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Attention impairment, a prevalent non-motor symptom in Parkinson's disease (PD), plays a crucial role in movement disorders. PD patients exhibit abnormalities in the attentional network related to alerting, orienting, and executive control. While dopamine medications have well-documented effects on motor function, their impact on attention networks and the underlying neural mechanisms involved in motor functions remain unclear. In this study, we utilized a modified attention network test to investigate the neural correlates underlying attention network effects measured by electroencephalography (EEG) in 29 PD patients, both on and off dopamine medication and examined their association with motor performance. Interestingly, we found that dopamine medication specifically modulated the orienting effect of the attention network. We analyzed event-related potential components, time-frequency oscillations, and brain network connectivity, as determined by the weighted phase lag index, within the orienting effect under different dopamine medication states. We observed that event-related desynchronization in the betalow, event-related synchronization in the betahigh, and functional connectivity of the betalow in the frontal, central, and parietal were regulated by dopamine medication in the orienting effect. We discovered an association between the attention network's orienting effect and motor performance alterations, which may be attributed to enhanced functional connectivity within the betalow-brain network. Enhanced weighted phase lag index of the betalow-brain network in the orienting effect may contribute to dopamine-dependent changes in motor performance. These preliminary findings provide insights into the EEG mechanisms that underlie the impact of the orienting effect in individuals with PD, shedding light on the influence of dopamine medication and its potential role in regulating top-down attention processes. These findings could help in the advancement of substitution strategies and may have the potential to address both motor and cognitive deficits in PD patients. [ABSTRACT FROM AUTHOR]

Movement disorders, stemming from central nervous system dysfunction, affect voluntary and involuntary movements. These include hypokinetic disorders, like Parkinson's disease and akinetic-rigid syndromes (multiple-system atrophy and progressive supranuclear palsy), and hyperkinetic disorders, like tremor, chorea, akathisia, myoclonus and tics. These conditions are difficult to diagnose, and thorough clinical evaluation, imaging and specialised tests can help in reaching a diagnosis. Dystonia, marked by involuntary muscle contractions, varies in severity and profoundly impacts quality of life. Treatment options include medication, neurotoxin injections, deep brain stimulation, and other therapies. A multidisciplinary approach and ongoing research are crucial for improving outcomes and quality of life for those affected. [ABSTRACT FROM AUTHOR]

Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. A widely accepted assumption is that drugs of abuse result in disparate dopamine responses to cues that predict drug vs. natural rewards. The leading hypothesis is that drug-induced dopamine release represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation. However, this hypothesis has not been directly tested. Here, we develop Pavlovian and operant procedures in male rats to measure firing responses within the same dopamine neurons to drug versus natural reward cues, which we find to be similarly enhanced compared to cues predicting natural rewards in drug-naive controls. This enhancement is associated with increased behavioral reactivity to the drug cue, suggesting that dopamine neuronal activity may still be relevant to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting revised models of dopaminergic function in opioid addiction, and provide insights into the neurobiology of cue reactivity with potential implications for relapse prevention. A widely accepted assumption in addiction research is that overvaluation of drug cues is caused by enhanced dopaminergic response to these cues. Here, the authors show similar dopamine neuronal responses to cues predicting opioids vs. natural rewards. [ABSTRACT FROM AUTHOR]

Pain is a morbidity or comorbidity with a high incidence that significantly impacts the well‐being of patients. In this study, we evaluated the effects of systemic administration of tramadol, a weak mu‐opioid receptor (MOR) agonist, plus quinpirole (a D2‐like receptor agonist). The study was performed in naïve rats and in rats with induced inflammatory and neuropathic pain. To measure the antinociceptive effect of the drugs, thermonociceptive and mechanonociceptive stimuli were applied and the emotional aspects of pain were evaluated using conditional place preference (CPP) experiments. Systemic quinpirole produced an antinociceptive effect only in naïve male rats. In naïve female animals, a small but significant pronociceptive effect was observed following quinpirole application. Tramadol plus quinpirole in male animals reversed allodynia and hyperalgesia induced by inflammatory and neuropathic insults, which were not alleviated by either drug alone. CPP experiments revealed that systemic quinpirole plus tramadol treatment was effective only in an inflammatory pain model. To evaluate whether tolerance to the antinociceptive effect was prevented by the combination of the drugs, a repeated administration five‐day trial of tramadol plus quinpirole was evaluated under inflammatory pain conditions; quinpirole only slightly prevented the antinociceptive tolerance of MOR agonists. D2‐like agonists are effective adjuvants for treating painful conditions in combination with a low dose of MOR agonists. Our results could lead to an investigation of whether these dopaminergic drugs in combination with opioids might reduce the MOR agonist dose while obtaining a higher analgesic effect with fewer side effects in humans. [ABSTRACT FROM AUTHOR]

• Probenecid enhances tenofovir concentration in plasma and kidneys. • Co-administration increases tenofovir entry into the brain. • Tenofovir alone elevates IL-1β concentration post-administration. • Probenecid's anti-inflammatory impact may need longer duration. • Neither drug affects dopamine concentration in the brain. The blood–brain barrier's limited permeability to tenofovir restricts its ability to clear HIV from the brain. Probenecid acting as an adjuvant increases tenofovir concentrations in plasma and the kidneys thereby enhancing its therapeutic effect. However, the probenecid effect on brain tenofovir concentration and possible adverse effects remains poorly understood. We investigated the effect of probenecid co-administered tenofovir on tenofovir brain concentration, interleukin-1β (IL-1β) and dopamine concentration in the prefrontal cortex (PFC) and the cerebellum. Ninety-six male BALB/c mice were divided into four groups viz: a control group, Tenofovir disoproxil fumarate (TDF) treated, probenecid treated, and TDF + probenecid treated. We orally administered a single dose of TDF (5 mg/kg), and probenecid (8.3 mg/kg), and sacrificed six mice per group after 1 h, 4 h, and 6 h post-treatment to collect plasma, PFC, and cerebellar tissue. Co-administered tenofovir increased tenofovir concentration, peaking at 6 h with the cerebellum having the highest concentration. This suggests that probenecid enhanced the entry of tenofovir into the brain. Tenofovir alone increased IL-1β concentration at all intervals post-administration, while probenecid alone had no impact on IL-1β concentration. Co-administered tenofovir also increased IL-1β concentration. Probenecid's limited impact on IL-1β concentration following co-administration suggests that its anti-inflammatory properties may require more than 6 h to have an effect. Furthermore, neither tenofovir nor probenecid affected dopamine concentration. In conclusion, probenecid enhances the concentration and retention of tenofovir in the brain, making it a possible pharmacokinetic enhancer. However, its anti-inflammatory effects may require a longer duration to fully manifest. [ABSTRACT FROM AUTHOR]

Drug addiction often correlates with criminal behavior. When investigating criminal behavior among individuals grappling with drug addiction, it becomes crucial to scrutinize the influence of dopamine. Substances such as heroin, morphine, methamphetamine and other drugs can cause abnormal dopamine secretion when people are addicted to them, which promotes changes in the brain's reward circuit and emotional balance, thereby increasing susceptibility to criminal behavior. The pivotal role of dopamine within the reward pathway and its regulatory function in emotional processes exert profound influence on behavior following drug simulation. These influences are primarily manifested by three distinct attributes: a singular criminal motive and objective, lack of moral sense, and impulsive decision-making processes. Drawing upon the distinctive dopaminergic dynamics inherent in individuals afflicted by drug addiction, this study advocates for targeted corrective interventions. The preventive paradigm encompasses the cultivation of supportive community environments, the establishment of comprehensive databases, and providing legal education and protection, among other initiatives. In terms of treatment, along with judicial sanctions and protections, exercise regimens and psychotherapeutic interventions are advocated. The corrective endeavor necessitates a synergistic integration of community-based and legalistic frameworks. The objective is to furnish guiding principles for tackling criminal behavior precipitated by aberrant dopamine secretion, underpinned by a scientifically informed approach. [ABSTRACT FROM AUTHOR]

Negative symptoms can be an integral part of schizophrenia spectrum pathology and can be secondary to other psychotic symptoms or caused by antipsychotic medication. As antipsychotic drugs differ in their affinity to dopamine receptors and some antipsychotics have partial agonistic effects, antipsychotic drugs are expected to vary in their ability to cause negative symptoms. The association between negative symptoms and antipsychotic medication divided into partial agonists, or antagonists with high or low D 2 affinity was assessed in 310 remitted first episode psychosis (FEP) patients. Severity of negative symptoms was assessed with the Comprehensive Assessment of Symptoms and History, and the Positive and Negative Syndrome Scale. Linear regression analyses were performed while controlling for differences in clinical and sociodemographic characteristics between the groups using inverse probability of treatment weighting. Patients using partial agonists (n = 78) showed fewer negative symptoms compared to those using high affinity antagonists (n = 84). Patients using partial agonists displayed less severe negative symptoms compared to those using low affinity antagonists (n = 148) at a trend level (p = 0.051). Negative symptom severity was higher in patients who had higher antipsychotic doses. In remitted FEP patients, we observed that the use of antipsychotic medication classified as partial agonists was associated with lower severity of negative symptoms, while the use of antagonists with high D 2 affinity was associated with more severe negative symptoms. • In remitted FEP patients, persistence of negative symptoms reduces quality of life and social and vocational recovery. • FEP patients using antipsychotics with partial D2R agonism showed less severe negative symptoms than high affinity antagonists. • There was a trend that FEP patients on partial agonists had milder negative symptoms than those on low affinity antagonists • Aripiprazole treatment was related to less severe negative symptoms, a potentially important advantage for recovery. [ABSTRACT FROM AUTHOR]

Restless legs syndrome/Willis–Ekbom disease (RLS/WED) causes a strong urge to move legs while resting. Restless legs syndrome/WED is an often-inherited disease occurring in 3% to 10% of adult populations, increasing with age. Severity varies from mild disturbance of sleep to painful restless legs and arms, loss of sleep, fatigue, and risk of suicide. Dopaminergic drugs relieve symptoms, but cause augmentation, ie, initially helpful but later increase the burden of symptoms. Oral gabapentinoids and opioids are often added, but opioid tolerance and adverse effects are common. With the high prevalence and incomplete help from oral drugs, significant unmet needs exist for effective therapy for severe RLS/WED. Ongoing spinal intrathecal infusion of low-dose morphine is effective, but not generally recognized, as only 12 cases have been published since 2002. We report 7 patients suffering from severe RLS/WED, who had no relief from oral dopaminergic, gabapentinoid, or opioid drugs; they all had excellent relief during ongoing spinal intrathecal infusion of morphine at only 1 to 5 μg/h, ongoing for 1 to 21 years without need of higher doses of morphine.. We suggest that morphine may be transported with the cerebrospinal fluid reaching and readjusting malfunctioning dopamine neuronal systems in the brain and spinal cord. The effects last only as long as the infusion continues. A patient with RLS/WED and persistent genital arousal disorder (PGAD) was relieved of both RLS/WED and PGAD symptoms. These case reports suggest that intrathecal infusion of low-dose morphine is an effective treatment of severe RLS. [ABSTRACT FROM AUTHOR]

Background: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. Patients and Methods: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. Results: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). Conclusion: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life. [ABSTRACT FROM AUTHOR]

Impulsive‐compulsive behaviors (ICB) are common non‐motor symptoms of Parkinson's disease (PD) often associated with dopaminergic drugs (DD) therapy. We investigated the acute effects of DD on decision‐making in PD patients with ICB (ICB+) and without it (ICB−), and in healthy controls (HC). Participants performed a risk‐based decision‐making task twice, with PD patients tested before (DD OFF) and after (DD ON) DD intake. In DD OFF, all groups developed a risk‐averting strategy. In DD ON, ICB+ patients (but not ICB− nor HC) reverted to riskier choices. We conclude that DD has a specific strong acute effect on ICB+ patients' decision‐making. [ABSTRACT FROM AUTHOR]

Oral therapeutic delivery remains challenged by gastrointestinal tract (GI) barriers, which hinders the successful transition of therapeutic candidates into clinical treatments. Polydopamine (PDA), with its versatile ability to overcome GI barriers, offers a promising drug formulation technology to address the challenge. Nevertheless, many critical questions remain unanswered regarding the practicality of PDA‐based formulations. Building on the previous research, which tackled multiple physicochemical aspects, the current study aims to address another three outstanding issues, including the quantification of residual dopamine (DA) in PDA‐based formulations, the examination of these formulations stimulatory effects on colon tissue, and the potential anti‐inflammatory properties. To facilitate this investigation, a curcumin‐containing nanomedicine (CP@CCS) is prepared as a representative PDA‐based formulation. The results reveal a marked decrease of residual DA within the formulation. In the treatment of ulcerative colitis (UC), the formulation do not provoke the substantial contractions in colon tissue typically induced by DA. Furthermore, in vivo evaluation verified the supplementary anti‐UC benefits of PDA. These outcomes add evidence for the practicality of PDA‐based formulations in terms of safety and therapeutic efficacy. Finally, a conceptual framework is proposed for understanding the role of PDA in oral therapeutic delivery, thereby providing insightful directions for subsequent research. [ABSTRACT FROM AUTHOR]

Background: The search for neuroprotective treatments for Parkinson's disease (PD) still relies largely on motor disability scales. A limitation of these tools is the strong influence of symptomatic dopaminergic treatment effects. Drawing on a wealth of published information, we conducted a systematic review and meta-analysis of motor progression in PD and its relationships with dopaminergic therapy. Methods: We searched Medline, Embase, and Central to identify 84 publications with adequate serial motor scores to calculate progression, expressed as an increase in the percentage of maximum disability. Results: A random-effects model showed motor progression at 2.0% p.a. (95% CI 1.7–2.4%). There were no significant differences by baseline age, sample size, or observation period. However, untreated patients, in 8 publications, progressed at 4.5% p.a. compared to 1.6% p.a. in 76 studies containing individuals on dopaminergic drugs (p = 0.0004, q = 0.003). This was supported by research on phenoconversion in prodromal PD, where motor progression exceeded 5% p.a. in the 2 years before diagnosis. Starting levodopa improved pre-treatment disability by 40.3 ± 15.2%. Practically defined off state measurements increase faster than on scores by a modest degree (p = 0.05). Conclusion: This survey suggests that accurate long-term measurements of motor progression to assess disease-modifying therapies can be conducted despite the sequential commencement of dopaminergic drugs and sample attrition over time. While study designs involving prodromal or untreated PD avoid confounding effects of symptomatic treatment, different assumptions about motor progression may be needed. A defined off state with the levodopa test dose method maximizes information about the medication cycle once dopaminergic therapy has begun. [ABSTRACT FROM AUTHOR]

This study undertook neuropharmacological research on the clinical course of controlled medication discontinuation to guide practitioners who are considering stopping medications for youths with attention-deficit hyperactivity disorder (ADHD). This study analyzed the data for 14 ADHD children (12 male and 2 female) in two datasets: The children prescribed methylphenidate (MPH) were at an initial mean age of 7.5 years (SD = 1.70, range: 6–11) with a mean ADHD-Rating Score (ADHD-RS) of 26.6 (SD = 8.64, range 15–40). The children who discontinued MPH based on clinical judgment were at a mean age of 12.21 years (SD = 2.12, range: 8–15) with a mean ADHD-RS of 15.9 (SD = 6.86, range 5–27). The go/no-go task was used to assess response inhibition, while functional near-infrared spectroscopy (fNIRS) was used to measure cerebral hemodynamics. Oxygenated hemoglobin (Oxy-Hb) values from fNIRS data were analyzed for each subject, focusing on past and current measurements. Baseline was set at 10 s pre-task, with interval means from 4 to 24 s analyzed. One-sample t -tests were used to evaluate brain activity magnitude. The results of the study demonstrate that the children who had discontinued the medication exhibited activation in specific brain regions including the frontopolar cortex and the right ventrolateral prefrontal cortex. Activation (t = 2.363, p = 0.034, Cohen's d = 0.632) was found especially in the right dorsolateral prefrontal cortex during the performance of the go/no-go task. These activated areas were consistent with those observed in a previous study comparing brain activity during a go/no-go task between children with ADHD and healthy children. The present study showed differences in cerebral hemodynamics before and after discontinuation of MPH in ADHD children whose ADHD symptoms did not recur after MPH was discontinued. In the near future, further investigations that include control groups will be conducted to demonstrate the effects of MPH prior to discontinuation based on the changes in cerebral blood flow in the right prefrontal cortex, which is involved in behavioral inhibition, as observed in this study. This and future research will facilitate the development of criteria for discontinuing treatment. [ABSTRACT FROM AUTHOR]

Background: Studies that assess the effects of the interaction of psychoactive substances on dopamine release, the key neurotransmitter in the neurochemical and behavioral effects related to drug consumption, are crucial to understand both their roles and the dysfunctions they produce in the central nervous system. Objective: We evaluated the effects of individual and combined administration of the three most widely consumed psychoactive substances in the world, ethanol, caffeine, and nicotine, on dopaminergic neurotransmission in three brain regions of rats related to addiction: the prefrontal cortex (PFC), the nucleus accumbens (NAcc), and the dorsal striatum. Methods: The dopamine levels were measured in vivo by cerebral microdialysis associated with HPLC-ED. Results: We observed that local administration of a single concentration of caffeine (5 mM) or nicotine (5 mM) significantly increased the dopamine levels in all three areas studied, while ethanol (300 mM) increased them in the NAcc and striatum. Perfusion of nicotine + caffeine produced a synergistic effect in both the NAcc and striatum, with increases in the in vivo dopamine release greater than the sum of the effects of both substances. When administering the combination of nicotine + caffeine + ethanol, we observed an additive effect in the NAcc, while in the PFC we observed a synergistic effect. Conclusions: Our results support the stimulating effects of caffeine, nicotine, and ethanol on the brain reward system. In addition, we also observed that the administration of different mixtures of these substances produces synergistic and additive effects on the release of dopamine in the mesocortical and nigrostriatal systems. [ABSTRACT FROM AUTHOR]

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder. [Display omitted] • Globus pallidus is part of a 4-node circuit controlling cocaine sensitivity • KCNQ3 and KCNQ5 expression is reduced following cocaine administration • Carnosic acid inhibits GPePV cells through activating KCNQ3/5 heteromers • Carnosic acid reduces cocaine reward, sensitization, and self-administration Tian et al. demonstrate that the activity of cells in the mouse globus pallidus can predict neurophysiological and behavioral responses to cocaine. This discovery leads to the identification of carnosic acid, derived from the ancient medicinal plant rosemary, as a potential therapeutic that reduces cocaine reward and self-administration. [ABSTRACT FROM AUTHOR]

The surprising omission or reduction of vital resources (food, fluid, social partners) can induce an aversive emotion known as frustrative nonreward (FNR), which can influence subsequent behavior and physiology. FNR is an integral mediator of irritability/ aggression, motivation (substance use disorders, depression), anxiety/fear/threat, learning/conditioning, and social behavior. Despite substantial progress in the study of FNR during the twentieth century, research lagged in the later part of the century and into the early twenty-first century until the National Institute of Mental Health’s Research Domain Criteria initiative included FNR and loss as components of the negative valence domain. This led to a renaissance of new research and paradigms relevant to basic and clinical science alike. The COVID-19 pandemic’s extensive individual and social restrictions were correlated with increased drug and alcohol use, social conflict, irritability, and suicide, all potential consequences of FNR. This article highlights animal models related to these psychiatric disorders and symptoms and presents recent advances in identifying the brain regions and neurotransmitters implicated. [ABSTRACT FROM AUTHOR]

Clinical Scenario: Individuals with Parkinson Disease (PD) often present with impaired balance, resulting in increased fall risk. Evidence suggests that balance can be improved with physical therapy balance training interventions applied through video game play, or 'exergaming'. However, best practices regarding the prescription of exergaming for persons with PD are unknown. The goal of this appraisal was to identify the Nintendo Wii exergame (NWE) parameters that have been shown to improve dynamic balance in individuals with PD, specifically Hoehn and Yahr (HY) stages 1-3, and make recommendations for the prescription of NWE balance interventions for this population. Methods: The literature was searched to identify randomized controlled trials (RCT) that utilized NWE as a balance intervention for individuals with PD within HY stages 1-3. The search was limited to articles published within the last 10 years that assessed dynamic balance outcomes via the Dynamic Gait Index (DGI) or Functional Gait Assessment (FGA). Participants had no other known comorbidities that would impact dynamic balance and were on a stable dopaminergic prescription. 3 RCTs were identified and included in this appraisal. Conclusion and Implications for Practice: NWE may improve dynamic balance in individuals with PD, HY stages 1-3. Recommended parameters include a variety of NWE modes, performed for 45-50 min per session, at a frequency of 2-3 times a week for 6-8 weeks. Clinicians should utilize a skilled approach when prescribing NWE including ongoing assessment to determine progress and to maintain safety. Future research is needed to determine the necessary intensity of NWE to improve dynamic balance in individuals with PD. [ABSTRACT FROM AUTHOR]

The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis. [ABSTRACT FROM AUTHOR]

Conventional DBS (cDBS) for Parkinson's disease uses constant, predefined stimulation parameters, while the currently available adaptive DBS (aDBS) provides the possibility of adjusting current amplitude with respect to subthalamic activity in the beta band (13–30 Hz). This preliminary study on one patient aims to describe how these two stimulation modes affect basal ganglia dynamics and, thus, behavior in the long term. We collected clinical data (UPDRS-III and -IV) and subthalamic recordings of one patient with Parkinson's disease treated for one year with aDBS, alternated with short intervals of cDBS. Moreover, after nine months, the patient discontinued all dopaminergic drugs while keeping aDBS. Clinical benefits of aDBS were superior to those of cDBS, both with and without medications. This improvement was paralleled by larger daily fluctuations of subthalamic beta activity. Moreover, with aDBS, subthalamic beta activity decreased during asleep with respect to awake hours, while it remained stable in cDBS. These preliminary data suggest that aDBS might be more effective than cDBS in preserving the functional role of daily beta fluctuations, thus leading to superior clinical benefit. Our results open new perspectives for a restorative brain network effect of aDBS as a more physiological, bidirectional, brain–computer interface. [ABSTRACT FROM AUTHOR]

Rationale: Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Objectives: Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. Methods: The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Results: Ecopipam (0.05–0.2 mg/kg) and haloperidol (0.05–0.15 mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0 mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0 mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0 mg/kg, while females showed augmented immunoreactivity at 2.0 mg/kg. Conclusions: The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology. [ABSTRACT FROM AUTHOR]

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence‐based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady‐state concentration)–response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure–response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease–drug–dropout models were developed using patient‐level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure–response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure–response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13‐17 years with schizophrenia. [ABSTRACT FROM AUTHOR]

Observational studies have suggested the potential benefits of several medications for Parkinson's disease (PD) and their potential for repurposing. However, the conclusions drawn from these studies are not entirely consistent. To address this inconsistency, we used the two-sample Mendelian randomization (MR) method to explore the putative causal relationships between 23 medications and the risk and progression of PD. We applied inverse-variance weighted meta-analysis (IVW) to combine MR estimates. Additionally, sensitivity analyses were conducted to evaluate the robustness of the results. Our genetic evidence suggests that thyroid preparations and calcium channel blockers reduce the risk of PD, and salicylic acid and derivatives slow the progression of PD motor symptoms. Additionally, genetic evidence also suggests that four medications were associated with PD risk or progression, but the sensitivity analysis revealed that three of the medications may have interference caused by reverse causality. Our findings suggest that there are weak causal relationships between several medications and the risk or progression of PD. Though further replication studies are needed to verify these findings, these new insights may help in understanding the etiology of the disease, generate new clues related to drug discovery, and quantify the risk of future drug intake. [ABSTRACT FROM AUTHOR]

Introduction: Global obesity rates are rising due to rapid urbanisation and sedentary lifestyles, affecting health and economics. Modifications to one's way of life, medical interventions, and surgical procedures are among the methods that can be utilised to manage obesity. New dopaminergic drugs show promise, but regulatory hurdles remain. Dopamine modulation may reduce metabolic dysfunctions, but more research is needed. Aim and objectives: This study aims to examine the impact of Cabergoline on glucose tolerance and weight in obese adults. Method: The impact of cabergoline on blood glucose levels was examined in a double-blind research including 120 obese patients who were given either the active ingredient or a placebo. There was no statistically significant difference seen between the groups (P = 0.792). Medications were delivered every week for 3 months in addition to the ongoing therapy. The study involved the implementation of fundamental laboratory tests and measures to continuously monitor the outcomes. Result: This study presents the initial characteristics of the Cabergoline and Control groups, and compares them at 3 and 6 months. There were no notable disparities observed in terms of weight, waist circumference, blood pressure, or BMI. Once more, it examines the laboratory attributes before and following a 3-month therapy period, revealing that there are no notable disparities between the Cabergoline and Control groups in the majority of measures. Conclusion: Cabergoline did not differ significantly from the control group in terms of weight, waist circumference, blood pressure, body mass index (BMI), or the majority of laboratory values after three months. [ABSTRACT FROM AUTHOR]

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is a proven treatment modality for Parkinson’s disease (PD), reducing dyskinesia and time spent in the “OFF” state. This study evaluates the long-term outcomes of STN-DBS in PD patients up to 10 years post-surgery in Singapore. Method: We conducted a retrospective review of Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) scores, activities of daily living (ADLs), disease milestones, dopaminergic drug prescriptions, and adverse events in patients before and after STN-DBS surgery. Results: A total of 94 PD patients who underwent bilateral STN-DBS were included. STN-DBS reduced time in the “OFF” state by 36.9% at 1 year (P=0.034) and 40.9% at 5 years (P=0.006). Time with dyskinesia did not significantly change. Levodopa equivalent daily dose was reduced by 35.1% by 5 years (P<0.001). MDS-UPDRS-II and III scores increased from 5 years post-DBS by 40.5% and 35.4%, respectively. Independence in ADLs decreased, though not significantly. The prevalence of frequent falls increased at 5 years. Surgery- and device-related adverse events were uncommon and generally mild. Conclusion: STN-DBS provides sustained relief from motor complications and reduced medication requirements in PD patients in Singapore. This study highlights STN-DBS as an effective treatment option, significantly enhancing the quality of life for those with PD. [ABSTRACT FROM AUTHOR]

Following reports of low striatal dopamine content in Parkinson's disease, levodopa was shown to rapidly reverse hypokinesis, establishing the model of disease as one of dopamine deficiency. Dopaminergic therapy became standard of care, yet it failed to reverse the disease, suggesting the understanding of disease was incomplete. The literature suggests the potential for toxicity of dopamine and its metabolites, perhaps more relevant given the recent evidence for elevated cytosolic dopamine levels in the dopaminergic neurons of people with Parkinson's. To understand the relevance of these data, multiple investigations are reviewed that tested dopamine reduction therapy as an alternative to dopaminergic agents. The data from use of an inhibitor of dopamine synthesis in experimental models suggest that such an approach could reverse disease pathology, which suggests that cytosolic dopamine excess is a primary driver of disease. These data support clinical investigation of dopamine reduction therapy for Parkinson's disease. Doing so will determine whether these experimental models are predictive and this treatment strategy is worth pursuing further. If clinical data are positive, it could warrant reconsideration of our disease model and treatment strategies, including a shift from dopaminergic to dopamine reduction treatment of the disease. [ABSTRACT FROM AUTHOR]

Polydopamine, a mussel-inspired self-adherent polymer of dopamine, has impressive adhesive properties and thus is one of the most versatile approaches to functionalize tissue engineering scaffolds. To date, many types of polydopamine-functionalized scaffolds have been manufactured and extensively applied in bone tissue engineering at the preclinical stage. However, how polydopamine is biodegraded and metabolized during the bone healing process and the side effects of its metabolite remain largely unknown. These issues are often neglected in the modern manufacture of polydopamine-functionalized materials and restrict them from stepping forward to clinical applications. In this study, using our bioinspired polydopamine-laced hydroxyapatite collagen calcium silicate material as a representative of polydopamine-functionalized tissue engineering scaffolds, we discovered that polydopamine can be metabolized to dopamine specifically by osteoclasts, which we termed "osteoclast-driven polydopamine-to-dopamine release". The released dopamine showed an osteoinductive effect in vitro and promoted bone regeneration in calvarial critical-sized defects. The concept of "osteoclast-driven polydopamine-to-dopamine release" has considerable application potential. It could be easily adopted by other existing polydopamine-functionalized scaffolds: just by recruiting osteoclasts. Once adopted, scaffolds will obtain a dopamine-releasing function, which enables their modulation of osteoblast activity and hence elevates the osteoinductive effect. Thus, "osteoclast-driven polydopamine-to-dopamine release" serves as an upgrade patch, which is useful for many existing polydopamine-functionalized materials. [ABSTRACT FROM AUTHOR]

Motivation allows us to energise actions when we expect reward and is reduced in depression. This effect, termed motivational vigour, has been proposed to rely on central dopamine, with dopaminergic agents showing promise in the treatment of depression. This suggests that dopaminergic agents might act to reduce depression by increasing the effects of reward or by helping energise actions. The aim of the current study was to investigate whether the dopamine agonist pramipexole enhanced motivational vigour during a rewarded saccade task. In addition, we asked whether the effects of pramipexole on vigour differ between reward contingent on performance and guaranteed reward. Healthy adult participants were randomised to receive either pramipexole (n = 19) or placebo (controls n = 18) for 18 days. The vigour of saccades was measured twice, once before the administration of study medication (Time 1) and after taking it for 12–15 days (Time 2). To separate motivation by contingency vs. reward, saccadic vigour was separately measured when (1) rewards were contingent on performance (2) delivered randomly with matched frequency, (3) when reward was guaranteed, (4) when reward was not present at all. Motivation increased response vigour, as expected. Relative to placebo, pramipexole also increased response vigour. However, there was no interaction, meaning that the effects of reward were not modulated by drug, and there was no differential drug effect on contingent vs. guaranteed rewards. The effect of pramipexole on vigour could not be explained by a speed/accuracy trade-off, nor by autonomic arousal as indexed by pupillary dilation. Chronic D2 stimulation increases general vigour, energising movements in healthy adults irrespective of extrinsic reward. [ABSTRACT FROM AUTHOR]

Introduction: Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse. Methods: Using a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60αg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats. Results: Nicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT1A receptor antagonists, WAY-100,635 (100 αg/kg, i.v.) or S-15535 (300 αg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPATstimulated [35S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala. Discussion: Given their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT1A receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT1A activity after nicotine or fluoxetine exposure may potentiate hyperresponsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse. [ABSTRACT FROM AUTHOR]

Dysfunction of the mesocorticolimbic dopamine system in medication overuse headache (MOH) is unknown. This study aimed to determine dopamine transporter (DAT) availability, which is sensitive to dopamine levels, in the mesocorticolimbic dopamine system in MOH patients. This case–control study investigated eligible MOH patients admitted to the International Headache Centre in the neurological department of Chinese PLA General Hospital between July 2018 and August 2019. All subjects underwent an integrated positron emission tomography (PET)/magnetic resonance (MR) brain scans with 11CFT, a radioligand that binds to DAT. Standardised uptake value ratio (SUVr) images were compared voxelwise between MOH patients and healthy controls (HCs). SUVr values from significantly changed regions were extracted, and partial correlation analyses with clinical measures were conducted. We examined 17 MOH patients and 16 HCs. MOH patients had lower SUVr levels in the medial rather than lateral orbitofrontal cortex (OFC) than HCs (T = −5.0317, PGRF < 0.01), which showed no correlation with clinical features. MOH is characterised by decreased DAT availability in the medial OFC, which might reflect compensatory downregulation due to low dopamine signalling within the mesocorticolimbic dopamine system and provide a new perspective to understand the pathogenesis of MOH. [ABSTRACT FROM AUTHOR]

Background: Delirium is a neuropsychiatric condition that commonly occurs in medical settings, especially among older individuals. Despite the lack of strong evidence in the literature, haloperidol is considered the first-line pharmacological intervention. Unfortunately, its adverse effects can be severe, and psychiatrists are considering the use of alternative drugs targeting dopamine and serotonin domains (atypical antipsychotics). Among them, aripiprazole is considered to have one of the safest pharmacological profiles. Aims: The purpose of this study is to examine the studies on aripiprazole as a pharmacological treatment of delirium present in today's literature. Methods: We carried out systematic research of MedLine, PubMed, Cochrane, Embase, and ScienceDirect examining articles written between January 2002 and September 2023, including experimental studies published in peer-reviewed journals. Results: The 6 final included studies examined a total of 130 patients, showing a delirium resolution in a 7-day span of 73.8% of patients treated with aripiprazole. Conclusions: Considering the limited data currently available, we can assert that aripiprazole is at least as efficient as haloperidol, the true point is that it has a far better tolerability and safety profile. Nonetheless, further studies are necessary to provide more compelling data, together with a more precise indication regarding minimum efficient dose, as the main limitations of our review are the very small sample size, the small percentage of subjects with preexisting dementia, and the fact that most studies used scales with low specificity for the examined condition. [ABSTRACT FROM AUTHOR]

ObjectivesThe objective of this review is to provide updated information on the epidemiology, correlating factors and treatment of chronic kidney disease associated restless legs syndrome (CKD-A-RLS) in both adult and pediatric population.Materials and methodsWe have reviewed the Medline search and Google Scholar search up to May 2022, using key words restless legs syndrome, chronic kidney disease and hemodialysis and kidney transplant. The reviewed articles were studied for epidemiology, correlating factors, as well as pharmacologic and non-pharmacologic treatment options.ResultsOur search revealed 175 articles, 111 were clinical trials or cross- sectional studies and 64 were review articles. All 111 articles were retrieved and studied in detail. Of these, 105 focused on adults and 6 on children. A majority of studies on dialysis patients reported a prevalence between 15-30%, which is notably higher than prevalence of RLS in general population (5-10%). The correlation between presence of CKD-A-RLS with age, gender, abnormalities of hemogram, iron, ferritin, serum lipids, electrolytes and parathyroid hormones were also reviewed. The results were inconsistent and controversial. Limited studies have reported on the treatment of CKD-A-RLS. Non-pharmacological treatment focused on the effect(s) of exercise, acupuncture, massage with different oils and infra-red light whereas, pharmacologic treatment options include the effects of dopaminergic drugs, Alpha2-Delta ligands (gabapentin and pregabalin), vitamins E and C, and intravenous iron infusion.ConclusionThis updated review showed that RLS is two to three times more common in patients with CKD compared to the general population. More patients with CKD-A-RLS demonstrated increased mortality, increased incidence of cardiovascular accident, depression, insomnia and impaired quality of life than those with CKD without RLS. Dopaminergic drugs such as levodopa, ropinirole, pramipexole and rotigotine as well as calcium channel blockers (gabapentin and pregabalin) are helpful for treatment of RLS. High quality studies with these agents are currently underway and hopefully confirm the efficacy and practicality of using these drugs in CKD-A-RLS. Some studies have shown that aerobic exercise and massage with lavender oil can improve symptoms of CKD-A- RLS suggesting that these measures can be useful as adjunct therapy.

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587–42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421–7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach. [ABSTRACT FROM AUTHOR]

Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [3H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [3H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders. [ABSTRACT FROM AUTHOR]

Graphene-based materials have presented significant attention owing to their intriguing properties and the potential for the production of diverse composite formulations. Among these avenues, the incorporation of dopamine as an anchoring agent stands out, fostering the emergence of multiple phases at the graphene surface. In this study, we propose a straightforward methodology for the fabrication of reduced graphene oxide/zinc composites, leveraging dopamine molecules as intermediaries, facilitated by UV-C irradiation. The outcomes vividly underscore the adeptness of dopamine in mediating the attachment of zinc hydroxide and zinc hydroxide nitrate hydrate onto the core-reduced graphene oxide (RGO). These interactions engender the retention of RGO's structural–functional groups, a reduction in interplanar spacing, and the establishment of a mesoporous framework characterized by pore diameters surpassing 200 Å. Collectively, the results firmly establish the successful synthesis of RGO/Zn composites, positioning them as promising candidates for diverse applications by capitalizing on the inherent attributes of graphene-based materials and the laminar architecture of zinc hydroxide. [ABSTRACT FROM AUTHOR]

Infantile dystonia-parkinsonism type 2 (PKDYS2) is a rare inherited autosomal recessive movement disorder with onset in infancy. The disease is associated with a mutation in the solute carrier family 18 member A2 gene (SLC18A2). There are reports of trials with dopaminergic drugs and the condition of patients given levodopa almost always worsens and dopamine agonists give varying degrees of benefit to some. Here, we report a PKDYS2 patient with a new variant in the SLC18A2 gene who underwent multiple trials of pharmacotherapy. The abnormalities in development and neurological examination of the case were first noted at the age of 2 months, and after a series of treatment attempts (e.g., with antiepileptics) and diagnostic procedures, the diagnosis of PKDYS2 was determined when whole exome sequencing (WES) at age 6, revealed a homozygous pathologic variant NM_003054.4:c.1107dup, p.(Val370Serfs ∗ 91) in the SLC18A2 gene. The patient then received treatment with multiple dopaminergic drugs (e.g., levodopa, pramipexole, and methylphenidate). The patient with PKDYS2 harbored a new variant in SLC18A2. The phenotype of the patient resembles that of some previously reported patients with PKDYS2. The patient received minor benefits from certain dopaminergic drugs, such as pramipexole, but side effects led to the discontinuation of tested medications. [ABSTRACT FROM AUTHOR]

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the signal detection method for allergic reactions induced by inpatient iodixanol injection. Methods: A database of 3,719,217 hospitalized patients from 20 large Chinese general hospitals was processed and analyzed using the prescription sequence symmetry analysis (PSSA) method. Results: 126,680 inpatients who used iodixanol and were concurrently treated with anti-allergic drugs were analyzed. In the medical records of these patients, only 32 had documented iodixanol allergies. Statistical analysis identified 22 drugs in 4 categories--calcium preparations, adrenergic/dopaminergic agents, glucocorticoids, and antihistamines--as marker drugs. With time intervals of 3, 7, and 28 days, the adjusted sequence ratios (aSRs) for all anti-allergics and the 4 categories were greater than 1. The 7-day aSRs were 2.12 (95% CI: 2.08-2.15), 1.70 (95% CI: 1.68-1.73), 3.85 (95% confidence interval [CI]: 3.75-2.30), 2.30 (95% CI: 2.26-2.35), and 1.95 (95% CI: 1.89-2.02), respectively. The proportions of adverse drug events indicated by each signal were as follows: all anti-allergics (2.92%-3%), calcium gluconate (0.19%-0.52%), adrenergic/dopaminergic agents (2.20%-3.37%), glucocorticoids (3.13%-3.76%), and antihistamines (1.05%-1.32%). Conclusion: This first multi-center Chinese inpatient database study detected iodixanol-induced allergy signals, revealing that reactions may be much higher than those in collected spontaneous reports. Iodixanol risk exposure was closer to actual pharmaceutical care findings. PSSA application with =7-day intervals appears better suited for monitoring late allergic reaction signals with these drugs. [ABSTRACT FROM AUTHOR]

Purpose: Dopamine transporter (DAT) imaging is used to support the diagnosis of neurodegenerative parkinsonian disorders. Specific medications have been reported to confound the interpretation of [123I]I-FP-CIT SPECT scans, but there is limited data. The aim of the current study is to identify potential medication effects on the interpretation of [123I]I-FP-CIT SPECT scans in routine practice. Materials and methods: Consecutive patients undergoing a [123I]I-FP-CIT SPECT/CT scan on a 360° CZT camera between September 2019 and December 2022 were included. An exhaustive review of patient medications (antidepressants, antipsychotics, anti-epileptics, anti-parkinsonians, benzodiazepines, lithium, opioids, and stimulants) was performed. Two experienced nuclear physicians, blinded to the medication reports, interpreted the [123I]I-FP-CIT SPECT scans visually and a semi-quantitative analysis was performed using a local normal database. Results: The study included 305 patients (71.0 ± 10.4, 135 women) and 145 (47.5%) visually interpreted normal scans. In normal scans, the striatum/occiput radioligand uptake ratio was decreased by noradrenergic and specific serotonergic antidepressants (NASSAs) (n = 15, z-score of − 0.93) and opioid medication (tramadol, n = 6, z-score of − 0.85) and was associated with a younger age in the multivariate analysis. In the overall population, the striatum/occiput ratio was influenced by NASSAs and associated with consensual visual analysis, age, sex, and anti-parkinsonian medications related to the status of the disease. Conclusion: Our study confirms the potential impact of antidepressant (NASSA) and opioid (tramadol) medications on the semi-quantitative analysis of [123I]I-FP-CIT SPECT scans. However, when performing a visual analysis, only NASSAs significantly impacted the interpretation of [123I]I-FP-CIT SPECT scans. [ABSTRACT FROM AUTHOR]

Background: Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD. Methods: PD patients with Hoehn and Yahr stage ≥ 2 ("On" state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III "On", while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson's disease questionnaire-39 at the final assessment. Results: Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation. Conclusion: ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL. Trial registration: Clinicaltrials.gov, NCT04182399, in 24/11/2019. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) often shows disrupted brain connectivity and autonomic dysfunctions, progressing alongside with motor and cognitive decline. Recently, PD has been linked to a reduced sensitivity to cardiac inputs, that is, cardiac interoception. Altogether, those signs suggest that PD causes an altered brain–heart connection whose mechanisms remain unclear. Our study aimed to explore the large‐scale network disruptions and the neurophysiology of disrupted interoceptive mechanisms in PD. We focused on examining the alterations in brain–heart coupling in PD and their potential connection to motor symptoms. We developed a proof‐of‐concept method to quantify relationships between the co‐fluctuations of brain connectivity and cardiac sympathetic and parasympathetic activities. We quantified the brain–heart couplings from electroencephalogram and electrocardiogram recordings from PD patients on and off dopaminergic medication, as well as in healthy individuals at rest. Our results show that the couplings of fluctuating alpha and gamma connectivity with cardiac sympathetic dynamics are reduced in PD patients, as compared to healthy individuals. Furthermore, we show that PD patients under dopamine medication recover part of the brain–heart coupling, in proportion with the reduced motor symptoms. Our proposal offers a promising approach to unveil the physiopathology of PD and promoting the development of new evaluation methods for the early stages of the disease. [ABSTRACT FROM AUTHOR]

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs. [ABSTRACT FROM AUTHOR]

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This is a case report of three cases of trazodone-induced buccal–lingual dyskinesias. Each case demonstrated the distinct pattern of the development of this dyskinesia after trazodone exposure for several months. All cases showed abrupt cessation of the movement disorder when the drug was discontinued. One of the three cases demonstrated a highly unusual presentation of an on/off pattern of buccal dyskinesia directly related to repetitive exposure and termination of the drug trazodone. Two of the three cases had no prior exposure to any dopamine blocking agents. One of the three had a distant exposure to a dopamine antagonist. As opposed to other antidepressants, trazodone has a mechanism of action which can account for both the development and treatment of dyskinetic movements. Its metabolite, M/chlorophenylpiperazine (M-CPP) is a 5HT2C agonist capable of causing abnormal oral-facial movements in rodent models. The presence of oromandibular dyskinetic movements can occur spontaneously with age, with trazodone being a potential predisposing factor. This article will discuss proposed mechanisms for trazodone's action with an emphasis on case reports of dystonic movements. [ABSTRACT FROM AUTHOR]

Astrocytes, glial cells in the central nervous system, perform a multitude of homeostatic functions and are in constant bidirectional communication with neuronal cells, a concept named the tripartite synapse; however, their role in the dopamine homeostasis remains unexplored. The aim of this study was to clarify the pharmacological and molecular characteristics of dopamine transport in cultured cortical astrocytes of adult rats. In addition, we were interested in the expression of mRNA of dopamine transporters as well as dopamine receptors D1 and D2 and in the effect of dopaminergic drugs on the expression of these transporters and receptors. We have found that astrocytes possess both Na+‐dependent and Na+‐independent transporters. Uptake of radiolabelled dopamine was time‐, temperature‐ and concentration‐dependent and was inhibited by decynium‐22, a plasma membrane monoamine transporter inhibitor, tricyclic antidepressants desipramine and nortriptyline, both inhibitors of the norepinephrine transporter. Results of transporter mRNA expression indicate that the main transporters involved in cortical astrocyte dopamine uptake are the norepinephrine transporter and plasma membrane monoamine transporter. Both dopamine receptor subtypes were identified in cortical astrocyte cultures. Twenty‐four‐hour treatment of astrocyte cultures with apomorphine, a D1/D2 agonist, induced upregulation of D1 receptor, norepinephrine transporter and plasma membrane monoamine transporter, whereas the latter was downregulated by haloperidol and L‐DOPA. Astrocytes take up dopamine by multiple transporters and express dopamine receptors, which are sensitive to dopaminergic drugs. The findings of this study could open a promising area of research for the fine‐tuning of existing therapeutic strategies. [ABSTRACT FROM AUTHOR]

Three liquid selective electrodes were synthesized based on particle pair to selective dopamine chloride. The construction electrodes consist of phosphomolybdic acid (dopamine), di-n-butyl phosphate, Di-n-butyl phthalate, and di-octylphenylphosphonate as plasticizers materials. The construction of preparing probes was examined potentially with successes Nernstain response around 52.50 and 50. 50 mV/decade for electrodes on both DBPH and DOPH were as plasticizers, respectively. The most direct ranges concentrations of dopamine in drug form were found to be around 2.5×10-5-1.0×10-2 for DBPH and 4.30×10-5 -1.0×10-1 M for DOPH. The detection limits were reached to 2.31×10-6 in DBPH and 5. 63×10-6 M in DOPH electrode type. While third electrode relied on di-n-butyl phosphate (DPH), a non-Nernstain equivalent of around 19.10 mV/decade with a range of concentration about 2.2×10-5 -1.0×10-1 with a detection limit equivalent to 6.35×10-6. The pH values in the experimental application were asses to obtain the best determination of dopamine concentration at 10-3M. The optimisation of both electrodes DBPH and DOPH achieved good agreements to lifetime, selectivity, potentiometric techniques and accuracy of measurements. At the same time the standard expansion, various standard expansions and potentiometric titration result in an immediate strategy for the assurance of dopamine in drug form. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia (TD) is a movement disorder that can arise as a side efect of treatment with dopamine receptor-blocking agents (DRBAs), including antipsychotic drugs (APDs) used to manage psychotic illnesses. Second-generation APDs (SGAs) are often preferred to first-generation drugs due to their lower propensity to cause TD, however many SGAs-treated patients still develop the condition. Although TD is a global health concern, evidence regarding the occurrence of TD and how it is managed in Asian countries is currently limited. This article reports the results of a systematic review of the published literature on TD focusing on its prevalence, types of patients, knowledge of the condition, causative factors, and usual treatment pathways in clinical practice in Asian countries. Epidemiological data suggest that the prevalence of TD is increasing globally due to an overall rise in APD use, contributing factors being polypharmacy with multiple APDs, the use of higher than necessary doses, and off-label use for non-psychotic indications. Although exact prevalence figures for TD in Asian countries are difficult to define, there is a similar pattern of rising APD use which will result in increasing numbers of TD patients in this region. These issues need to be addressed and strategies developed to minimize TD risk and manage this disabling condition which impacts patients' quality of life and daily functioning. To date, both research into TD has been predominantly psychiatry focused and the perspectives from neurologists regarding the clinicalmanagement of this challenging condition are scarce. However, neurologists have an essential role inmanaging themovement disorders manifestations that characterize TD. Optimum management of TD, therefore, should ideally involve collaboration between psychiatrists and neurologists in joint care pathways, wherever practical. Collaborative pathways are proposed in this article, and the challenges that will need to be addressed in Asian countries to improve the care of people with TD are highlighted, with a focus on the neurologist's viewpoint and the implications for the management of TD globally. [ABSTRACT FROM AUTHOR]

In Parkinson's disease (PD), progressive degeneration of nigrostriatal innervation leads to atrophy and loss of dendritic spines of striatal medium spiny neurons (MSNs). The loss disrupts corticostriatal transmission, impairs motor behavior, and produces nonmotor symptoms. Nigral neurons express brain-derived neurotropic factor (BDNF) and dopamine D3 receptors, both protecting the dopamine neurons and the spines of MSNs. To restore motor and nonmotor symptoms to normality, we assessed a combined therapy in a bilateral rat Parkinson's model, with only 30% of surviving neurons. The preferential D3 agonist pramipexole (PPX) was infused for four ½ months via mini-osmotic pumps and one month after PPX initiation; the BDNF-gene was transfected into the surviving nigral cells using the nonviral transfection NTS-polyplex vector. Overexpression of the BDNF-gene associated with continuous PPX infusion restored motor coordination, balance, normal gait, and working memory. Recovery was also related to the restoration of the average number of dendritic spines of the striatal projection neurons and the number of TH-positive neurons of the substantia nigra and ventral tegmental area. These positive results could pave the way for further clinical research into this promising therapy. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease (PD) have been reported to exhibit unusual bouts of creativity (e.g., painting, writing), in particular in the context of treatment with dopaminergic agents. Here we investigated divergent and convergent thinking thought to underlie creativity. In addition we assessed cognitive estimation. Method: Twenty PD patients and 20 matched healthy control participants were subjected to the Guilford Alternate Uses task (divergent thinking), the remote associates task (convergent thinking) and two tests of cognitive estimation. Results: No group differences were found for the convergent thinking task, while the Guilford Alternate Uses task revealed a decreased number of correct responses and a reduced originality for PD patients. Originality in PD was correlated to total daily dose of dopaminergic medication. Moreover, both tasks of cognitive estimation showed an impairment in PD. Conclusion: Only minor effects were found for psychometric indices of subprocesses of creative thinking, while estimation, relying on executive functioning, is impaired in PD. We suggest to take a product oriented view of creativity in further research on altered creative processes in PD. [ABSTRACT FROM AUTHOR]

The assessment of motivation and its modulation during treatment are essential aspects of physical therapy practice. However, the modulation of motivation has been sparsely investigated in persons with Parkinson's disease (PD) and at present no studies have synthesized its effects on movement performance. The purpose of this study was to systematically examine the efficacy of motivational modulation on movement performance in PD and to provide recommendations for its role in physical therapy practice. Systematic identification of published literature was performed adhering to PRISMA guidelines, from January 2005 to March 2023. Keywords were used in the following electronic databases: PubMed, Academic Search Complete, the Cochrane Database, Google Scholar, and the Physiotherapy Evidence Database (PEDro). A level of evidence rating was completed according to the scale provided by the American Academy of Cerebral Palsy and Development Medicine. Quality assessments were performed using the Modified Downs and Black checklist. Eight studies were included in this review, all achieving level III evidence. The methodological quality of studies was varied, with most studies attaining a fair rating. Persons with PD performed upper extremity movement tasks with greater intensity when incentivized with larger rewards compared to smaller incentives. Dopamine replacement medication, Deep Brain Stimulation, and a history of depression, had mediating effects on the response to motivational modulation. Our findings suggest that it is plausible to improve adherence to exercise when physical therapists modulate motivation through computerized game achievements, gamification of tasks, or other forms of reward and non-rewarding stimuli. [ABSTRACT FROM AUTHOR]

There is increasing evidence that the left lateral frontal cortex is hierarchically organized such that higher-order regions have an asymmetric top–down influence over lower order regions. However, questions remain about the underlying neuroarchitecture of this hierarchical control organization. Within the frontal cortex, dopamine plays an important role in cognitive control functions, and we hypothesized that dopamine may preferentially influence top–down connections within the lateral frontal hierarchy. Using a randomized, double-blind, within-subject design, we analyzed resting-state fMRI data of 66 healthy young participants who were scanned once each after administration of bromocriptine (a dopamine agonist with preferential affinity for D2 receptor), tolcapone (an inhibitor of catechol-O-methyltransferase), and placebo, to determine whether dopaminergic stimulation modulated effective functional connectivity between hierarchically organized frontal regions in the left hemisphere. We found that dopaminergic drugs modulated connections from the caudal middle frontal gyrus and the inferior frontal sulcus to both rostral and caudal frontal areas. In dorsal frontal regions, effectivity connectivity strength was increased, whereas in ventral frontal regions, effective connectivity strength was decreased. These findings suggest that connections within frontal cortex are differentially modulated by dopamine, which may bias the influence that frontal regions exert over each other. [ABSTRACT FROM AUTHOR]