Dopamine Receptor Agonist Research Articles

Clinical management model for impulse control disorders in Parkinson's disease.

Over the last decade, we have gained a better understanding of impulse control disorder in Parkinson's disease (PD-ICD), a medication complication in PD. Researchers were aware of its complexity and took efforts to learn more about its diagnostic and treatment possibilities. Nevertheless, clinical management for it is currently neglected. We conducted a narrative overview of literature published from 2012 to October 2023 on various aspects of clinical management for PD-ICD. A potential "susceptibility-catalytic-stress" model in the development of PD-ICD was proposed and a profile encoding predictors for PD-ICD was created. Based on these predictors, some methods for prediction were recently developed for better prediction, such as the polymorphic dopamine genetic risk score and the clinic-genetic ICD-risk score. A variety of treatment options, including dose reduction of dopamine receptor agonists (DAs), DAs removal, DAs switch, and add-on therapy, are investigated with inconsistent reports. Based on current findings, we developed a clinical management model prototype centered on prevention, consisting of prediction, prevention, follow-up and monitoring, therapy, and recurrence prevention, for clinical reference, and further proposed 4 key clinical management principles, including standardization, prediction centered, persistence, and whole course.

Abnormal EEG Effects of Acute Apomorphine Injection in 5xFAD Transgenic Mice Are Partially Normalized in Those Chronically Pretreated with Apomorphine: The Time–Frequency Clustering of EEG Spectra

Background: In experimental and clinical studies of pharmacological treatments for Alzheimer’s disease (AD), the electroencephalogram (EEG) frequency spectrum approach has demonstrated its efficacy in determining the characteristics of pathological changes in the functioning of different cerebral structures, interconnections between them, and disturbances in the brain neurotransmitter systems. The main results have been obtained in frames of traditionally used so-called “classical” EEG frequency bands: delta, theta, alpha, and beta. Objective: This unified approach simplifies comparing data from different studies but loses the dynamic peculiarities of the effects because of their time-dependent transition through the borders of the “classical” bands. Methods: In this study on non-narcotized freely moving 5xFAD transgenic mice, a model of AD, chronically pretreated with a non-selective dopamine (DA) receptor agonist, apomorphine (APO), we analyze the transitory EEG effects of acute APO injection in different brain areas by use of our “time–frequency” clustering program. The acute injection of APO was used to compare DA receptor sensitivity in 5xFAD mice pretreated with either APO or saline vs. wild-type (WT) mice pretreated with saline. Results: After acute APO injection, the clusters of enhanced EEG activity centered in the theta–alpha frequency range observed in WT mice disappeared in 5xFAD mice pretreated with saline and practically recovered in 5xFAD mice pretreated with APO. Conclusions: In 5xFAD mice pretreated with saline, the sensitivity of DA receptors was disturbed; chronic APO pretreatment mainly recovered this characteristic in 5xFAD mice. The “clustering” of pharmacological EEG effects and their time-dependent transition between classical frequency bands is a new effective approach for analyzing cerebral neurotransmission in neurodegenerative pathologies.

Pramipexole, a D3 receptor agonist, increases cortical gamma power and biochemical correlates of cortical excitation; implications for mood disorders.

Major depressive disorder (MDD) has been associated with deficits in working memory as well as underlying gamma oscillation power. Consistent with this, overall reductions in cortical excitation have also been described with MDD. In previous work, we have demonstrated that the monoamine reuptake inhibitor venlafaxine increases gamma oscillation power in ex vivo hippocampal slices and that this is associated with concomitant increases in pyramidal arbour and reduced levels of plasticity-restricting perineuronal nets (PNNs). In the present study, we have examined the effects of chronic treatment with pramipexole (PPX), a D3 dopamine receptor agonist, for its effects on gamma oscillation power as measured by in vivo electroencephalography (EEG) recordings in female BALB/c and C57Bl6 mice. We observe a modest but significant increase in 20-50 Hz gamma power with PPX in both strains. Additionally, biochemical analysis of prefrontal cortex lysates from PPX-treated BALB/c mice shows a number of changes that could contribute to, or follow from, increased pyramidal excitability and/or gamma power. PPX-associated changes include reduced levels of specific PNN components as well as tissue inhibitor of matrix metalloproteases-1 (TIMP-1), which inhibits long-term potentiation of synaptic transmission. Consistent with its effects on gamma power, PNN proteins and TIMP-1, chronic PPX treatment also improves working memory and reduces anhedonia. Together these results add to an emerging literature linking extracellular matrix and/or gamma oscillation power to both mood and cognition.

Molecular mechanisms underlying the effects of hypo- and hyper-prolactinemia on spermatogenesis and fertility in male rats.

Hypo- and hyper-prolactinemia have deleterious effects on male reproduction, yet there is a dearth of information regarding the underlying mechanisms. The aim of this study was to delineate the molecular mechanisms by which hypo- and hyper-prolactinemia affects spermatogenesis and fertility in male rats. In vivo male rat models for hypo- and hyper-prolactinemia were established using dopamine receptor agonist, Bromocriptine (Brm), and antagonist, Fluphenazine (Flu), respectively. Effects on fertility and spermatogenesis were assessed by studying pre- and post-implantation loss, litter size, sperm parameters, hormonal profile, testicular histology, testicular cell population, and testicular transcriptome in rats. Treatment with Brm and Flu for 60 days led to subfertility, which was indicated by an increase in pre- and post-implantation loss and decrease in litter size, when mated with control female rats. Decreased sperm count was observed after both treatments, whereas reduced sperm motility was noted in Flu group. Serum FSH was unaffected, and LH was decreased by Flu treatment. Testosterone was decreased in both the groups, whereas estradiol was decreased in the Flu group. An arrest in spermatogenic cycle beyond round spermatids was observed in the Flu group. Additionally, testicular apoptosis in germ cells, mostly spermatocytes of Stage IX-XIV was noted in both the groups. Further, testicular RNA-Seq analysis revealed a total of 1539 and 824 differentially expressed genes/DEGs in Brm and Flu, respectively (Sequence Read Archive/SRA Database accession number: PRJNA1150513). Gene ontology and pathway analysis of DEGs highlighted enrichment of steroid metabolic pathway and ribosomal biogenesis pathway. Hub genes identified from the DEGs were validated by qPCR and the results showed that Uba52, Rps27a, Rpl23, Rps5, Rps16 were significantly down-regulated by Brm, whereas Rps27a, Rps29, Rps15, Rps27, Faul1 were significantly down-regulated by Flu. Hypo- and hyper-prolactinemia leads to subfertility and decreased sperm parameters possibly through an effect on steroid metabolism and ribosomal biogenesis pathway. Therefore, maintaining prolactin levels in physiological range is crucial.

Fenoldopam for Renal Protection in Cardiac Surgery: Pharmacology, Clinical Applications, and Evolving Perspectives

This comprehensive review examines the role of Fenoldopam, a selective dopamine-1 receptor agonist, in preventing and treating acute kidney injury (AKI) during cardiac surgery. AKI remains a significant complication in cardiac surgery, associated with increased morbidity, mortality, and healthcare costs. The review explores Fenoldopam’s pharmacological properties, mechanism of action, and clinical applications, synthesizing evidence from randomized controlled trials, meta-analyses, and observational studies. While some studies have shown promising results in improving renal function and reducing AKI incidence, others have failed to demonstrate significant benefits. The review discusses these conflicting findings, explores potential reasons for discrepancies, and identifies areas requiring further research. It also compares Fenoldopam to other renoprotective strategies, including dopamine, diuretics, and N-acetylcysteine. The safety profile of Fenoldopam, including common side effects and contraindications, is addressed. Current guidelines and recommendations for Fenoldopam use in cardiac surgery are presented, along with a cost-effectiveness analysis. The review concludes by outlining future research directions and potential new applications of Fenoldopam in cardiac surgery. By providing a thorough overview of the current state of knowledge, this review aims to facilitate informed decision-making for clinicians and researchers while highlighting areas for future investigation.

Rewarding properties of L-Dopa in experimental parkinsonism are mediated by sensitized dopamine D1 receptors in the dorsal striatum.

Treatment of Parkinson's disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients' quality of life. Here we replicate DDS in a PD mouse model based on a bilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. Administration of L-Dopa induced locomotor sensitization and conditioned place preference in 6-OHDA lesion, but not in control mice, indicative of the acquisition of addictive-like properties following nigrostriatal dopamine depletion. These behavioral effects were accompanied by abnormal dopamine D1 receptor (D1R) signaling in the medium spiny neurons of the dorsal striatum, leading to hyperactivation of multiple signaling cascades and increased expression of ΔFosB, a stable transcription factor involved in addictive behavior. Systemic administration of the D1R antagonist, SCH23390, abolished these effects and the development of place preference, thereby counteracting the psychostimulant-like effect of L-Dopa. The rewarding properties of L-Dopa were also prevented by chemogenetic inactivation of D1R-expressing neurons in the dorsal striatum. Our results indicate the association between abnormal D1R-mediated transmission and DDS in PD and identify potential approaches for the treatment of this disorder.

Utilizing erythrosine B absorption spectrum shifts for quantitative determination of octreotide and bromocriptine in their pure forms and pharmaceutical formulations. Evaluation of the method greenness

In the present study, two drugs for treating acromegaly are investigated which are either synthetic growth hormone inhibiting hormone (GHIH) or dopamine receptor agonist. Octreotide (OCT) and bromocriptine (BCT) were quantified with a quick, simple, and sensitive spectrophotometric approach in their authentic forms and commercial dosage forms. This approach was based upon formation of ion pair complex between erythrosine B and investigated drugs in an aqueous buffered solution. For OCT determination the higher sensitivity was obtained using ΔA at 525 nm. On the other hand, BCT was estimated using the absorbance at 556 nm. Under optimal conditions for the reaction, construction of calibration curves were performed within concentration range of 0.4–4 µg ml−1 for OCT and 1–9 µg ml−1 for BCT with with low detection limits (0.094 and 0.235 µg ml−1) and low quantitation limits (0.29 and 0.71 µg ml−1) for OCT and BCT respectively. The developed approach was assessed for linearity, accuracy, precision, limits of detection, and limits of quantitation in compliance with ICH validation recommendations. The suggested approaches demonstrated good linearity, as evidenced by determination coefficients (r2) of 0.999 with a slope 0.14 for OCT and 0.9989 with a slope 0.06 for BCT. Additionally, the environmental friendliness of the investigated method was assessed with some of the recent green analytical chemistry metrics.

Clinical symptoms and neuroanatomical substrates of daytime sleepiness in Parkinson’s disease

Clinical and neuroanatomical correlates of daytime sleepiness in Parkinson’s disease (PD) remain inconsistent in the literature. Two studies were conducted here. The first evaluated the interrelation between non-motor and motor symptoms, using a principal component analysis, associated with daytime sleepiness in PD. The second identified the neuroanatomical substrates associated with daytime sleepiness in PD using magnetic resonance imaging (MRI). In the first study, 77 participants with PD completed an extensive clinical, cognitive testing and a polysomnographic recording. In the second study, 29 PD participants also underwent MRI acquisition of T1-weighted images. Vertex-based cortical and subcortical surface analysis, deformation-based morphometry, and voxel-based morphometry were performed to assess the association between daytime sleepiness severity and structural brain changes in participants. In both studies, the severity of daytime sleepiness and the presence of excessive daytime sleepiness (EDS; total score >10) were measured using the Epworth Sleepiness Scale. We found that individuals with EDS had a higher score on a component including higher dosage of dopamine receptor agonists, motor symptoms severity, shorter sleep latency, and greater sleep efficiency. Moreover, increased daytime sleepiness severity was associated with a larger surface area in the right insula, contracted surfaces in the right putamen and right lateral amygdala, and a larger surface in the right posterior amygdala. Hence, daytime sleepiness in PD was associated with dopaminergic receptor agonists dosage, motor impairment, and objective sleep measures. Moreover, neuroanatomical changes in cortical and subcortical regions related to vigilance, motor, and emotional states were associated with more severe daytime sleepiness.

Impaired dopamine signaling in early diabetic retina: Insights from D1R and D4R agonist effects on whole retina responses

The retina has low dopamine levels early in diabetes. To determine how low dopamine levels affected dopamine signaling, the effects of dopamine receptor agonists and mRNA localization were measured after 6 weeks of diabetes. Whole retina ex vivo electroretinogram (ERG) recordings were used to analyze how dopamine type 1 receptor (D1R) and type 4 (D4R) agonists change the light-evoked retinal responses of non-diabetic and 6-week diabetic (STZ injected) mouse retinas. Fluorescence in situ hybridization was utilized to analyze D4R and D1R mRNA locations and expression levels. D4R activation reduced A- and B-wave ERG amplitudes and increased B-wave implicit time and rise-time in the non-diabetic group without a corresponding change in the diabetic group. D1R activation increased B-wave rise-time and oscillatory potential peak time in the non-diabetic group also with no change in the diabetic group. The lack of responsivity to D1R or D4R agonists shows an impairment of dopamine signaling in the diabetic retina. D4R mRNA was found primarily in the outer nuclear layer where photoreceptor cell bodies reside. D1R mRNA was found in the inner nuclear layer and ganglion cell layer that contain bipolar, amacrine, horizontal and ganglion cells. There was no change in D4R or D1R mRNA expression between the non-diabetic and diabetic retinas. This suggests that the significant dopamine signaling changes observed were not from lower receptor expression levels but could be due to changes in dopamine receptor activity or protein levels. These studies show that changes in retinal dopamine signaling could be an important mechanism of diabetic retinal dysfunction.

Diagnostics and treatment of impulse control disorders, psychosis and delirium: systemic review-based recommendations- guideline "Parkinson's disease" of the German Society of Neurology.

Impulse control disorders (ICD), psychosis and delirium are part of the spectrum of behavioural changes associated with Parkinson's disease (PD). The diagnostic and therapeutic management of these rather complex neuropsychiatric conditions has been updated in the clinical guideline by the German Society of Neurology (DGN). Recommendations are based on a systematic literature reviews, other relevant guidelines and expert opinion. Patients receiving dopamine agonists (DA) therapy should be informed about the symptoms and risks of an ICD and should be routinely screened for ICD symptoms. In the presence of an ICD, DA should be reduced or discontinued and psychotherapeutic treatment may be considered. Non-oral therapies (levodopa/carbidopa intestinal gel infusion or deep brain stimulation) may also be an option for appropriate candidates. Psychosis in PD often has a gradual onset. Cognitive and affective disorders, psychiatric and medical comorbidities as well as polypharmacy are risk factors for a psychosis. Non-pharmacological treatments should be implemented as soon as possible and anti-parkinsonian medications should be adjusted/reduced if feasible. For psychosis associated with PD, quetiapine or clozapine should be used on an as-needed basis and for as short a time as is necessary, with safety monitoring. Delirium in PD may be underdiagnosed due to an overlap with chronic neuropsychiatric features of PD. Although transient by definition, delirium in PD can lead to permanent cognitive decline, motor impairment and increased mortality. Management of delirium includes pharmacological and non-pharmacological interventions. The updated guideline encompasses the evidence-based diagnostic, non-pharmacological and pharmacological management of ICD, psychosis and delirium in PD.

Dementia after Ischemic Stroke, from Molecular Biomarkers to Therapeutic Options.

Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD.

Network pharmacology analysis and molecular mechanism of paeoniflorin and its metabolite in prolactinoma cells.

Prolactinoma was the most common functionalpituitary neuroendocrine tumor tissue type, which was caused by excessive proliferation of pituitary prolactin (PRL) cells. Drug therapy of dopamine receptoragonists was generally considered as the prior treatment for prolactinoma patients. However, there were still prolactinoma patients who were resistant to dopamine agonists. Studies have been reported that paeoniflorin can inhibit the secretion of PRL in prolactinoma cells lacking dopamine D2 receptor (D2R) expression, and paeoniflorin can be metabolized into albiflorin by intestinal flora in rats. The effect of albiflorin on prolactinoma has not been reported yet. In this study, network pharmacology was used to analyze the mechanism of paeoniflorin and its metabolite albiflorin as multi-target therapy for prolactinoma, and the experimental verification was carried out. In order to clarify the complex relationship among paeoniflorin, albiflorin and prolactinoma, we constructed a component-target-disease network, and further constructed interaction network, MMP9, EGFR, FGF2, FGFR1 and LGALS3 were screened as the core targets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that paeoniflorin and albiflorin may be involved in various pathways in the treatment of prolactinoma, included relaxin signaling pathway and PI3K-Akt signaling pathway. Molecular docking analysis showed that paeoniflorin and albiflorin had good binding activity with MMP9. Western blotting results showed that paeoniflorin and albiflorin could significantly reduce the expression of MMP9, and ELISA results showed that paeoniflorin and albiflorin could significantly reduce the concentration of PRL in GH3 cells, and the reduce degree of albiflorin was stronger than paeoniflorin at 50μM, which indicated that albiflorin might be a potential drug to treat prolactinoma, which can regulate prolactinoma through MMP9 and reduce the concentration of PRL. Our study provided a new therapeutic strategy for prolactinoma.

Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions.

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.

Dopamine receptor agonist cabergoline promotes immunogenic phenotype in human monocyte-derived dendritic cells.

Dendritic cells (DCs) are known as antigen-presenting cells that are capable of regulating immune responses. DCs and T cells can interact mutually to induce antigen-specific T-cell responses. Cabergoline, which is a dopamine (DA) receptor agonist, seems to implement anti-inflammatory properties in the immune system, and therefore in the present study the impact of a DA receptor agonist cabergoline on the monocyte-derived DCs (moDCs) was assessed. Immature moDCs were treated with lipopolysaccharide to produce mature DCs (mDCs). The expression of DCs' related surface markers namely: CD11c, HLA-DR, and CD86 was measured by utilizing of flow cytometry. Real-time PCR was the technique of choice to determine the levels at which diverse inflammatory and anti-inflammatory factors in cabergoline-treated and control mDC groups were expressed. DCs treated with cabergoline displayed a significant decrease in CD86 and HLA-DR expression, markers linked to maturation and antigen presentation, respectively. In addition, the cabergoline-mDC group showed a considerable decline in terms of the levels at which IL-10, TGF-β, and IDO genes were expressed, and an increase in the expression of TNF-α and IL-12 in comparison to the mDC control group. Our findings revealed that cabergoline as an immunomodulatory agent can relatively shift DCs into an immunogenic state, and there is a requirement for further investigations to evaluate the effects of cabergoline-treated DCs on the T cell responses in vitro, and also in various diseases including cancer in animal models.

Lanreotide versus placebo for tumour reduction in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma (GALANT study): a randomised, multicentre, phase 3 trial with blinded outcome assessment

No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. Invivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was+1·2 (2·5) mm with lanreotide and+1·3 (1·5) mm with placebo; adjusted mean difference versus placebo-0·1mm (95% CI-1·3 to 1·2, p=0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Ipsen Farmaceutica BV.

Kinetic Properties and Pharmacological Modulation of High- and Low-Affinity Dopamine Transport in Striatal Astrocytes of Adult Rats.

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.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Pramipexole improves depression-like behavior in diabetes mellitus with depression rats by inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing impaired neuroplasticity

BackgroundDiabetes mellitus (DM) is frequently associated with the occurrence and development of depression, and the co-occurrence of diabetes mellitus with depression (DD) may further reduce patients' quality of life. Recent research indicates that dopamine receptors (DRs) play a crucial role in immune and metabolic regulation. Pramipexole (PPX), a D2/3R agonist, has demonstrated promising neuroprotective and immunomodulatory effects. Nevertheless, the therapeutic effects and mechanisms of action of PPX on DM-induced depression are not clear at present. MethodsDepression, DM, and DD were induced in a rat model through a combination of a high-fat diet (HFD) supplemented with streptozotocin (STZ) and chronic unpredictable mild stress (CUMS) combined with solitary cage rearing. The pathogenesis of DD and the neuroprotective effects of DRs agonists were investigated using behavioral assays, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, Nissl staining, Western blotting (WB) and immunofluorescence (IF). ResultsDD rats exhibited more severe dopaminergic, neuroinflammatory, and neuroplastic impairments and more pronounced depressive behaviors than rats with depression alone or DM. Our findings suggest that DRs agonists have significant therapeutic effects on DD rats and that PPX improved neuroplasticity and decreased neuroinflammation in the hippocampus of DD rats while also promoting DG cell growth and differentiation, ultimately mitigating depression-like behaviors. LimitationOur study is based on a rat model. Further evidence is needed to determine whether the therapeutic effects of PPX apply to patients suffering from DD. ConclusionsNeuroinflammation mediated by damage to the dopaminergic system is one of the key pathogenic mechanisms of DD. We provide evidence that PPX has a neuroprotective effect on the hippocampus in DD rats and the mechanism may involve the inhibition of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation by DRs to attenuate the neuroinflammatory response and neuroplasticity damage.

Efficacy of antiparkinsonian therapy in tremor correction according to tremorography

Objective: to evaluate the efficacy of antiparkinsonian drugs of different groups considering the frequency-amplitude characteristics in the correction of tremulous hyperkinesis in Parkinson's disease (PD) using tremorography. Material and methods. 172 patients with a confirmed diagnosis of PD were observed. Taking into account age and contraindications, patients were divided into four groups receiving one of four drugs in monotherapy: dopamine receptor agonists (ADR; pramipexole), levodopa (Tidomet forte), anticholinergics (biperiden), amantadines (amantadine sulfate). Before starting treatment and after completion of the selected therapy, patients underwent tremorography to analyse the frequency, amplitude and duration of tremor over time in four standard tests. Results. All antiparkinsonian drugs reduced rest tremor, and the efficacy of pramipexole in treating tremor was comparable to that of levodopa in the early stages of the disease. As the severity of the disease increased, the efficacy of ADRs decreased, whereas levodopa became more important. Amantadine sulfate showed the lowest efficacy in rest tremor. The efficacy of anticholinergics against tremor is high but inconsistent. Conclusion. We demonstrated feasibility of using tremorography in the selection of an individualised treatment programme for patients with shaking hyperkinesis in PD , and the high efficacy of levodopa in shaking hyperkinesis was confirmed.

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats.

Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.