that excluded patients with ≥8 cycles in the past year.
CONCLUSIONS
In patients with non-rapid cycling bipolar depression, lurasidone monotherapy significantly improved depressive symptoms relative to placebo at both the 20-60 mg/day and 80-120 mg/day doses. In patients with rapid cycling, both doses of lurasidone displayed depressive symptom score reduction from baseline, but significant improvement was not observed likely due to high levels of improvement on placebo and small sample size.
Topics: Humans; Lurasidone Hydrochloride; Bipolar Disorder; Depression; Drug Therapy, Combination; Mania; Double-Blind Method; Antipsychotic Agents; Treatment Outcome
PubMed: 37245552
DOI: 10.1016/j.jad.2023.05.065 -
Journal of Experimental & Clinical... Jan 2024Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study...
BACKGROUND
Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context.
METHODS
GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo.
RESULTS
Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice.
CONCLUSIONS
DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.
Topics: Animals; Humans; Mice; Brain; CCAAT-Enhancer-Binding Proteins; Dopamine; Glioblastoma; Glioma; Mice, Nude; Multigene Family; Receptors, Dopamine D1; Ubiquitin-Protein Ligases; Dopamine Antagonists; Proto-Oncogene Proteins c-myc
PubMed: 38246990
DOI: 10.1186/s13046-024-02947-7