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Search Results (220)

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Keywords = dopamine-related disorders

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46 pages, 2278 KiB  
Review
Melanin-Concentrating Hormone (MCH): Role in Mediating Reward-Motivated and Emotional Behavior and the Behavioral Disturbances Produced by Repeated Exposure to Reward Substances
by Olga Karatayev and Sarah F. Leibowitz
Int. J. Mol. Sci. 2025, 26(15), 7143; https://doi.org/10.3390/ijms26157143 - 24 Jul 2025
Viewed by 327
Abstract
Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances [...] Read more.
Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior. This report first describes evidence in animals that exposure in adults and during adolescence to rewarding substances, such as the drugs alcohol, nicotine and cocaine and palatable fat-rich food, stimulates the expression of MCH as well as HCRT and their intracellular molecular systems. It also increases reward-seeking and emotional behavior, leading to excess consumption and abuse of these substances and neurological conditions, completing this positive feedback loop. Next, this review focuses on the model involving embryonic exposure to these rewarding substances. In addition to revealing a similar positive feedback circuit, this model greatly advances our understanding of the diverse changes that occur in these neuropeptide/molecular systems in the embryo and how they relate, perhaps causally, to the disturbances in behavior early in life that predict a later increased risk of developing substance use disorders. Studies using this model demonstrate in animals that embryonic exposure to these rewarding substances, in addition to stimulating the expression of peptide neurons, increases the intracellular molecular systems in neuroprogenitor cells that promote their development. It also alters the morphology, migration, location and neurochemical profile of the peptide neurons and causes them to develop aberrant neuronal projections to forebrain structures. Moreover, it produces disturbances in behavior at a young age, which are sex-dependent and occur in females more than in males, that can be directly linked to the neuropeptide/molecular changes in the embryo and predict the development of behavioral disorders later in life. These results supporting the close relationship between the brain and behavior are consistent with clinical studies, showing females to be more vulnerable than males to developing substance use disorders with co-occurring emotional conditions and female offspring to respond more adversely than male offspring to prenatal exposure to rewarding substances. It is concluded that the continued consumption of or exposure to rewarding substances at any stage of life can, through such peptide brain systems, significantly increase an individual’s vulnerability to developing neurological disorders such as substance use disorders, anxiety, depression, or cognitive impairments. Full article
(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease—3rd Edition)
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27 pages, 464 KiB  
Review
Caffeine in Aging Brains: Cognitive Enhancement, Neurodegeneration, and Emerging Concerns About Addiction
by Manuel Glauco Carbone, Giovanni Pagni, Claudia Tagliarini, Icro Maremmani and Angelo Giovanni Icro Maremmani
Int. J. Environ. Res. Public Health 2025, 22(8), 1171; https://doi.org/10.3390/ijerph22081171 - 24 Jul 2025
Viewed by 570
Abstract
This narrative review examines the effects of caffeine on brain health in older adults, with particular attention to its potential for dependence—an often-overlooked issue in geriatric care. Caffeine acts on central adenosine, dopamine, and glutamate systems, producing both stimulating and rewarding effects that [...] Read more.
This narrative review examines the effects of caffeine on brain health in older adults, with particular attention to its potential for dependence—an often-overlooked issue in geriatric care. Caffeine acts on central adenosine, dopamine, and glutamate systems, producing both stimulating and rewarding effects that can foster tolerance and habitual use. Age-related pharmacokinetic and pharmacodynamic changes prolong caffeine’s half-life and increase physiological sensitivity in the elderly. While moderate consumption may enhance alertness, attention, and possibly offer neuroprotective effects—especially in Parkinson’s disease and Lewy body dementia—excessive or prolonged use may lead to anxiety, sleep disturbances, and cognitive or motor impairment. Chronic exposure induces neuroadaptive changes, such as adenosine receptor down-regulation, resulting in tolerance and withdrawal symptoms, including headache, irritability, and fatigue. These symptoms, often mistaken for typical aging complaints, may reflect a substance use disorder yet remain under-recognized due to caffeine’s cultural acceptance. The review explores caffeine’s mixed role in neurological disorders, being beneficial in some and potentially harmful in others, such as restless legs syndrome and frontotemporal dementia. Given the variability in individual responses and the underestimated risk of dependence, personalized caffeine intake guidelines are warranted. Future research should focus on the long-term cognitive effects and the clinical significance of caffeine use disorder in older populations. Full article
(This article belongs to the Section Behavioral and Mental Health)
19 pages, 1316 KiB  
Review
Anabolic–Androgenic Steroids and Brain Damage: A Review of Evidence and Medico-Legal Implications
by Mario Giuseppe Chisari, Massimiliano Esposito, Salvatore Alloca, Sabrina Franco, Martina Francaviglia, Gianpietro Volonnino, Raffaella Rinaldi, Nicola Di Fazio and Lucio Di Mauro
Forensic Sci. 2025, 5(3), 31; https://doi.org/10.3390/forensicsci5030031 - 24 Jul 2025
Viewed by 561
Abstract
Background: Anabolic–androgenic steroids (AASs) are commonly used for performance enhancement but have been linked to significant neurobiological consequences. This review explores the impact of AASs on neurochemical pathways, cognitive function, and psychiatric disorders, highlighting their potential neurotoxicity. Methods: A narrative review of current [...] Read more.
Background: Anabolic–androgenic steroids (AASs) are commonly used for performance enhancement but have been linked to significant neurobiological consequences. This review explores the impact of AASs on neurochemical pathways, cognitive function, and psychiatric disorders, highlighting their potential neurotoxicity. Methods: A narrative review of current literature was conducted to examine AASs-induced alterations in neurotransmitter systems, structural and functional brain changes, and associated psychiatric conditions. The interplay between AASs use and other substances was also considered. Results: Chronic AASs exposure affects serotonin and dopamine systems, contributing to mood disorders, aggression, and cognitive deficits. Structural and functional changes in the prefrontal cortex and limbic regions suggest long-term neurotoxicity. AASs use is associated with increased risks of depression, anxiety, and psychosis, potentially driven by hormonal dysregulation and neuroinflammation. Co-occurring substance use exacerbates neurocognitive impairments and behavioral disturbances. Discussion: While evidence supports the link between AASs use and neurotoxicity, gaps remain in understanding the precise mechanisms and long-term effects. Identifying biomarkers of brain damage and developing targeted interventions are crucial for mitigating risks. Increased awareness among medical professionals and policymakers is essential to address AASs-related neuropsychiatric consequences. Conclusions: AASs abuse poses significant risks to brain health, necessitating further research and prevention efforts. Evidence-based strategies are needed to educate the public, enhance early detection, and develop effective interventions to reduce the neuropsychiatric burden of AASs use. Full article
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17 pages, 4451 KiB  
Article
Phenotype Differences Between ATP13A2 Heterozygous and Knockout Mice Across Aging
by Kristina Croucher, Josephine K. Lepp, Jennifer Bechtold, Edward J. Hamad, Sophia Scott, Christian Bittner, Sara Rogers, Christian Ong, Shannon Boehme, Zhuo Wang, Li Lin, Xinwen Wang and Sheila M. Fleming
Int. J. Mol. Sci. 2025, 26(15), 7030; https://doi.org/10.3390/ijms26157030 - 22 Jul 2025
Viewed by 264
Abstract
ATP13A2 is a lysosomal polyamine transporter with loss of function mutations linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Knockout of ATP13A2 in mice leads to age-related sensorimotor impairments and in the brain lipofuscinosis, gliosis, and modest alpha-synuclein (αSyn) pathology. However, few [...] Read more.
ATP13A2 is a lysosomal polyamine transporter with loss of function mutations linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Knockout of ATP13A2 in mice leads to age-related sensorimotor impairments and in the brain lipofuscinosis, gliosis, and modest alpha-synuclein (αSyn) pathology. However, few studies have included ATP13A2 heterozygous mice as a comparison. In the present study, the effect of reduced or complete loss of ATP13A2 function on behavior, αSyn, gliosis, dopamine, and polyamines were determined in mice. Male and female ATP13A2 wildtype (WT), heterozygous (Het), and knockout (KO) mice were assessed behaviorally at 3, 12, and 18 months of age. In the brain, αSyn, phosphorylated αSyn, and GFAP were measured in the prefrontal cortex, striatum, ventral midbrain, and cerebellum. Polyamine and neurotransmitter analyses were performed in the same brain regions. Similar to previous studies, KO mice developed motor impairments and widespread gliosis in the brain. In addition, polyamine content was altered in Het and KO mice. In contrast, Het mice showed impairments in cognitive function and an age-related increase in αSyn in the brain. These results indicate potentially different pathological mechanisms when ATP13A2 is reduced compared to when it is knocked out and may have important implications for disease modification in synucleinopathies including PD. Full article
(This article belongs to the Special Issue Optimizing Mechanistic Rationale for Parkinson’s Disease Treatment)
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17 pages, 2518 KiB  
Article
Blockade of Dopamine D3 Receptors in the Ventral Tegmental Area Mitigates Fear Memory Generalization
by Xiangjun Fang, Xiaoyan Ding, Ning Wu, Jin Li and Rui Song
Int. J. Mol. Sci. 2025, 26(13), 6520; https://doi.org/10.3390/ijms26136520 - 7 Jul 2025
Viewed by 405
Abstract
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 [...] Read more.
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
(This article belongs to the Special Issue Development of Dopaminergic Neurons, 4th Edition)
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22 pages, 597 KiB  
Viewpoint
Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs): A Pan-Steatotic Liver Disease Treatment?
by Lampros Chrysavgis, Niki-Gerasimoula Mourelatou and Evangelos Cholongitas
Biomedicines 2025, 13(7), 1516; https://doi.org/10.3390/biomedicines13071516 - 20 Jun 2025
Viewed by 894
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are long-acting drugs that have gathered a lot of attention worldwide for their utility in the treatment landscape of type 2 diabetes mellitus and obesity. Their widespread global use has been accompanied by an additional observation related to [...] Read more.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are long-acting drugs that have gathered a lot of attention worldwide for their utility in the treatment landscape of type 2 diabetes mellitus and obesity. Their widespread global use has been accompanied by an additional observation related to a potential reduction in alcohol consumption. Preclinical studies in animal models, along with preliminary clinical findings, suggest that GLP-1 RAs may exert beneficial effects on alcohol use disorder (AUD). The latter represents a significant public health challenge, contributing to a broad spectrum of health, social, and economic burdens. Concurrently, the use of GLP-1 RAs in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with a clinically meaningful reduction in all-cause mortality, major cardiovascular events, and progression to metabolic dysfunction-associated steatohepatitis (MASH). In this current opinion article, we firstly summarize the current literature dealing with the effect of GLP-1 RAs on AUD based on findings from experimental and human clinical studies. Additionally, beyond their role in MASLD, we explore in detail the potential impact of GLP-1 RAs on patients with alcoholic liver disease (ALD) and metabolic and alcohol-related/associated liver disease (MetALD). Finally, we highlight current challenges and unresolved issues, including concerns related to safety, accessibility, cost, and limitations in the clinical application of GLP-1 RAs. Full article
(This article belongs to the Section Endocrinology and Metabolism Research)
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15 pages, 2142 KiB  
Article
DNA Damage Response Regulation Alleviates Neuroinflammation in a Mouse Model of α-Synucleinopathy
by Sazzad Khan, Himanshi Singh, Jianfeng Xiao and Mohammad Moshahid Khan
Biomolecules 2025, 15(7), 907; https://doi.org/10.3390/biom15070907 - 20 Jun 2025
Cited by 1 | Viewed by 594
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach. Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks. In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy. Full article
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16 pages, 3942 KiB  
Article
Safety, Cognitive, and Behavioral Outcomes in Patients with Dementia with Lewy Bodies Treated with Nilotinib
by Fernando Pagan, Yasar Torres-Yaghi, Michaeline Hebron, Barbara Wilmarth, R. Scott Turner, Sara Matar, Xiaoguang Liu, Dalila Ferrante, Giuseppe Esposito, Jaeil Ahn and Charbel Moussa
J. Clin. Med. 2025, 14(12), 4245; https://doi.org/10.3390/jcm14124245 - 14 Jun 2025
Viewed by 685
Abstract
Background/Objectives: We previously demonstrated that nilotinib can sufficiently enter the brain to pharmacologically inhibit discoidin domain receptors (DDR)-1 in patients with Parkinson’s and Alzheimer’s disease. We primarily hypothesized that nilotinib is safe, and may alter disease-related biomarkers to improve, motor, cognitive and/or behavioral [...] Read more.
Background/Objectives: We previously demonstrated that nilotinib can sufficiently enter the brain to pharmacologically inhibit discoidin domain receptors (DDR)-1 in patients with Parkinson’s and Alzheimer’s disease. We primarily hypothesized that nilotinib is safe, and may alter disease-related biomarkers to improve, motor, cognitive and/or behavioral features in dementia with Lewy bodies (DLB). Methods: Forty-three participants were randomized 1:1 into nilotinib, 200 mg, or matching placebo in a single-center, phase 2, randomized, double-blind study. Study drug was taken orally once daily for 6 months followed by one-month wash-out. Results: Of 43 individuals enrolled, 14 were women (33%); age (mean ± SD) was 73 ± 8.5 years. Nilotinib was safe and well-tolerated, and more adverse events were noted in the placebo (74) vs. nilotinib (37) groups (p = 0.054). The number of falls were reduced in the nilotinib (six) compared to placebo (21) group (p = 0.006). Cerebrospinal fluid homovanillic acid, a biomarker of dopamine levels, was increased (p = 0.004), while the ratio of pTau181/Aβ42 was reduced (p = 0.034). The Alzheimer’s Disease Assessment Scale—cognition 14 improved by 2.8 pts (p = 0.037), and no differences were observed in Movement Disorders Society–Unified Parkinson’s Disease Rating Scale parts II and III. However, part I (cognition) improved (p = 0.044) in nilotinib compared to placebo. Conclusions: Nilotinib demonstrates favorable safety, biomarkers, and efficacy outcomes in patients with DLB supporting further trials in DLB or advanced Parkinson’s disease with dementia. Full article
(This article belongs to the Section Clinical Neurology)
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18 pages, 4138 KiB  
Review
Fibromyalgia in the Era of Brain PET/CT Imaging
by Elisabetta Abenavoli, Valentina Berti, Matilde Nerattini, Piercarlo Sarzi-Puttini, Georgios Filippou, Alessandro Lucia, Gilberto Pari, Stefano Pallanti, Fausto Salaffi, Marina Carotti, Silvia Sirotti and Francesco Porta
J. Clin. Med. 2025, 14(12), 4166; https://doi.org/10.3390/jcm14124166 - 12 Jun 2025
Viewed by 1094
Abstract
Fibromyalgia syndrome (FMS) is a complex, heterogeneous disorder characterized by chronic widespread pain, fatigue, and cognitive disturbances. The multifactorial nature of FMS, with the involvement of central and peripheral mechanisms, hampers diagnosis and effective treatment. In recent years, positron emission tomography (PET) imaging [...] Read more.
Fibromyalgia syndrome (FMS) is a complex, heterogeneous disorder characterized by chronic widespread pain, fatigue, and cognitive disturbances. The multifactorial nature of FMS, with the involvement of central and peripheral mechanisms, hampers diagnosis and effective treatment. In recent years, positron emission tomography (PET) imaging has emerged as a valuable tool for exploring the neurobiological underpinnings of FMS. Several studies have investigated alterations in glucose metabolism, neurotransmitter systems (including opioid, dopamine, and GABAergic pathways), and neuroinflammation using various PET tracers. These findings have revealed distinct brain metabolic and molecular patterns in FMS patients compared to healthy controls, particularly in pain-related regions such as the thalamus, insula, and anterior cingulate cortex (ACC). Moreover, preliminary data suggest that PET imaging may help identify FMS subgroups with different pathophysiological profiles, potentially allowing for tailored therapeutic approaches. This review summarizes the current evidence on PET applications in FMS and discusses the potential role of molecular imaging in improving patient stratification and predicting treatment response. Full article
(This article belongs to the Special Issue Imaging in Diagnosis and Treatment of Musculoskeletal Disorders)
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30 pages, 1795 KiB  
Review
Computational Neuroscience’s Influence on Autism Neuro-Transmission Research: Mapping Serotonin, Dopamine, GABA, and Glutamate
by Victoria Bamicha, Pantelis Pergantis, Charalabos Skianis and Athanasios Drigas
Biomedicines 2025, 13(6), 1420; https://doi.org/10.3390/biomedicines13061420 - 10 Jun 2025
Viewed by 2955
Abstract
Autism spectrum disorder is a complex and diverse neurobiological condition. Understanding the mechanisms and causes of the disorder requires an in-depth study and modeling of the immune, mitochondrial, and neurological systems. Computational neuroscience enhances psychiatric science by employing machine learning techniques on neural [...] Read more.
Autism spectrum disorder is a complex and diverse neurobiological condition. Understanding the mechanisms and causes of the disorder requires an in-depth study and modeling of the immune, mitochondrial, and neurological systems. Computational neuroscience enhances psychiatric science by employing machine learning techniques on neural networks, combining data on brain activity with the pathophysiological and biological characteristics of psychiatric–neurobiological disorders. The research explores the integration of neurotransmitter activity into computational models and their potential roles in diagnosing and treating autism using computational methods. This research employs a narrative review that focuses on four neurotransmitter systems directly related to the manifestation of autism, specifically the following neurotransmitters: serotonin, dopamine, glutamate, and gamma-aminobutyric acid (GABA). This study reveals that computational neuroscience advances autism diagnosis and treatment by identifying genetic factors and improving the efficiency of diagnosis. Neurotransmitters play a crucial role in the function of brain cells, enhancing synaptic conduction and signal transmission. However, the interaction of chemical compounds with genetic factors and network alterations influences the pathophysiology of autism. This study integrates the investigation of computational approaches in four neurotransmitter systems associated with ASD. It improves our understanding of the disorder and provides insights that could stimulate further research, thereby contributing to the development of effective treatments. Full article
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24 pages, 2331 KiB  
Article
Auditory Event-Related Potentials in Two Rat Models of Attention-Deficit Hyperactivity Disorder: Evidence of Automatic Attention Deficits in Spontaneously Hypertensive Rats but Not in Latrophilin-3 Knockout Rats
by Logan M. Brewer, Jankiben Patel, Frank Andrasik, Jeffrey J. Sable, Michael T. Williams, Charles V. Vorhees and Helen J. K. Sable
Genes 2025, 16(6), 672; https://doi.org/10.3390/genes16060672 - 30 May 2025
Viewed by 573
Abstract
Background/Objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, [...] Read more.
Background/Objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, impulsivity, and hyperactivity. However, inattention remains unexplored. Methods: We assessed automatic attention in Lphn3 KO (n = 19) and their control line (wildtype/WT, n = 20) through use of the following auditory event-related potentials (ERPs): P1, N1, P2, and N2. We also extended this exploratory study by comparing these same ERPs in spontaneously hypertensive rats (SHRs, n = 16), the most commonly studied animal model of ADHD, to their control line (Wistar–Kyoto/WKY, n = 20). Electroencephalograms (EEG) were recorded using subdermal needle electrodes at frontocentral sites while freely moving rats were presented with five-tone trains (50 ms tones, 400 ms tone onset asynchronies) with varying short (1 s) and long (5 s) inter-train intervals. Peak amplitudes and latencies were analyzed using GLM-mixed ANOVAs to assess differences across genotypes (KO vs. WTs) and strains (SHRs vs. WKYs). Results: The KOs did not demonstrate any significant differences in peak amplitudes relative to the WT controls, suggesting that the null expression of Lphn3 does not result in the development of inefficiencies in automatic attention. However, the SHRs exhibited significantly reduced peak P1 (and peak-to-peak P1–N1) values relative to the WKYs. These attenuations likely reflect inefficiencies in bottom-up arousal networks that are necessary for efficient automatic processing. Conclusions: Distinct findings between these animal models likely reflect differing alterations in dopamine and noradrenaline neurotransmission that may underlie ADHD-relevant phenotypes. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
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27 pages, 6634 KiB  
Article
A Novel Polyherbal Formulation Modulates Cyclophosphamide-Induced Cytotoxicity in TM3 Leydig Cells and Delays Fictive Ejaculation in Spinal Cord Transected Male Rats
by Patrick Brice Defo Deeh, Hye-Yong Kim, Kiseok Han, Anbazhagan Sathiyaseelan, Hyun-Jong Cho and Myeong-Hyeon Wang
Pharmaceuticals 2025, 18(6), 803; https://doi.org/10.3390/ph18060803 - 27 May 2025
Viewed by 590
Abstract
Background: Cyclophosphamide (CP) chemotherapy is commonly associated with various side effects. The development of an effective therapy capable of counteracting these effects is of great interest. Objectives: We evaluated the effects of a novel polyherbal formulation (PHF) on CP cytotoxicity in [...] Read more.
Background: Cyclophosphamide (CP) chemotherapy is commonly associated with various side effects. The development of an effective therapy capable of counteracting these effects is of great interest. Objectives: We evaluated the effects of a novel polyherbal formulation (PHF) on CP cytotoxicity in TM3 cells and fictive ejaculation in rats, and determined its possible mechanism. Methods: The phytochemical analysis of PHF was determined by GC-MS. Various oxidative stress-related parameters (DPPH, ABTS+, CUPRAC, FRAP, MMP, and DCF-DA) and the cytotoxicity (hemolysis and HET-CAM) of PHF were evaluated. Its effect on fictive ejaculation was tested by recording the electromyographic activities of bulbospongiosus muscles, and the involvement of TRPV1/TRPM2 channels was investigated using their specific agonists and antagonists. Results: We found that PHF contained various phytocompounds. PHF prevented CP-induced oxidative stress in TM3 cells, probably due to its strong antioxidant potential. For instance, PHF inhibited apoptosis, lipid peroxidation, and ROS generation. Furthermore, the activities of capsaicin (CAP) and cumene hydroperoxide (CHPx) were significantly lowered by PHF, indicating TRPV1 and TRPM2 inhibition. In the in vivo study conducted in spinal male rats, the number of contractions of the bulbospongiosus muscles was significantly (p < 0.001) lowered in the PHF + DOPA (1.54 ± 0.3) and PHF + CAP (2.43 ± 0.74) groups, compared with the DOPA (8.75 ± 0.71) and CAP (7.41 ± 1.01) groups, respectively. Additionally, PHF delayed the pro-ejaculatory effects of dopamine (by 17.6%) and capsaicin (by 32.69%). The in silico study revealed a strong binding affinity between the selected PHF phytocompounds and the active pockets of TRPV1 and TRPM2. HET-CAM and hemolysis assays revealed no harmful effects of PHF. Conclusions: PHF prevented CP cytotoxicity in TM3 cells and delayed the pro-ejaculatory effects of dopamine and capsaicin in spinal rats through dopamine and TRPV1 inhibition. PHF could be a potential candidate for the management of CP chemotherapy-related disorders, such as premature ejaculation, in particular. Full article
(This article belongs to the Section Natural Products)
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11 pages, 648 KiB  
Article
Heart Rate Variability Prediction of Stimulant-Induced Creativity Gains in Attention-Deficit/Hyperactivity Disorder
by Carrina Appling, Nanan Nuraini, Eric Hart, David Wang, Aneesh Tosh, David Beversdorf and Bradley Ferguson
J. Clin. Med. 2025, 14(10), 3570; https://doi.org/10.3390/jcm14103570 - 20 May 2025
Viewed by 1494
Abstract
Background/Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent condition etiologically related to suboptimal levels of dopamine (DA) and norepinephrine (NE) that is typically treated with psychostimulant medication. In individuals with ADHD, divergent thinking abilities have been shown to improve with the use of [...] Read more.
Background/Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent condition etiologically related to suboptimal levels of dopamine (DA) and norepinephrine (NE) that is typically treated with psychostimulant medication. In individuals with ADHD, divergent thinking abilities have been shown to improve with the use of psychostimulants. Furthermore, psychostimulants affect autonomic nervous system (ANS) functioning, which can impact creative cognition. However, it is not known how DA and NE affect creative cognition in this setting and how this effect is related to autonomic activity in ADHD. Therefore, our objective was to elucidate ANS function and its relationship with divergent creativity gains related to psychostimulant treatment in ADHD. Method: Seventeen individuals diagnosed with ADHD (age 27.9 ± 6.7 sd) participated in two counterbalanced sessions—one while on their prescribed stimulant medication and another after abstaining for at least 24 h. During each session, participants completed convergent (anagrams) and divergent (Torrance Test of Creative Thinking) thinking tasks. An 8 min electrocardiogram prior to cognitive testing was taken to measure heart rate variability (HRV), which is an index of ANS functioning. Results: The hypothesized baseline pNN50 HRV measure was not predictive of enhanced creativity gains on convergent anagrams or divergent creativity on the Torrance when taking stimulants. Conclusions: In this pilot study, the relationship between baseline HRV and the impact of stimulants on anagram performance suggests the noradrenergic system may not play a role in the effect of stimulants on convergent or divergent creativity. The lack of a relationship between baseline HRV and stimulant-related changes in TTCT and anagram scores lends some support to the hypothesis that dopaminergic effects may be the predominant factor in the effect of stimulants on creativity in ADHD. Future research should further investigate the interaction between hypoactive neurotransmitter systems, particularly dopamine in divergent and norepinephrine in convergent creativity, using neuroimaging techniques to assess neurotransmitter dynamics during creativity-based tasks. Full article
(This article belongs to the Special Issue Clinical Advances in Child Neurology)
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25 pages, 2404 KiB  
Article
Network Pharmacology-Guided Evaluation of Ginger and Cornelian Cherry Extracts Against Depression and Metabolic Dysfunction in Estrogen-Deficient Chronic Stressed Rats
by Nara Lee, Ting Zhang, Hanbin Joe and Sunmin Park
Int. J. Mol. Sci. 2025, 26(10), 4829; https://doi.org/10.3390/ijms26104829 - 18 May 2025
Viewed by 871
Abstract
This study investigated the therapeutic effects of water extracts from Zingiber officinale Roscoe (ginger) and Cornus officinalis Siebold and Zucc. fruits (COF) water extracts on depression-like behavior and metabolic dysfunction in estrogen-deficient rats exposed to chronic mild stress (CMS). Network pharmacology analysis identified [...] Read more.
This study investigated the therapeutic effects of water extracts from Zingiber officinale Roscoe (ginger) and Cornus officinalis Siebold and Zucc. fruits (COF) water extracts on depression-like behavior and metabolic dysfunction in estrogen-deficient rats exposed to chronic mild stress (CMS). Network pharmacology analysis identified three bioactive compounds in ginger and four in COF, with 11 overlapping targets linked to both depression and metabolic pathways, primarily involving NR3C1, HTR2A, MAOA, and SLC6A4 genes associated with hypothalamic–pituitary–adrenal (HPA) axis regulation and neurotransmitter modulation. Ovariectomized rats received 200 mg/kg/day of ginger or COF extracts for 7 weeks, with a 4-week CMS protocol initiated at week 3. Both extracts significantly improved depression-like behaviors, memory performance, glucose tolerance, lipid profiles, and bone mineral density, normalized HPA axis markers (corticosterone and ACTH), and increased hippocampal serotonin and dopamine levels. Ginger demonstrated greater efficacy in improving memory and metabolic outcomes compared to COF. Molecular docking further validated these findings, revealing strong and stable interactions between key phytochemicals—such as hydroxygenkwanin and telocinobufagin—and target proteins MAOA, HTR2A, and NR3C1, supporting their mechanistic role in stress and mood regulation. These results support supplementing ginger and COF extracts as promising botanical interventions for estrogen-deficiency-related mood and metabolic disorders, with potential clinical application at a human-equivalent dose of 1.5 g/day. Full article
(This article belongs to the Special Issue Medicinal Plants and Bioactive Compounds in Health and Disease)
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18 pages, 5907 KiB  
Article
A Novel Ashwagandha (Withania somnifera) Formulation Mitigates Sleep Deprivation-Induced Cognitive Impairment and Oxidative Stress in a Rat Model
by Besir Er, Busra Ozmen, Emre Sahin, Cemal Orhan, Nurhan Sahin, Abhijeet A. Morde, Muralidhara Padigaru and Kazim Sahin
Biomolecules 2025, 15(5), 710; https://doi.org/10.3390/biom15050710 - 12 May 2025
Cited by 1 | Viewed by 1434
Abstract
Ashwagandha (Withania somnifera) is a well-known adaptogenic herb traditionally used to enhance sleep quality and mitigate stress-induced cognitive decline. This study investigated the effects of different doses of ashwagandha root extract (AE) formulations on cognitive function, oxidative stress, and neuronal plasticity [...] Read more.
Ashwagandha (Withania somnifera) is a well-known adaptogenic herb traditionally used to enhance sleep quality and mitigate stress-induced cognitive decline. This study investigated the effects of different doses of ashwagandha root extract (AE) formulations on cognitive function, oxidative stress, and neuronal plasticity in a rat model of sleep deprivation (SD). Forty-nine rats were randomly assigned to seven groups: control, wide platform (WP), SD, SD + A1 (15 mg/kg AE 1.5%), SD + A2 (30 mg/kg AE 1.5%), SD + A3 (5.5 mg/kg AE 8.0%), and SD + A4 (11 mg/kg AE 8.0%). The extract was administered orally for four weeks. SD induced via a modified wide platform model significantly impaired spatial memory, increased oxidative stress, and suppressed GABA receptor activity. Treatment with all AE doses, except 15 mg/kg AE 1.5%, considerably reduced serum corticosterone (12% for SD + A2, 15% for SD + A3, and 32% for SD + A4), CRH (11% for SD + A2, 14% for SD + A3, and 17% for SD + A4), ACTH (22% for SD + A2, 26% for SD + A3, and 38% for SD + A4), and MDA levels (31% for SD + A2, 34% for SD + A3, and 46% for SD + A4) (p < 0.05). All doses improved antioxidant enzyme activity and memory performance, while AE 8.0% doses notably increased serotonin (19% for SD + A3 and 33% for SD + A4) and dopamine levels (40% for SD + A3 and 50% for SD + A4). Moreover, AE treatment enhanced markers of neuronal plasticity and partially improved GABAergic function. These findings suggest that AE formulations, particularly at higher concentrations, exert neuroprotective effects against SD-induced cognitive impairment by modulating oxidative stress, neurotransmitter balance, and neuroplasticity, indicating their potential application in managing stress-related neurological disorders. Full article
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