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Various factors are responsible for sleep bruxism; however, whether the dopaminergic agonist group of drugs is effective in the treatment of sleep bruxism is unclear.The purpose of this systematic review was to evaluate the effect of the dopaminergic agonist group of drugs in controlling sleep bruxism in comparison with no treatment or placebo-controlled treatment.Two electronic databases, PubMed and Cochrane Central, were searched by using the keywords bruxism, sleep bruxism, dopamine, and dopamine agonist. After screening titles and abstracts, only those articles which met predefined inclusion criteria were selected for full-text assessment. Clinical trials using the dopaminergic agonist group of drugs as a treatment approach to sleep bruxism were included.The literature search yielded a total of 64 articles from the 2 electronic databases (PubMed, 53; Cochrane Central, 11). After removal of the duplicates (n=8), the initial screening of titles and abstracts was performed by 2 independent reviewers, removing 46 articles. A total of 10 articles were selected for full-text reading, and 4 studies were included for qualitative analysis.Levodopa (L-DOPA) and Bromocriptine showed decrease in root mean square value in electromyography per bruxism burst (P.001) and 20% to 30% reduction of bruxism episodes during sleep in 2 different studies. However, treatment with bromocriptine led to conflicting result in another study in terms of frequency of bruxism episodes and amplitude of muscle contractions in electromyography (EMG). Bruxism bursts and episodes were also not significantly improved with another dopaminergic agonist group of drugs, Pramipexole (P.001). Based on the limited evidence and conflicting results, significant conclusions cannot be generated, and further studies are required.

In addition to the legs, restless legs syndrome (RLS) affects various other parts of the body, including the arms, abdomen, face, head-neck, oral cavity, genital area and bladder. RLS is also associated with several comorbid conditions, including irritable bowel syndrome (IBS). We are reporting two cases of RLS who also had IBS, fulfilling the Rome IV criteria. The administration of levodopa and dopamine agonists provided a complete improvement in both IBS and RLS. Review of the literature suggest that the clinical semiology and clinical pattern of IBS (urge to defaecate, abdominal pain, abdominal distension, bloating, disturbed sleep and circadian rhythm) simulate the semiology and pattern of RLS. Similarities are also noted in the associated comorbid conditions, effective drugs and proposed hypotheses for both clinical syndromes. We hypothesise that RLS may affect intestine, and IBS-like symptoms in a subset of patients with RLS may be the part of RLS symptoms complex.

17β-estradiol treatment has shown benefit against schizophrenia symptoms, however longterm use may be associated with negative side-effects. Selective estrogen receptor modulators, such as raloxifene and tamoxifen, have been proposed as suitable alternatives to 17β- estradiol. An isomer of 17β-estradiol, 17α-estradiol, is considered less carcinogenic, and non-feminising in males, however little is known about its potential as a treatment for schizophrenia. Moreover, the mechanism underlying the therapeutic action of estrogens remains unclear. We aimed to investigate the ability of these estrogenic compounds to attenuate psychosis-like behaviour in rats. We used two acute pharmacologically-induced assays of psychosis-like behaviour: psychotomimetic drug-induced hyperlocomotion and disruption of prepulse inhibition (PPI). Female Long Evans rats were either intact, ovariectomised (OVX), or OVX and chronically treated with 17β-estradiol, 17α-estradiol, raloxifene or tamoxifen. Only 17β-estradiol treatment attenuated locomotor hyperactivity induced by the indirect dopamine receptor agonist, methamphetamine. 17β-estradiol- and tamoxifen-treated rats showed attenuated methamphetamine- and apomorphine (dopamine D1/D2 receptor agonist)- induced disruption of PPI. Raloxifene-treated rats showed attenuated apomorphineinduced PPI disruption only. Baseline PPI was significantly reduced following OVX, and this deficit was reversed by all estrogenic compounds. Further, PPI in OVX rats was increased following administration of apomorphine. This study confirms a protective effect of 17β- estradiol in two established animal models of psychosis, while tamoxifen showed beneficial effects against PPI disruption. In contrast, 17α-estradiol and raloxifene showed little effect on dopamine receptor-mediated psychosis-like behaviours. This study highlights the utility of some estrogenic compounds to attenuate psychosis-like behaviour in rats, supporting the notion that estrogens have therapeutic potential for psychotic disorders.

The primary dystonia DYT6 is caused by mutations in the transcription factor Thanatos‐associated protein 1 (THAP1). To understand THAP1’s functions, we generated mice lacking THAP1 in the nervous system. THAP1 loss causes locomotor deficits associated with transcriptional changes. Since many of the genes misregulated involve dopaminergic signaling, we pharmacologically challenged the two striatal canonical dopamine pathways: the direct, regulated by the D1 receptor, and the indirect, regulated by the D2 receptor. We discovered that depleting THAP1 specifically interferes with the D2 receptor responses, pointing to a selective misregulation of the indirect pathway in DYT6 with implications for pathogenesis and treatment.

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA’s hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy- N, N-di- n-propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N-methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.

Background and ObjectivesTo review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide recommendations to clinicians.MethodsA multidisciplinary panel developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.ResultsInitial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia. The comparison of different formulations of dopamine agonists yielded little evidence that any one formulation or method of administration is superior. Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease. There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa. Recommendations on initial therapy for motor symptoms are provided to assist the clinician and patient in choosing between treatment options and to guide counseling, prescribing, and monitoring of efficacy and safety.

Background: Impulse control disorders (ICD) occur frequently in individuals with Parkinson's disease. So far, prevention is the best treatment. Several strategies for its treatment have been suggested, but their frequency of use and benefit have scarcely been explored. Objective: To investigate which strategy is the most commonly used in a real-life setting and its rate of response. Methods: A longitudinal study was conducted. At the baseline evaluation, data on current treatment and ICD status according to QUIP-RS were collected. The treatment strategies were categorized as “no-change”, dopamine agonist (DA) dose lowering, DA removal, DA switch or add-on therapy. At the six-month follow-up visit, the same tools were applied. Results: A total of 132 individuals (58.3% men) were included; 18.2% had at least one ICD at baseline. The therapeutic strategy most used in the ICD group was no-change (37.5%), followed by DA removal (16.7%), DA switch (12.5%) and DA lowering (8.3%). Unexpectedly, in 20.8% of the ICD subjects the DA dose was increased. Overall, nearly 80% of the subjects showed remission of their ICD at follow-up. Conclusions: Regardless of the therapy used, most of the subjects presented remission of their ICD at follow-up Further research with a longer follow-up in a larger sample, with assessment of decision-making processes, is required in order to better understand the efficacy of strategies for ICD treatment. Resumen Antecedentes: Los trastornos del control de impulsos (TCI) son frecuentes en personas con enfermedad de Parkinson. A la fecha, la prevención es el mejor tratamiento. Existen varias estrategias sugeridas para su tratamiento, pero su frecuencia de uso y beneficio ha sido escasamente explorada. Objetivo: Investigar qué estrategia es la más utilizada en un entorno de la vida real y su tasa de respuesta. Métodos: Se realizó un estudio longitudinal. En la evaluación inicial, se recopiló el tratamiento actual y el estado del TCI de acuerdo con el QUIP-RS. La estrategia de tratamiento se clasificó como "sin cambios", reducción de la dosis de agonista de la dopamina (AD), eliminación de AD, cambio de AD o terapia complementaria. En la visita de seguimiento a los 6 meses, se aplicaron las mismas herramientas. Resultados: Se incluyeron un total de 132 (58.3% hombres) personas. El 18.2% tenía al menos un TCI al inicio del estudio. La estrategia terapéutica más utilizada en el grupo de TCI fue sin cambios (37.5%), seguida de eliminación de DA (16.7%), cambio de AD (12.5%) y reducción de DA (8.3%). En el 20.8% de los sujetos con TCI se aumentó la dosis de AD. Casi el 80% de los sujetos tuvieron una remisión del TCI al seguimiento. Conclusiones: Independientemente de la terapia utilizada, la mayoría de los sujetos tuvieron una remisión del TCI. Se requiere más investigación con un seguimiento y una muestra mayor para evaluar l proceso de toma de decisiones para comprender mejor la eficacia de las estrategias.

Brain mechanisms of sexual attraction toward reproductive partners develop from a systematic interrelationship between biology (nature) and learning (nurture). However, the causes of attraction toward non-reproductive partners are poorly understood. Here, we explored the role of Pavlovian learning under dopaminergic agonism on the development of sexual preference and brain activation for young male rats. During conditioning, adult sexually naïve males received either Saline (Saline-Paired) or the D2-receptor agonist quinpirole (QNP-Paired) and cohabited in contingency, or out of contingency (QNP-Unpaired) during 24 h with an almond-scented prepubertal juvenile male (PD25). Conditioning occurred every 4 days for three trials. Social and sexual responses were assessed four days after the last conditioning trial in a drug-free test, and males chose freely between a scented young male (PD37) and a novel receptive female. Four days later, males were exposed to the conditioned odor only and brain Fos-IR and serum testosterone were analyzed. Saline-Paired and QNP-Unpaired males displayed more non-contact erections (NCEs) and genital investigations for females, whereas QNP-Paired males expressed more NCEs and genital investigations for young males. In the QNP-Paired group, exposure to the young male-paired odor evoked more Fos-IR in limbic, hypothalamic and cortical areas, but no differences in serum testosterone were observed. Cohabitation with juvenile males during enhanced D2 agonism results in atypical appetitive sexual responses and a higher pattern of brain response for the young male-paired odor, with no changes in serum testosterone. We discuss the potential implications for the development of pedophilic disorder and perhaps other paraphilias.

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

Background Dopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes. Methods Both bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size. Results Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p Conclusions The examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.

Prevalence, presentation and clinical outcome of prolactinomas vary in children and adults. In this study, we evaluated the clinical features and outcome of children and adolescents with prolactinoma to identify the differences from that of adults, and thus to establish the management strategies for this age group.Patients with prolactinoma diagnosed before 18 years of age from a single center in the last 20-years were included. Clinical and laboratory data, radiological findings and treatment outcome were evaluated retrospectively.Twenty-eight patients (23 female; 82.1%) with prolactinoma were included. Median age at diagnosis was 15.2 years (12.6-17.7 years) in girls, 12.9 years (12.0-16.7 years) in boys. First line treatment was cabergoline in 82% of patients and normal prolactin level was achieved with maximum dose of 2 mg/week in 78%. Surgery was required in 28% of patients. Adenomas 13.5 mm responded conventional doses of CAB. Adenomas 30 mm were drug resistant or required surgery. Adenomas between 13.5 mm and 30 mm with invasion/extension were more likely to have drug resistance. CAB had to be continued following surgery in all patients. One macroprolactinoma had an increase in size which was accompanied with increasing prolactin level.All microprolactinomas responded well to DA treatment. However, all adenomas larger than 30 mm was resistant to CAB or required surgery. Probability of drug resistance and requirement of second line therapy were higher in adenomas between 13.5 mm and 30 mm with invasion/extension. Doses over 2 mg/week of CAB in drug-resistant patients may not provide additional benefit. The frequency of follow-up MRI could be determined based on prolactin levels and emergence of new neurological symptoms.

The objective was to evaluate the transdermal iontophoretic delivery of pramipexole using constant and complex multi-phasic current profiles from an iontophoretic patch system in vitro and in vivo. Preliminary in vitro experiments were performed to optimize iontophoretic patch design and configuration. "Single" compartment systems containing only pramipexole dihydrochloride, and designed to maximize delivery efficiency, suffered from an insufficiency of chloride ions with anodal electrochemistry passing from an Ag/AgCl couple to an Ag dissolution electrode. Addition of NaCl to provide more chloride ions decreased pramipexole delivery efficiency due to competition between pramipexole and sodium cations. A "two-compartment" iontophoretic patch where the drug reservoir was separated from the anodal compartment, which now included NaCl, was shown to be a good compromise since it ensured Ag/AgCl electrochemistry at the anode and an acceptable delivery efficiency. In vivo studies using this iontophoretic patch demonstrated that the plasma concentration of pramipexole closely followed the variation of the applied continuous and multi-phasic current profiles and underlined the control provided by iontophoresis and its unique ability to rapidly change drug input rates. The applied current density and duration of current application were also shown to modulate pramipexole delivery to the brain and CSF.

Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD. To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains. Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01–0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls. All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability. These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD.

Dopamine agonists (DA) comprise first-line treatment for prolactinomas. However, some patients show no response to DA and are considered resistant. In this study, we retrospectively analyzed the outcomes of DA-resistant prolactinoma patients after transsphenoidal surgery (TSS). A total of 94 consecutive patients with DA-resistant prolactinomas who underwent TSS were retrospectively enrolled in the present study. Early postoperative remission rate, prolactin (PRL) levels, and recurrence rate were analyzed. Of 94 DA-resistant patients, 47 (50%) achieved early remission 1 week post-surgery, including 41.18% of macroprolactinoma patients and 73.08% of microprolactinoma patients. PRL levels on the first postoperative day were significantly lower than preoperative PRL levels (p

Background Dopamine agonists such as bromocriptine and cabergoline have been found to be an effective treatment for hyperprolactinemia, not only inducing adenoma shrinkage but also lowering serum prolactin levels. Among known dopamine agonists, cabergoline is the drug of choice due to its enhanced tolerability compared with bromocriptine. This study aimed to evaluate cabergoline's effectiveness, along with transsphenoidal surgery, in the treatment of hyperprolactinemia. Methods We retrieved all patients with a diagnosis of prolactinoma who were treated in our hospital during 2000-2018. A total of 208 patients were enrolled in the analysis after applying exclusion criteria. Patients were divided into four groups according to the treatments received. The demographic data, dosage and duration of cabergoline, and serum prolactin levels at different time points were collected for analysis. Results Normalization was achieved in 59 patients (83.10%) within a short median duration of 2.80 months among those treated with cabergoline only. Although cabergoline alone was effective and well-tolerated, our data showed that long-term remission rates were more favorable when surgery was involved. The long-term remission rate of all patients enrolled was 53.8% (112 patients among 208 patients). The long-term remission rates for the different treatment groups were 17.8% (8 of 45 patients) in Group 1 (Operation→Drug), 83.3% (5 of 6 patients) in Group 2 (Drug→Operation), 79.0% (68 of 86 patients) in Group 3 (Operation only), and 43.7% (31 of 71 patients) in Group 4 (Drug only). Conclusion Cabergoline has been demonstrated to be effective and should be considered as a first-line treatment for hyperprolactinemia. In our study, transsphenoidal surgery was also demonstrated to achieve good results compared with medical treatment. Surgical intervention may resurface as an alternative first-line treatment. When used in combination with cabergoline, surgery offers a higher disease remission rate than either drug or operation alone.

OBJECTIVE To study the outcome of men with macroprolactinoma following cabergoline treatment based on tumour size. DESIGN Retrospective cohort study. METHODS The study included 94 men, divided into three groups according to adenoma diameter: 10-19 mm (Group A, n = 36); 20-39 mm (Group B, n = 41); or ≥40 mm (Group C, giant prolactinomas, n = 17). Patients were followed for a mean of 7.5 years with sellar magnetic resonance imaging, visual fields and hormone measurements. RESULTS Mean baseline prolactin was 767, 2090 and 24,806 ng/ml in Groups A, B and C, respectively (p

Background Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. Methods We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. Results Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. Conclusion Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.

Aim A reduced mismatch negativity (MMN) response is a promising electrophysiological endophenotype of schizophrenia that reflects neurocognitive impairment. Dopamine dysfunction is associated with symptoms of schizophrenia. However, whether the dopamine system is involved in MMN impairment remains controversial. In this study, we investigated the effects of the dopamine D2‐like receptor agonist quinpirole on mismatch responses to sound frequency changes in an animal model. Methods Event‐related potentials were recorded from electrocorticogram electrodes placed on the auditory and frontal cortices of freely moving rats using a frequency oddball paradigm consisting of ascending and equiprobable (ie, many standards) control sequences before and after the subcutaneous administration of quinpirole. To detect mismatch responses, difference waveforms were obtained by subtracting nondeviant control waveforms from deviant waveforms. Results Here, we show the significant effects of quinpirole on frontal mismatch responses to sound frequency deviations in rats. Quinpirole delayed the frontal N18 and P30 mismatch responses and reduced the frontal N55 MMN‐like response, which resulted from the reduction in the N55 amplitude to deviant stimuli. Importantly, the magnitude of the N55 amplitude was negatively correlated with the time of the P30 latency in the difference waveforms. In contrast, quinpirole administration did not clearly affect the temporal mismatch responses recorded from the auditory cortex. Conclusion These results suggest that the disruption of dopamine D2‐like receptor signaling by quinpirole reduces frontal MMN to sound frequency deviations and that delays in early mismatch responses are involved in this MMN impairment., The subcutaneous administration of quinpirole delayed early mismatch response latencies and reduced a late MMN‐like response amplitude recorded from the frontal cortex but had no effect on those recorded from the auditory cortex. These observations suggest that increased dopamine D2‐like receptor signaling impairs MMN generation to sound frequency changes in the frontal cortex and that the neurochemical mechanisms of MMN vary according to the cortical area. As MMN is associated with cognitive function, these new findings may help develop treatment modalities for cognitive dysfunctions in schizophrenia.

Doxorubicin (DOX) is a broad-spectrum antineoplastic drug; however, its serious cardiotoxic side effects in inflammatory responses limit its use in clinical applications. Dopamine D1 receptor (DRD1), a G protein-coupled receptor, is crucial for the development and function of the nervous system; additionally, it also play a role in immune regulation. However, the specific role of DRD1 in DOX-induced cardiac inflammation has not yet been clarified. Here, we discovered that DRD1 expression was induced by DOX treatment in H9C2 cardiomyocytes. DRD1 activation by A-68930, a DRD1-specific agonist, decreased DOX-induced nucleotide-binding domain-like receptor protein 3 (NLRP3) expression, caspase-1 activation, and IL-1β maturation in H9C2 cells. Expression of the cytokines IL-1β and IL-18 in the supernatants was also inhibited by A-68930 treatment. DRD1 knockdown, using siRNA, abolished the effects of A-68930 on the DOX-induced NLRP3 inflammasome. Furthermore, we found that DRD1 signaling downregulated the NLRP3 inflammasome in H9C2 cells through cyclic adenosine monophosphate (cAMP). Moreover, application of A-68930 to activate DRD1 reduced cardiac injury and fibrosis in a DOX-treated mouse model by suppressing the NLRP3 inflammasome in the heart. These findings indicate that DRD1 signaling may protect against DOX-induced cardiac injury by inhibiting the NLRP3 inflammasome-mediated inflammation.

Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors’ proliferative index (Ki67) increased from 5–6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.

Dopamine receptor, a polypeptide chain composed of 7 hydrophobic transmembrane regions, is a new and vital drug target, especially Dopamine receptor 2(D2). Targeting dopamine receptors, Dopamine receptor agonists are a class of drugs similar in function and structure to dopamine and can directly act on dopamine receptors and activate it. Clinically, Dopamine receptor agonist drugs have achieved significant therapeutic effects on prolactinoma and Parkinson's Disease. In the study, we virtually screened a series of potential effective agonists of Dopamine receptor by computer techniques. Firstly, we used the Molecular Docking (LibDock) step to screen out some molecules that can dock well with the protein. Then, analysis of toxicity prediction and ADME (adsorption, distribution, metabolism and excretion) were carried out. More precise molecular docking (CDOCKER) and 3-Dimensional Quantitative Structure-Activity Relationship Modeling Study(3D-QSAR) pharmacophore generation were implemented to research and explore these compounds' binding mechanism with Dopamine receptor. Last but not least, to assess compound's binding stabilities, we carried out a molecular dynamic analysis. As the results show, two compounds (ZINC000008860530 and ZINC000004096987) from the small molecule database (ZINC database) were potential effective agonists of Dopamine receptor. These two compounds can combine with Dopamine receptor with higher affinity and proved to be no toxic. The cell experiment showed that two compounds could inhibit the proliferation and PRL secretion of MMQ cells (pituitary tumor cells). Thus, this study provided valuable information about Dopamine receptor agonist-based drug discovery. So, this study will benefit patients with prolactinoma and Parkinson’s disease a lot.

Cabergoline (CAB) is the first choice for treatment of prolactinoma and the most common subtype of pituitary adenoma. However, drug resistance and lack of effectiveness in other pituitary tumor types remain clinical challenges to this treatment. Brusatol (BT) is known to inhibit cell growth and promote apoptosis in a variety of cancer cells. In our present studies, we investigate the effects of BT on pituitary tumor cell proliferation in vitro and in vivo. BT treatment resulted in an increase in Annexin V-expressing cells and promoted the expression of apoptosis-related proteins in rat and human pituitary tumor cells. Investigation of the mechanism underlying this effect revealed that BT increased the production of reactive oxygen species (ROS) and inhibited the phosphorylation of 4EBP1 and S6K1. Furthermore, treatment with a combination of BT and CAB resulted in greater antitumor effects than either treatment alone in nude mice and pituitary tumor cells. Collectively, our results suggest that the BT-induced ROS accumulation and inhibition of mTORC1 signaling pathway leads to inhibition of tumor growth. Combined use of CAB and BT may increase the clinical effectiveness of treatment for human pituitary adenomas.

Othello syndrome (OS) is a type of delusional jealousy, characterized by the false absolute certainty of the infidelity of a partner. This syndrome is not uncommon in Parkinson's Disease (PD), appearing as side effect of Dopaminergic Agonists (DA) therapy. We analyze the observations of five patients with OS, diagnosed in a series of 250 consecutive PD patients during two years. All patients are men, with a particularly young age at onset of PD. The mean duration of DA therapy at OS onset was 3 years. One patient had hypersexuality and another had punding. Significant cognitive impairment was present in two patients. All patients were treated with DA: two with Pramipexol and three with Piribedil. At the time of the management of the OS, three patients had already divorced their spouse. It is imperative for clinicians to know this underestimated syndrome in order to identify it early and approach it adequately to avoid irreversible negative prejudice.

The surveillance strategy for patients taking low dose cabergoline for hyperprolactinaemia is controversial. As more evidence has emerged that the risks of cardiac valvulopathy in this population of patients are low, fewer and fewer endocrinologists adhere strictly to the original medicines and healthcare products agency MHRA guidance of "at least" annual echocardiography. Strict adherence to this guidance would be costly in monetary terms (£5.76 million/year in the UK) and also in resource use (90,000 extra echocardiograms/year). This article reviews the proposed pathophysiological mechanism underlying the phenomenon of dopamine agonist valvulopathy, the characteristic echocardiographic changes seen, summarises the published literature on the incidence of valvulopathy with low dose cabergoline and examines the previous and current evidence-based screening guidelines.

A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. Compared to the wild type D2 receptor, the novel allelic variant D2-I(212)F activates a Gα(i1)β(1)γ(2) heterotrimer with higher potency and modestly enhanced basal activity in human embryonic kidney (HEK) 293 cells, and has decreased capacity to recruit arrestin3. We now report that omitting overexpressed G protein-coupled receptor kinase-2 (GRK2) decreased the potency and efficacy of quinpirole for arrestin recruitment. The relative efficacy of quinpirole for arrestin recruitment to D2-I(212)F compared to D2-WT was considerably lower without overexpressed GRK2 than with added GRK2. D2-I(212)F exhibited higher basal activation of Gα(oA) than Gα(i1), but little or no increase in the potency of quinpirole relative to D2-WT. Other signs of D2-I(212)F constitutive activity for G protein-mediated signaling, in addition to basal activation of Gα(i/o), were enhanced basal inhibition of forskolin-stimulated cyclic AMP accumulation that was reversed by the inverse agonists sulpiride and spiperone and a ~4-fold increase in the apparent affinity of D2-I(212)F for quinpirole, determined from competition binding assays. In mouse midbrain slices, inhibition of tonic current by the inverse agonist sulpiride in dopamine neurons expressing D2-I(212)F was consistent with our hypothesis of enhanced constitutive activity and sensitivity to dopamine relative to D2-WT. Molecular dynamics simulations with D2 receptor models suggested that an ionic lock between the cytoplasmic ends of the third and sixth α-helices that constrains many G protein-coupled receptors in an inactive conformation spontaneously breaks in D2-I(212)F. Overall, these results confirm that D2-I(212)F is a constitutively active and signaling-biased D2 receptor mutant, and also suggest that the effect of the likely pathogenic variant in a given brain region will depend on the nature of G protein and GRK expression.

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify®). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti®), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists., “Dopamine‐system stabilizer” activity of aripiprazole.

Augmentation is a major complication of long-term pramipexole treatment of restless legs syndrome (RLS). However, there have been no studies on augmentation in Chinese patients with RLS. We therefore investigated the clinical characteristics of augmentation in RLS patients treated with pramipexole in a real-world Chinese setting. This study was an observational, retrospective assessment of 103 patients with RLS, who had been continuously treated with pramipexole for at least one month between January 2016 and December 2018 in a tertiary hospital in East China. Demographic data and disease and drug treatment information were collected from electronic medical records and telephone interviews to analyze the rate and clinical features of augmentation. Augmentation was confirmed by Max Planck Institute criteria. Comparisons were made between patients with and without augmentation. Fifteen patients (15%) were classified as having augmentation. Compared to RLS patients without augmentation, more patients with augmentation switched from other dopaminergic drugs (P

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. Prevention Relevance: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

Activation of dopamine (DA) neurons is essential for the transition from sleep to wakefulness and maintenance of awakening, and sufficient to accelerate the emergence from general anesthesia in animals. Dopamine receptors (DR) are involve in arousal mediation. In the present study, we showed that the olfactory tubercle (OT) was active during emergence from isoflurane anesthesia, local injection of dopamine D1 receptor (D1R) agonist chloro-APB (1 mg/mL) and D2 receptor (D2R) agonist quinpirole (1 mg/mL) into OT enhanced behavioural and cortical arousal from isoflurane anesthesia, while D1R antagonist SCH-23390 (1 mg/mL) and D2R antagonist raclopride (2.5 mg/mL) prolonged recovery time. Optogenetic activation of DAergic terminals in OT also promoted behavioural and cortical arousal from isoflurane anesthesia. However, neither D1R/D2R agonists nor D1R/D2R antagonists microinjection had influences on the induction of isoflurane anesthesia. Optogenetic stimulation on DAergic terminals in OT also had no impact on the anesthesia induction. Our results indicated that DA signals in OT accelerated emergence from isoflurane anesthesia. Furthermore, the induction of general anesthesia, different from the emergence process, was not mediated by the OT DAergic pathways.

Background and Objective Safinamide is a novel anti-parkinsonian drug with possible anti-dyskinetic properties. Parkinson's disease (PD) is a complex disease. The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of safinamide administration compared to placebo in PD patients on multiple outcomes. Methods PubMed, EMBASE, Cochrane CENTRAL, LILACS, and trial databases were searched up to 23 December 2020 for randomized controlled studies (RCTs) comparing safinamide to placebo, alone or as add-on therapy in PD. Data were extracted from literature and regulatory agencies. Primary outcomes were ON-time without troublesome dyskinesia, OFF-time, and Unified Parkinson’s Disease Rating Scale (UPDRS) section III (UPDRS-III). Secondary outcomes included any dyskinesia rating scale (DRS), ON-time with troublesome dyskinesia, UPDRS-II, and Parkinson’s Disease Questionnaire 39 (PDQ-39). In order to estimate mean difference (MD) and odds ratios with 95% confidence intervals (CI), generic inverse variance and Mantel–Haenszel methods were used for continuous and dichotomous variables, respectively. Analyses were performed grouping by PD with (PDwMF) or without (PDwoMF) motor fluctuations, safinamide dose, and concomitant dopaminergic treatment. Summary of findings with GRADE were performed. Results Six studies with a total of 2792 participants were identified. In PDwMF patients, safinamide 100 mg as add-on to levodopa (l-dopa) significantly increased ON-time without troublesome dyskinesia (MD = 0.95 h; 95% CI from 0.41 to 1.49), reduced OFF-time (MD = − 1.06 h; 95% CI from − 1.60 to − 0.51), and improved UPDRS-III (MD = − 2.77; 95% CI from − 4.27 to − 1.28) with moderate quality of evidence. Similar results were observed for the 50 mg dose. However, the quality of evidence was moderate only for ON-time without troublesome dyskinesia, whereas for OFF-time and UPDRS-III was low. In PDwoMF patients taking a single dopamine agonist, safinamide 100 mg resulted in little to no clinically significant improvement in UPDRS-III (MD = − 1.84; 95% CI from − 3.19 to − 0.49), with moderate quality of evidence. Conversely, in PDwoMF patients, the 200 mg and 50 mg doses showed nonsignificant improvement in UPDRS-III, with very low and moderate quality of evidence, respectively. In PDwMF patients taking safinamide 100 mg or 50 mg, nonsignificant differences were observed for ON-time with troublesome dyskinesia and DRS, with high and low quality of evidence, respectively. In the same patients, UPDRS-II was significantly improved at the 100 mg and 50 mg dose, with high and moderate quality of evidence. In PDwoMF, UPDRS-II showed a little yet significant difference only at 100 mg, with low quality of evidence. PDQ-39 resulted significantly improved only with the 100 mg dose in PDwMF, with low quality of evidence. Conclusion Overall, safinamide is effective in PDwMF patients taking l-dopa both at 100 and 50 mg daily. Evidence for efficacy in early PD is limited. Further trials are needed to better evaluate the anti-dyskinetic properties of safinamide. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01011-y.

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose This article aims to evaluate management options for antipsychotic-induced hyperprolactinemia and associated treatment considerations such as efficacy, tolerability, drug interactions, contraindications, and dosing regimens. Summary Hyperprolactinemia is a common adverse effect of antipsychotics. First-line management includes reducing the dose of the offending antipsychotic, discontinuing the antipsychotic, or switching to another antipsychotic associated with a lower risk of hyperprolactinemia. However, these options are not always practical and are associated with a risk of relapse of the psychiatric illness. Other management options include adjunctive aripiprazole, dopamine agonists (cabergoline and bromocriptine), metformin, and herbal supplements. A search of Embase, PubMed, and Google Scholar using key terms such as hyperprolactinemia, prolactin, antipsychotic, treatment guidelines, aripiprazole, dopamine agonist, cabergoline, bromocriptine, metformin, herbals, supplements, and medications was conducted for literature retrieval. Upon evaluation of the available literature we found the following: (1) aripiprazole is safe and effective in lowering prolactin levels within normal limits; (2) adjunctive cabergoline and bromocriptine decrease elevated prolactin levels, while cabergoline may be more effective in reducing prolactin but can also be associated with a more serious adverse effect of cardiac valvular abnormalities; (3) metformin causes a mild reduction of prolactin levels; and (4) there are limited data to support use of herbal medications (chamomile, Peony-Glycyrrhiza decoction, and shakuyaku-kanzo-to) in antipsychotic-induced hyperprolactinemia Conclusion There are treatments available for antipsychotic-induced hyperprolactinemia in patients who are unable to alter their current antipsychotic regimen. However, there remains a need for additional short- and long-term studies to determine the efficacy and safety of these treatment strategies, given that patients taking antipsychotics typically require chronic, life-long treatment for their illnesses.

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of-3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (+/- SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (+/- 674) and levodopa dose by 273 mg (+/- 515).Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.

Dopamine D2/3 receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D₂ receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the "wager") versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole's effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1–4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.

Introduction: Cabergoline is the treatment of choice for prolactinomas. However, 10–20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. Subjects and Methods: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26–61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38–386 ng/mL) under cabergoline treatment (2–7 mg/week) for at least 6 months (6–108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0–2.5 g v.o./day) was given according to patients’ tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30–60 days) and long-term (120–180 days) metformin treatment. Results: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30–60 days, and at 120–180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0–2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. Conclusion: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.

Background: Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist compound recently introduced to treat schizophrenia and bipolar disorder. Although cariprazine is clinically classified as a low-somnolence drug, to date no detailed polysomnographic study is available on its effect on sleep. Aims: This study examined the acute systemic effects of cariprazine on the rat sleep architecture and electroencephalography spectral power. Methods: Sprague Dawley rats were recorded during their normal sleep period for four hours, and their sleep stages were classified. Results: Cariprazine (0.3 mg/kg i.p.) reduced the time spent in rapid eye movement (REM) sleep and increased REM latency. This dose of cariprazine decreased the gamma (40–80 Hz) band frequency oscillations and increased the theta (4–9 Hz) and alpha (9–15 Hz) frequencies during the wake periods but not during slow-wave sleep. The 0.03 mg/kg dose of cariprazine only increased the alpha power during the wake periods, while the 0.003 mg/kg dose was without any effect. Conclusion: Taken together, the present results suggest that the REM-suppressing effect of cariprazine may be related to its effectiveness in improving depressive symptoms, as various drugs with similar REM-reducing properties effectively treat the depressive state, whereas the gamma power-reducing effect of cariprazine may be indicative of its efficacy in schizophrenia or mania, as similar effects have been observed with other D2 and 5-HT2 receptor antagonist drugs. These data contribute to our understanding of the complex mechanism of action that may stand behind the clinical efficacy of cariprazine.

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients’ quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01019-4.

In 11 patients with Parkinson's disease (PD) who were using levodopa and had hallucinations and/or delusions considered to be attributed to use of dopamine agonists (DAs), we reduced or discontinued DAs and added zonisamide, and we then evaluated the effects of this treatment on psychiatric and motor symptoms. As a result, changes in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part 1.2 (Hallucinations and Psychosis) and Part 3 (Motor Examination) scores 12 weeks from baseline were -2.4 ± 0.2 and -5.1 ± 0.9 (least-squares mean ± standard error), respectively, with the score reductions being statistically significant. These results indicated that zonisamide switching therapy is a useful strategy for managing psychiatric and motor symptoms in patients with PD when DAs are reduced or discontinued to avoid the onset or exacerbation of hallucinations and delusions.

To report the clinical presentation, management and outcomes of young patients with prolactinomas (20 years) and conduct a systematic review and meta-analysis.Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p .02) and higher serum prolactin concentration (p .005). All patients with macroprolactinoma20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%).Macroprolactinoma, particularly if20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.

Introduction Impulse control disorders (ICDs) have been described as a side effect of dopamine agonists (DAs) in neurological as well as endocrine conditions. Few studies have evaluated the neuropsychological effect of DAs in hyperprolactinemic patients, and these have reported a relationship between DAs and ICDs. Our objective was to screen for ICD symptoms in individuals with DA-treated endocrine conditions. Materials and methods A cross-sectional analysis was conducted on 132 patients with pituitary disorders treated with DAs (DA exposed), as well as 58 patients with pituitary disorders and no history of DA exposure (non-DA exposed). Participants responded to the full version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease (QUIP). Results Compared with the non-DA-exposed group, a higher prevalence of DA-exposed patients tested positive for symptoms of any ICD or related behavior (52% vs. 31%, p p p p p Discussion Despite the QUIP limitations, a clear sign of increased risk of ICDs emerges in individuals with DA-treated pituitary disorders. Our data contribute to the growing evidence of DA-induced ICDs in endocrine conditions.

Cabergoline (CAB) therapy for prolactinomas has been associated with serum IGF-1 levels modifications, with recent reports indicating a paradoxical increase of IGF-1 levels during ongoing therapy. As a result, IGF-1 measurement has been proposed not only at diagnosis of a prolactinoma, but also during follow-up. In this follow-up study on prolactinoma patients with chronic CAB therapy, we investigated whether there are long-term changes in IGF-1 levels that necessitate continuous monitoring. We reviewed our institutional database on prolactinoma patients with long-term CAB therapy, in whom IGF-1 levels were measured at baseline, at 3-months follow-up and in the long term. Chronic CAB therapy was noted in 20 patients (13 men, 7 women). Median (±SD) age was 43.5 ± 12.6 years. 17 (85%) patients presented with a macroprolactinoma. Median CAB treatment time was 75 ± 43 months (range 24–187). Median IGF-1 levels increased at last follow-up, though not significantly; from 122 ± 37 ng/ml (IQR 104–160 ng/ml) to 133 ± 54 (IQR 121–162 ng/ml), p = 0.10. Thereby, 18 (90%) patients showed normal serum IGF-1 levels adjusted for age, one (5%) patient above (1.05 × ULN) and 1 (5%) patient below the normal range (0.34 × ULN). No patient was or became symptomatic of acromegaly. Our long-term results indicate that chronic treatment with CAB in prolactinoma patients does not significantly modify serum IGF-1 levels. Bearing in mind the sample size of this study, continuing IGF-1 monitoring is not indicated in prolactinoma patients with long-term CAB therapy.

The present study was to find a pathogenic evidence for dopamine agonist application in patients with endometriosis associated pain syndrome.The study involved 227 patients of reproductive age with histologically confirmed genital endometriosis (GE) of I-III degree according to ASRM classification. The control group included 12 women with no laparoscope detected gynecologic pathology. The levels of prolactin (PRL), peripheral blood (PB), and peritoneal fluid (PF) were evaluated by chemiluminescence immune assay. The pain syndrome was measured by McGill visual analogue scale. Statistica10 program (StatSoft, Inc., Tulsa, OK) was applied for obtained data processing.A correlation was established between GE rate and levels of PRL and PB (Rs = 0.28,PRL involvement in GE pathogenesis and more intense therapeutic impact on pain syndrome in case of combined administration of dopamine and standard hormone therapy prove cabergoline application in clinical practice.

Restless genital syndrome (RGS) is a rare disorder with unpleasant sensation in the genital area and unwanted sexual arousal. Only a few cases of RGS have been reported, so we presented four cases of RGS. Four cases were all middle-age female, and was commonly complaint paresthesia on their genital area and unwanted sexual arousal. The typical symptoms of restless legs syndrome (RLS), affecting on their lower extremities were accompanied. RGS is difficult to diagnose because it presents ambiguous sensations that are difficult to describe, along with embarrassment in reporting sexual feelings. Clinicians should be aware of the genital discomfort and sexual arousal that can develop in RLS.

Introduction CVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented. Methods Patients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC). Results Most frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV1, FVC, and DLCO were −0.092 L, −0.097 L, and −0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5–91.9% over 12 months. Conclusion CVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC.

Any common disease (including Parkinson’s disease) is inevitably overgrown with myths. As a result, not scientifically grounded approaches based on the principles of evidence-based medicine, but irrational ideas, especially often of a pharmacophobic nature, begin to dominate in primary clinical practice among doctors and patients. In clinical practice, we can often face to a situation when doctors, dogmatically accepting the principle of delayed initiation of levodopa therapy, for a long time try to guide the patient on other antiparkinsonian drugs, despite the obvious ineffectiveness of such therapy and the increasingly growing immobility of the patient. This phenomenon, based on the irrational beliefs of not only doctors, but also patients in the toxicity of levodopa, is commonly referred to as levodopa phobia. Levodopa phobia, along with the emergence of a new generation of dopamine agonists (DAs), whose ability to delay the development of fluctuations and dyskinesias has been proven in a series of placebo-controlled studies, as well as the erroneous interpretation of the withdrawal syndrome of DAs as evidence of their high effectiveness, have led to the widespread use of this class. drugs. However, the use of DA turned out to be associated with an increased risk of such adverse events as daytime sleepiness, leg edema, impulsive-compulsive disorders, and withdrawal syndrome. All this served as the basis for the appearance of “dopamine agonists phobia”, which can lead to unjustifiably early prescription of levodopa and the development of dyskinesias. What is the optimal way for managementof PD patients today? In our opinion, the patient management formula that doctors should adhere to should be as follows: early prescription of dopaminergic drugs (more often DAs or levodopa) is necessary, which provides a quick possible, albeit incomplete, correction of a motor defect, which would be sufficient to preserve the patient’s motor activity, including his professional activity; as the symptoms increase, an escalation of antiparkinsonian therapy with the sequential addition of levodopa (or DAs), MAO B inhibitors, amantadines is necessary.

Although numerous studies have suggested that pharmacological alteration of the dopamine (DA) system modulates reward discounting, these studies have produced inconsistent findings. Here, we conducted a systematic review and pre-registered meta-analysis to evaluate DA drug-mediated effects on reward discounting of time, probability, and effort costs in studies of healthy rats. This produced a total of 1,343 articles to screen for inclusion/exclusion. From the literature, we identified 117 effects from approximately 1,549 individual rats. Using random-effects with maximum-likelihood estimation, we meta-analyzed placebo-controlled drug effects for (1) DA D1-like receptor agonists and (2) antagonists, (3) D2-like agonists and (4) antagonists, and (5) DA transporter-modulating drugs. Meta-analytic effects showed that DAT-modulating drugs decreased reward discounting. While D1-like and D2-like antagonists both increased discounting, agonist drugs for those receptors had no significant effect on discounting behavior. A number of these effects appear contingent on study design features like cost type, rat strain, and microinfusion location. These findings suggest a nuanced relationship between DA and discounting behavior and urge caution when drawing generalizations about the effects of pharmacologically manipulating dopamine on reward-based decision making.

Purpose The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin–dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25–6 mg. Methods Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. Results Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77–88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74–83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration–time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. Conclusion By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. Trial registration ClinicalTrials.gov NCT00805454 December 9, 2008.

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.

See Manohar (doi:10.1093/brain/awaa363) for a scientific commentary on this article. Parkinson’s disease is complicated by great variability in symptoms. Van Nuland et al. report that the well-established effects of levodopa on reinforcement learning apply only to patients without tremor symptoms, suggesting a need to revisit neurocognitive models of dopaminergic function in Parkinson’s disease., Parkinson’s disease is clinically defined by bradykinesia, along with rigidity and tremor. However, the severity of these motor signs is greatly variable between individuals, particularly the presence or absence of tremor. This variability in tremor relates to variation in cognitive/motivational impairment, as well as the spatial distribution of neurodegeneration in the midbrain and dopamine depletion in the striatum. Here we ask whether interindividual heterogeneity in tremor symptoms could account for the puzzlingly large variability in the effects of dopaminergic medication on reinforcement learning, a fundamental cognitive function known to rely on dopamine. Given that tremor-dominant and non-tremor Parkinson’s disease patients have different dopaminergic phenotypes, we hypothesized that effects of dopaminergic medication on reinforcement learning differ between tremor-dominant and non-tremor patients. Forty-three tremor-dominant and 20 non-tremor patients with Parkinson’s disease were recruited to be tested both OFF and ON dopaminergic medication (200/50 mg levodopa-benserazide), while 22 age-matched control subjects were recruited to be tested twice OFF medication. Participants performed a reinforcement learning task designed to dissociate effects on learning rate from effects on motivational choice (i.e. the tendency to ‘Go/NoGo’ in the face of reward/threat of punishment). In non-tremor patients, dopaminergic medication improved reward-based choice, replicating previous studies. In contrast, in tremor-dominant patients, dopaminergic medication improved learning from punishment. Formal modelling showed divergent computational effects of dopaminergic medication as a function of Parkinson’s disease motor phenotype, with a modulation of motivational choice bias and learning rate in non-tremor and tremor patients, respectively. This finding establishes a novel cognitive/motivational difference between tremor and non-tremor Parkinson’s disease patients, and highlights the importance of considering motor phenotype in future work.

BACKGROUND: Current drug treatments have limited efficacy and intolerable side effects in advanced-to-end-stage Parkinson’s disease (advPD). D(1) agonists have the potential to provide symptomatic benefit, but there are no data on safety and feasibility in this population. METHODS: A two-week, randomized, double blind, crossover phase Ib study was performed in advPD patients to compare standard-of-care (SoC) carbidopa/levodopa with PF-06412562, a selective D(1)/D(5) dopamine receptor partial agonist. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25+20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. RESULTS: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n=1, SoC: n=0), moderate (PF-06412562: n=1, SoC: n=1), or severe but non-serious (PF-06412562: n=3, SoC: n=2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians’ and four participants per caregivers’ rating. CONCLUSIONS: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs. TRIAL REGISTRATION#: ClinicalTrials.gov:NCT03665454