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Basic & Clinical Pharmacology &... Oct 2016The currently recommended first-line treatments of erectile dysfunction (ED), phosphodiesterase type 5 inhibitors (PDE5i), for example sildenafil, are efficacious in... (Review)
Review
The currently recommended first-line treatments of erectile dysfunction (ED), phosphodiesterase type 5 inhibitors (PDE5i), for example sildenafil, are efficacious in many patients with ED of vascular origin, but this therapy is insufficient in approximately 30-40% of men with ED where there is also a neuronal affection. There is a demand of novel approaches to treat the condition. We review the possibility of modulating the dopaminergic pathways to improve erectile function. Dopamine D (D , D )- and D (D -D )-like receptors in the paraventricular area, the medial pre-optic area, the spinal cord, and in the erectile tissue are involved in erection, and several agonists developed for the treatment of Parkinson's disease are associated with increased libido. A therapeutic window for the treatment of ED was found by sublingual administration of the general dopamine receptor agonist apomorphine, but it failed mainly due to less efficacy on erectile function compared with PDE5i. To avoid the dose-limiting side effects mediated by D receptors, nausea and emesis, dopamine D receptor agonists were developed, and they induce erection in rodents, but these drugs were never introduced clinically. The β-lactamase inhibitor clavulanic acid increases dopamine and serotonin and was found to increase sexual arousal and erections, but the dose-response curve is bell-shaped. Bupropion has selectivity for inhibition of the dopamine reuptake transporter and can be used to alleviate sexual symptoms caused by other antidepressant medication, hence providing an interesting approach to treat ED. In summary, modulation of the dopaminergic pathways provides a possibility to improve the treatment of ED.
Topics: Animals; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Drug Monitoring; Erectile Dysfunction; Genitalia, Male; Humans; Male; Models, Biological; Paraventricular Hypothalamic Nucleus
PubMed: 27541930
DOI: 10.1111/bcpt.12653 -
BMC Research Notes Sep 2022There are conflicting data regarding the relationship between Parkinson's disease (PD) and the atherosclerotic process. This study aimed to compare endothelial function...
OBJECTIVE
There are conflicting data regarding the relationship between Parkinson's disease (PD) and the atherosclerotic process. This study aimed to compare endothelial function in patients with PD and matched controls. In PD subjects, we searched for factors contributing to endothelial dysfunction as well. Traditional vascular risk factors, PD characteristics, and PD medication were considered.
RESULTS
We prospectively enrolled 41 patients with PD and 41 controls matched for age, sex, body mass index, and vascular risk factors. Endothelial function (EF) was assessed using peripheral arterial tonometry (EndoPAT 2000 device) and expressed as reperfusion hyperemia index (RHI). Clinical characteristics including PD medication were recorded. RHI was non-significantly lower in the PD group than in controls (1.8 ± 0.5 vs. 1.9 ± 0.5, p = 0.478). In PD patients, in linear regression analysis, smoking (beta = -0.453, p = 0.008) and use of dopamine agonists (beta = -0.365, p = 0.030) were significant contributors in a model predicting RHI. Despite non-significant differences in endothelial dysfunction between PD patients and controls, our results suggest an association between smoking, dopamine agonists, and impaired EF in PD patients. The small sample size, as well as the absence of an extended search for traditional and non-traditional vascular risk factors, are the most important factors limiting the interpretation of the current results.
Topics: Dopamine Agonists; Endothelium, Vascular; Humans; Hyperemia; Parkinson Disease; Risk Factors
PubMed: 36064624
DOI: 10.1186/s13104-022-06176-z -
ACS Chemical Neuroscience Mar 2020Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of...
Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of the neurotransmitter dopamine and tight temporal control over the release of dopamine receptor antagonists. The 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group was conjugated to dopamine and the dopamine receptor antagonist sulpiride to generate "caged" versions of these neuromodulators (CyHQ--DA and CyHQ-sulpiride, respectively) that could release their payloads with 365 or 405 nm light or through 2-photon excitation (2PE) at 740 nm. These compounds are stable under physiological conditions in the dark, yet photolyze rapidly and cleanly to yield dopamine or sulpiride and the caging remnant CyHQ-OH. CyHQ--DA mediated the light activation of dopamine-1 (D1) receptors on the breast cancer cell line MDA-MB-231 in culture. In mouse brain slice from the substantia nigra pars compacta, localized flash photolysis of CyHQ--DA accurately mimicked the natural presynaptic release of dopamine and activation of dopamine-2 (D2) receptors, causing a robust, concentration-dependent, and repeatable G protein-coupled inwardly rectifying potassium channel-mediated outward current in whole-cell voltage clamp recordings that was amplified by cocaine and blocked by sulpiride. Photolysis of CyHQ-sulpiride rapidly blocked synaptic activity, enabling measurement of the unbinding rates of dopamine and quinpirole, a D2 receptor agonist. These tools will enable more detailed study of dopamine receptors, their interactions with other GPCRs, and the physiology of dopamine signaling in the brain.
Topics: Animals; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Kinetics; Mice; Quinpirole; Receptors, Dopamine D1; Sulpiride
PubMed: 32077679
DOI: 10.1021/acschemneuro.9b00675 -
International Journal of Molecular... Oct 2023Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models....
Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus.
Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds. Dopamine D4 receptor (D4R) activation was shown to enhance gamma rhythm in freely moving rats and to specifically affect slow delta and theta oscillations in the urethane-anesthetized rat model. The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. Network activity was recorded in the prefrontal cortex (PFC), hippocampus (HC) and nucleus reuniens (RE) in control conditions and after injecting the D4R agonist A-412997 (3 and 5 mg/kg; systemic administration). We found that A-412997 elicited a lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE in a dose-dependent manner. It also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations and that the RE, providing an essential link between the PFC and HC, plays a prominent role in this mechanism.
Topics: Animals; Rats; Dopamine Agonists; Hippocampus; Midline Thalamic Nuclei; Prefrontal Cortex; Receptors, Dopamine D4
PubMed: 37894968
DOI: 10.3390/ijms242015289 -
The Journal of Clinical Endocrinology... Nov 2023To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas.
PURPOSE
To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas.
METHODS
Register-based study of patients with giant prolactinomas [serum prolactin (PRL) > 1000 µg/L, tumor diameter ≥40 mm] identified in the Swedish Pituitary Register 1991-2018.
RESULTS
Eighty-four patients [mean age 47 (SD ±16) years, 89% men] were included in the study. At diagnosis, the median PRL was 6305 µg/L (range 1450-253 000), the median tumor diameter was 47 mm (range 40-85), 84% of the patients had hypogonadotropic hypogonadism, and 71% visual field defects. All patients were treated with a dopamine agonist (DA) at some point. Twenty-three (27%) received 1 or more additional therapies, including surgery (n = 19), radiotherapy (n = 6), other medical treatments (n = 4), and chemotherapy (n = 2). Ki-67 was ≥10% in 4/14 tumors. At the last follow-up [median 9 years (interquartile range (IQR) 4-15)], the median PRL was 12 µg/L (IQR 4-126), and the median tumor diameter was 22 mm (IQR 3-40). Normalized PRL was achieved in 55%, significant tumor reduction in 69%, and combined response (normalized PRL and significant tumor reduction) in 43%. In the primary DA-treated patients (n = 79), the reduction in PRL or tumor size after the first year predicted the combined response at the last follow-up (P < .001 and P = .012, respectively).
CONCLUSION
DAs effectively reduced PRL and tumor size, but approximately 1 patient out of 4 needed multimodal treatment. Our results suggest that the response to DA after 1 year is useful for identifying patients who need more careful monitoring and, in some cases, additional treatment.
Topics: Male; Humans; Middle Aged; Female; Prolactinoma; Pituitary Neoplasms; Follow-Up Studies; Sweden; Prolactin; Dopamine Agonists
PubMed: 37403202
DOI: 10.1210/clinem/dgad393 -
Biological Psychiatry Jan 2022Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal...
Dopaminergic Activity in Antipsychotic-Naïve Patients Assessed With Positron Emission Tomography Before and After Partial Dopamine D Receptor Agonist Treatment: Association With Psychotic Symptoms and Treatment Response.
BACKGROUND
Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of F-DOPA to F-dopamine (k) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D receptor agonist (aripiprazole) on k and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method.
METHODS
Sixty-two individuals (31 patients and 31 control subjects) underwent F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale.
RESULTS
High baseline decarboxylation rates (k) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment.
CONCLUSIONS
Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k and treatment effect potentially implicate on new treatment strategies.
Topics: Antipsychotic Agents; Corpus Striatum; Dopamine; Dopamine Agonists; Humans; Positron-Emission Tomography; Psychotic Disorders
PubMed: 34743917
DOI: 10.1016/j.biopsych.2021.08.023 -
Seminars in Neurology Apr 2017Impulsive and compulsive behaviors in Parkinson's disease (PD) patients are most often attributed to dopamine agonist therapy; dysregulation of the mesocorticolimbic... (Review)
Review
Impulsive and compulsive behaviors in Parkinson's disease (PD) patients are most often attributed to dopamine agonist therapy; dysregulation of the mesocorticolimbic system accounts for this behavioral phenotype. The clinical presentation is commonly termed (ICD): Behaviors include hypersexuality, compulsive eating, shopping, pathological gambling, and compulsive hobby participation. However, not all PD individuals taking dopamine agonists develop these behavioral changes. In this review, the authors focus on the similarities between the phenotypic presentation of ICDs with that of other reward-based behavioral disorders, including binge eating disorder, pathological gambling, and substance use disorders. With this comparison, we emphasize that the transition from an impulsive to compulsive behavior likely follows a ventral to dorsal striatal pattern, where an altered dopaminergic reward system underlies the emergence of these problematic behaviors. The authors discuss the neurobiological similarities between these latter disorders and ICDs, emphasizing similar pathophysiological processes and discussing treatment options that have potential for translation to PD patients.
Topics: Disruptive, Impulse Control, and Conduct Disorders; Dopamine; Dopamine Agonists; Humans; Impulsive Behavior; Parkinson Disease
PubMed: 28511259
DOI: 10.1055/s-0037-1601887 -
CNS Drug Reviews 2005Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an... (Review)
Review
Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an individual patient is rendered difficult because of the large number of substances available on the market. This review article provides a closer look at the experimental and clinical studies with ropinirole published so far. Ropinirole is a non-ergoline dopamine agonist which has been proven to be effective in both, monotherapy and combination therapy of idiopathic Parkinson's disease. In addition to ameliorating bradykinesia, rigor, and tremor, ropinirole facilitates the daily life and improves depressive moods of patients with Parkinson's disease. The long-term complications of levodopa are avoided, and problems commonly associated with levodopa treatment are reduced. Ropinirole appears to have a neuroprotective effect. In addition to Parkinson's disease, ropinirole has also been used successfully in the treatment of restless legs syndrome.
Topics: Animals; Antiparkinson Agents; Dopamine Agonists; Drug Interactions; Humans; Indoles; Mental Disorders; Tremor
PubMed: 16389293
DOI: 10.1111/j.1527-3458.2005.tb00046.x -
Neurotherapeutics : the Journal of the... Oct 2020Parkinson disease (PD), as a slowly progressive neurodegenerative disorder, undergoes six neuropathological stages. The earliest clinical manifestation presents in the... (Review)
Review
Parkinson disease (PD), as a slowly progressive neurodegenerative disorder, undergoes six neuropathological stages. The earliest clinical manifestation presents in the middle stage of the disorder pathologically, when 50% or more of the dopaminergic neurons have degenerated in the substantia nigra. This discrepancy between the early stage clinically and that pathologically has, in part, spurred the debate as to when it is best to initiate symptomatic therapy. The most well-studied monotherapeutic agents for PD in its early course include levodopa (the cornerstone of PD therapy), dopamine agonists, and monoamine oxidase inhibitors (MAOIs). With several options for initiating pharmacologic therapy, along with the heterogenous presentation of the disorder, an individualized approach is warranted. Careful deliberation must be done to optimize risk reduction while providing effective symptom control, taking the chronological age, comorbidities, social and financial disposition, work status, and both immediate- and long-term goals into consideration. Generally, treatment can be delayed in patients with mild symptoms and minimal functional impairment at any age. If treatment must be initiated, dopamine agonists and monoamine oxidase type B inhibitors can be used, especially in younger patients with milder disease. However, for older patients, those with moderate to severe PD symptoms, regardless of age, or for patients with greater comorbidities, levodopa generally remains the better choice. Eventually, regardless of initial therapy, studies have shown that most will eventually require levodopa therapy when symptoms become more disabling.
Topics: Antiparkinson Agents; Dopamine Agonists; Early Diagnosis; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Treatment Outcome
PubMed: 32935299
DOI: 10.1007/s13311-020-00924-4 -
Movement Disorders : Official Journal... Mar 2021No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD).
OBJECTIVE
Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD.
METHODS
Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population.
RESULTS
Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders.
CONCLUSIONS
This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Antiparkinson Agents; Deep Brain Stimulation; Dopamine Agonists; Humans; Levodopa; Parkinson Disease; Single-Blind Method; Treatment Outcome
PubMed: 33165964
DOI: 10.1002/mds.28382