Search Results (454)

Clozapine, a second-generation antipsychotic known for its effectiveness in treating resistant schizophrenia, is often linked with serious hematological side effects, particularly neutropenia and agranulocytosis. This review investigates the underlying pathophysiological mechanisms of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA), outlines associated risk factors, and evaluates current clinical management strategies. Clozapine’s pharmacological profile, marked by its antagonism of dopamine D4 and serotonin receptors, contributes to both its therapeutic advantages and hematological toxicity. Epidemiological data show a prevalence of CIN and CIA at approximately 3.8% and 0.9%, respectively, with onset typically occurring within the first six months of treatment. Key risk factors include older age, Asian and African American ethnicity, female sex, and certain genetic predispositions. The development of CIN and CIA may involve bone marrow suppression and autoimmune mechanisms, although the exact processes remain partially understood. Clinical presentation often includes nonspecific symptoms such as fever and signs of infection, necessitating regular hematological monitoring in accordance with established guidelines. Management strategies include dosage adjustments, cessation of clozapine, and the administration of granulocyte colony-stimulating factors (G-CSF). Advances in pharmacogenomics show promise for predicting susceptibility to CIN and CIA, potentially improving patient safety. This review emphasizes the importance of vigilant monitoring and personalized treatment approaches to reduce the risks associated with clozapine therapy. Full article

The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. While generalization has adaptive value, fear generalization is maladaptive and is a significant feature of stress-related disorders such as post-traumatic stress disorder (PTSD). The dopamine system plays a crucial role in both reward- and fear-related processes; however, the contribution of dopamine D3 receptors (D3Rs) to fear generalization in intense foot-shock models remains unclear. In this study, we administered a highly selective D3R antagonist, YQA14 (1 μg/0.2 μL/side), in the ventral tegmental area (VTA), which significantly inhibited fear generalization in novel contexts within foot-shock models. This effect was mediated by reducing the neuronal activity in the basolateral amygdala (BLA). These findings enhance our understanding of the neurobiology of generalization, which is essential from a translational perspective and has broad implications for treating generalized fear disorders. Full article

Glutamate and dopamine receptors play a crucial role in regulating synaptic plasticity throughout the sleep–wake cycle. These receptors form various heterocomplexes in synaptic areas; however, the role of this protein interactome in sleep–wake cycles remains unclear. Co-immunoprecipitation experiments were conducted to observe the complexation of the NMDA glutamate receptor (NMDAR) subunits GluN2A and GluN2B, metabotropic glutamate receptors mGluR1/5, and dopamine receptors (D1R and D2R) with the scaffold protein Homer in the synaptic membranes of the hippocampus after six hours of sleep deprivation (SD) in rats. Our findings indicate that the level of Homer in the GluN2A/mGluR1/D1R interactome decreased during SD, while the content of Homer remained unchanged in the GluN2B/mGluR1/D2R heterocomplex. Moreover, Homer immunoprecipitated a reduced amount of inositol trisphosphate receptor (IP3R) in the microsomal and synaptic fractions, confirming the dissociation of the ternary supercomplex Homer/mGluR1/IP3R during SD. Additionally, our findings indicate that SD increases the synaptic content of the AMPA receptor (AMPAR) subunit GluA1. Unlike AMPAR, NMDAR subunits in synaptic membranes do not undergo significant changes. Furthermore, the G-to-F actin ratio decreases during SD. Changes in the assembly of actin filaments occur due to the dephosphorylation of cofilin. These results suggest that SD causes the dissociation of the GluN2A/mGluR1/D1R/Homer/IP3R heterocomplex in synaptic and endoplasmic membranes. Full article

The limited efficacy of antipsychotics in treating the negative and cognitive symptoms of schizophrenia has prompted the exploration of adjuvant therapies. Several drugs developed for other indications—including caffeine, metformin, and furosemide—have shown procognitive potential. This study evaluated the effects of these agents on behavioral parameters using the reward-based Ambitus test, and on the cerebral D2 dopamine receptor (D2R) expression and binding. The drugs were administered individually and in combination in a schizophrenia-like triple-hit animal model (Lisket rats), derived from the Long Evans (LE) strain. Lisket rats received 14 days of drug treatment via drinking water; water-drinking LE rats served as the controls. The Ambitus test was conducted before treatment and on days 11–14. Caffeine enhanced activity without affecting learning or memory. Metformin and furosemide reduced exploratory behavior but improved reference memory; these effects were inhibited by caffeine co-administration. Although no statistically significant behavioral differences were found compared to water-treated Lisket rats, a trend toward reduced exploratory visits was observed in the triple-combination group. Lisket rats exhibited moderately reduced D2R binding in the cortex and increased binding in the hippocampus. Caffeine alone and in combination enhanced hippocampal D2R binding, while furosemide increased cortical D2R expression. This study is the first to highlight the behavioral and molecular effects of these non-antipsychotic agents in a schizophrenia model, supporting their potential for adjunctive use. Full article

Clinically nonfunctioning pituitary tumors (CNFPTs) typically do not cause hormonal excess, progress insidiously, and are often large and invasive at presentation. Complete resection is frequently not attainable; radiotherapy (RT) may effectively limit growth but carries a significant risk of hypopituitarism. Medical therapy with dopamine D2 receptor agonists and/or somatostatin analogs has been explored in CNFPTs but have yielded inconsistent results, and there is an unmet need for novel efficacious and safe medical therapies. The authors used the PubMed database to identify and review articles published from January 1982 to July 2024, that discussed the medical treatment of CNFPTs. The most commonly studied medical therapies were somatostatin receptor ligands (SRLs) and dopamine D2 receptor agonists. Of 111 patients with CNFPTs treated with SRLs, 31 (28%) exhibited tumor shrinkage. Following dopamine agonist treatment in 355 patients, tumor shrinkage occurred in 113 (32%), tumor stabilization in 182 (51%), and tumor growth in 60 (17%). The efficacy of other less commonly employed therapies such as GnRH analogs, PRRT, and temozolomide was also reviewed. Efficacious and safe medical therapies evaluated in robust randomized placebo-controlled clinical trials are needed to improve the management of CNFPTs. Full article

Background: Personality traits, particularly Conscientiousness, are recognised as crucial psychological factors contributing to success in elite-level athletes. Emerging evidence suggests that individual differences in these traits are influenced by environmental exposure and genetic variation, especially within the dopaminergic system. The DRD2 promoter polymorphism rs1799732, which affects dopamine D2 receptor expression, may modulate goal-directed behaviour and self-regulation traits. Methods: This study included 323 participants (141 elite mixed martial arts (MMA) athletes and 182 non-athlete controls). Participants completed the NEO Five-Factor Inventory (NEO-FFI). Genotyping for the DRD2 rs1799732 polymorphism was conducted using real-time PCR. Group comparisons and two-way ANOVA were used to assess genotype–phenotype associations and gene × environment interactions. Results: Athletes scored significantly higher on Conscientiousness than controls. A significant main effect of the DRD2 rs1799732 genotype and a genotype × group interaction were observed for Conscientiousness. Specifically, athletes with the ins/ins genotype exhibited the highest levels of Conscientiousness, whereas individuals with the del/del genotype showed the lowest scores. No significant associations were found for other personality traits. Conclusions: These findings suggest that the DRD2 promoter polymorphism rs1799732 moderates the expression of Conscientiousness, particularly under the structured and demanding conditions experienced by elite athletes. Our results support a gene × environment interaction model, highlighting the importance of considering genetic predispositions in high-performance environments. These insights may inform personalised psychological support strategies tailored to athletes’ genetic profiles, enhancing motivation, self-regulation and long-term athletic development. Full article

Prenatal cannabis exposure (PCE) has been associated with altered prefrontal cortex (PFC) activity and connectivity in adulthood, potentially increasing the risk of psychopathology later in life. This risk is thought to involve a complex interplay between the endocannabinoid and dopaminergic systems. We investigated the transcriptional regulation of genes associated with these systems in an animal model of PCE during adolescence, focusing on DNA methylation and specific microRNAs (miRNAs). Our study revealed increased mRNA levels of dopamine D1 and D2 receptors (Drd1 and Drd2) in the PFC, with a notable effect on Drd2 in male offspring. Notably, we observed a consistent reduction in Drd2 DNA methylation levels in PCE male rats. Both Drd1 and Drd2 expressions were regulated by selective miRNAs. Accordingly, we found changes in the excitability of PFC pyramidal neurons in male adolescent PCE offspring, along with alterations in the Netrin-1/DCC guidance cue system. Our findings highlight PCE-induced modifications of the PFC dopaminergic system while maintaining stable gene expression of the endocannabinoid system in male offspring. Changes in this complex interaction during sensitive developmental periods like adolescence might lead to sex-dependent divergent behavioral outcomes induced by PCE. Full article

Objective:Burning mouth syndrome (BMS) is a chronic, intractable orofacial pain condition characterized by a burning sensation in the oral mucosa without discernible lesions. The syndrome predominantly affects menopausal and postmenopausal women and is considered a form of nociplastic pain, where the processing of pain stimuli is altered. Given the significant sex disparity, it is crucial to consider underlying neurobiological differences that may inform treatment. This review explores potential pharmacological targets by examining the pathological mechanisms of BMS. Method of Research: A narrative review approach was utilized to systematically explore and synthesize literature regarding the pathophysiology of BMS and to identify receptors implicated in the enhancement of sensory transmission and the altered processing of pain stimuli. Results: The mechanism of enhanced sensory transmission points to receptors such as TRPV1, P2X3, and CB2 as potential targets. However, considering the nociplastic nature of BMS and its prevalence in women, mechanisms involving altered central pain processing are paramount. Research indicates significant sex differences in glutamate transmission and plasticity within reward-related brain regions. This suggests that the N-methyl-D-aspartate (NMDA) receptor, a cornerstone of glutamate signaling and synaptic plasticity, is a primary therapeutic target. Furthermore, the altered processing of pain and reward, which is a key feature of chronic pain, implicates the brain’s dopaminergic system. A decrease in dopamine D2 receptor function within this system is believed to contribute to the pathology of BMS. Estrogen receptors are also considered relevant due to the menopausal onset. Conclusions: Based on the evidence, the most promising targets for pharmacotherapy in BMS are likely the NMDA receptor and the dopamine D2 receptor. The high prevalence of BMS in women, coupled with known sex differences in the glutamate and dopamine pathways of the reward system, provides a strong rationale for this focus. Effective treatment strategies should therefore aim to modulate these specific systems, directly or indirectly controlling NMDE receptor hyperactivity and addressing the decreased D2 receptor function. Further research into therapies that specifically target this sex-linked neurobiology is essential for developing effective pharmacotherapy for BMS. Full article

Retinal dysfunction is emerging as a potential early marker of neurodegenerative diseases. Within the retina, the dopaminergic circuit, comprising dopaminergic amacrine cells, dopamine synthesis and turnover, and dopamine receptor signalling, is essential for visual processing, particularly colour contrast perception. Disruption of this circuit may underline early retinal alterations observed in Huntington’s disease (HD) and Alzheimer’s disease (AD). In this study, we systematically analysed retinal dopaminergic dysfunction in murine models of HD (genetic origin) and AD (sporadic), across different disease stages. We assessed dopamine levels, turnover, tyrosine hydroxylase expression, D1 and D2 receptor gene expression, and neurotransmitter balance. HD mice showed early and marked alterations: reduced dopamine content, decreased tyrosine hydroxylase, increased turnover, and downregulation of D1 receptor expression—all preceding motor symptoms and detectable brain pathology. In contrast, AD mice showed only mild changes at later stages; however, clinical evidence suggests that similar dysfunction may occur earlier in human AD. These findings position retinal dopaminergic disruption as a potential early biomarker in HD and possibly in AD. While the current study relies on invasive techniques in animal models, it lays the groundwork for non-invasive retinal assessments, such as electroretinography or optical coherence tomography, as promising tools for early diagnosis and disease monitoring in neurodegeneration. Full article

Geraniin (GRN), an ellagitannin from Phyllanthus urinaria, shows antioxidant, anti-inflammatory, and neuroprotective effects. This study evaluated GRN’s potential against haloperidol (HPD)-induced orofacial dyskinesia (OD). Rats treated with HPD (1 mg/kg i.p.) for 21 days exhibited dopamine D2 receptor blockade, neurotoxicity, and OD, characterized by vacuous chewing movements (VCM) and tongue protrusion (TP). Then, 60 min post-HPD, GRN was administered i.p. daily for 21 days. OD behaviors were assessed, and on Day 21, striatal tissues were analyzed for oxidative stress, mitochondrial function, inflammation, and apoptosis. GRN alone did not cause OD but significantly reduced HPD-induced VCM and TP. It also reduced oxidative stress, improved antioxidant defense, preserved mitochondrial function, and decreased neuroinflammation and apoptosis. These effects were blocked by ML385, a nuclear factor erythroid-2-related factor 2 (Nrf2) pathway inhibitor. GRN protects against HPD-induced OD, likely via Nrf2 activation. It may be a promising candidate for TD therapy, pending further clinical investigation. Full article

Polychlorinated biphenyls (PCBs) are synthetic chemical compounds that have bioaccumulated and contaminated the entire global ecosystem, causing neurotoxic effects. However, polyphenols may have protective effects against this neurotoxicity. We aimed to investigate the neuroprotective effect of a hydroalcoholic extract of fresh leaves of Alpinia zerumbet (ALE), which is rich in polyphenols, on the neurobehavioral changes induced by 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). We divided C57BL/6 male mice into four groups (n = 40): Control, Control + ALE, PCB, and PCB + ALE. We administered the ALE (50 mg/kg/day) through drinking water and PCB 126 (2 mg/kg/once a week) intraperitoneally for four weeks. The mice were subjected to the elevated plus maze (EPM) and open field (OF) tests in the last week of treatment. PCB 126 reduced locomotor activity, DOPAC levels, dopamine turnover, and D2 receptor expression. This compound also increased lipid peroxidation, tyrosine levels, and BAX expression in the cerebral cortex. Notably, ALE treatment prevented locomotor activity reduction and increased DOPAC levels, dopamine turnover, and D2 receptor expression. Moreover, the extract prevented the PCB-induced increases in BAX expression and lipid peroxidation. Finally, the ALE increased SOD antioxidant activity. Our investigation highlights that using the ALE may serve as a therapeutic strategy against PCB-induced neurotoxicity. Full article

Background/Objectives: D4R antagonists have recently been suggested as potential therapeutic alternatives to the standard treatments of glioblastoma (GBM). In this study, new piperidine-based ligands, analogs of the potent and selective D4R compounds 77-LH-28-1 (7) and its 4-benzyl analog 8, were synthesized and studied to investigate the effects produced by variations in the distances between the pharmacophoric features on the D4R affinity and selectivity. Methods: All the new compounds 9–20 were evaluated for their radioligand binding affinity at D2-like receptor subtypes and the results were rationalized by docking studies and molecular dynamics (MD) simulations. The functional profiles of the most interesting derivatives were assessed at D4R Go and Gi protein and β-arrestin by BRET assay and their potential anticancer activity was determined in GBM cell lines. Results: Radioligand binding results highlighted that the derivatives bearing a terminal butyl chain showed structure–activity relationships different from those with a benzyl terminal. From functional studies performed on the best derivatives 12 and 16, the response profiles of both compounds were more robust in antagonist mode, with derivative 16 showing higher antagonist potency than 12 across all three transducers. Interestingly, 12 and 16 dose-dependently decreased the cell viability of GBM cells, inducing cell death and cell cycle arrest, promoting an increase in ROS production, causing mitochondrial dysfunction, and significantly inhibiting colony formation. Conclusions: The promising biological profiles of 12 and 16 make them new lead candidates that warrant further investigation to gain a better understanding of the mechanism behind their antitumor activity and better evaluate their potential for GBM treatment. Full article

Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDA-R) hypofunction, in the pathophysiology of schizophrenia, making glutamate modulation a promising therapeutic approach. This review explores emerging glutamate-based treatment strategies, including NMDA receptor modulators, metabotropic glutamate receptor (mGluR) agents, glutamate transporter regulators, and kynurenine pathway inhibitors. We summarize preclinical and clinical findings on NMDA co-agonists (D-serine and glycine), glycine transporter inhibitors, D-amino acid oxidase inhibitors, and mGluR-targeted therapies, highlighting their mechanisms, efficacy, and limitations. In addition, we discuss novel interventions aimed at restoring glutamate homeostasis, including neuroinflammatory modulation and synaptic plasticity enhancers. Despite promising results, many glutamate-targeting therapies have yielded inconsistent clinical outcomes, underscoring the need for biomarker-driven patient selection and optimized treatment protocols. We propose that integrating glutamate modulators with existing antipsychotic regimens may enhance therapeutic response while minimizing side effects. Future research should focus on refining glutamate-based interventions, identifying predictive biomarkers, and addressing the heterogeneity in schizophrenia pathology. With continued advancements, glutamate modulation has the potential to transform schizophrenia treatment, particularly for cognitive and negative symptoms that remain largely unaddressed by current therapies. Full article

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. Full article

Both a shortage and an excess of dopamine (DA) in the prefrontal cortex and striatum result in their decreased functions, and the relationship between the DA levels and their functions exhibits an inverted-U shape. Increased DA transmission via dose reduction in the currently used antipsychotics may improve the activation of DA-related symptoms in schizophrenia; these include delusions and auditory hallucinations caused by increased DA release. In this case, reducing the dose of the antipsychotic may be a treatment option for relapse in patients with schizophrenia who are already on high doses of antipsychotics and find it difficult to further increase the dose. A total of 54 inpatients with schizophrenia receiving high-dose antipsychotic therapy were randomly assigned to either the halved-dose group or the high-dose group (symptomatic treatment). The study compared the time from relapse to improvement between the two groups. In the halved-dose group, the period until relapse improvement ranged from 1 to 3 weeks, while the high-dose group experienced improvement in 4 to 9 weeks, and a significant difference was observed between the two groups using Kaplan–Meier survival analysis (p < 0.001). Full article