Dopaminergic Agonist Treatment Research Articles

A rare case of silent pituitary macroadenoma with positive TSH and prolactin immunostaining

Silent thyroid stimulating hormone (TSH)-immunostaining pituitary adenomas are rare tumors, they can be either pure or immunoreactive to other pituitary hormones. We report a case of a silent macroadenoma with both TSH and prolactin immunostaining but with no clinical manifestations of hyperthyroidism or hyperprolactinemia. Pituitary magnetic resonance imaging revealed a macroadenoma. Transsphenoidal surgery was incomplete. The immunohistochemical staining showed that tumor cells were reactive to TSH (60%) and to prolactin (40%). Control pituitary imaging revealed a residual macroadenoma, and dopaminergic agonist treatment was administered. Mixed TSH and prolactin pituitary adenomas are rare and usually diagnosed incidentally or in the face of compression signs. Hormonal examinations for all patients who have a pituitary adenoma should be performed even in the absence of symptoms of hypersecretion. Pathological examination with immunostaining is key to diagnosis of clinically silent pituitary adenomas. Complementary therapies can be used when surgery is incomplete or contraindicated such as dopamine agonists and somatostatin analogs.

Impulse control symptoms in patients with Parkinson's disease: The influence of dopaminergic agonist

BackgroundImpulse control disorders and punding are common in Parkinson's disease patients. Cross-sectional studies suggest an association between dopamine replacement therapy, especially dopaminergic agonists, and impulse control and related disorders in Parkinson's disease. However, some surveys suggest that Parkinson's disease itself does not confer an altered risk for impulse control disorders and related behavior, although these disturbances are more frequently reported in Parkinsonian patients than in healthy controls. ObjectiveTo ascertain the frequency of impulse control disorders and punding symptoms in Parkinson's disease patients and healthy controls and to determine the influence of dopamine agonist treatment on the prevalence of these disturbances. MethodsA case-control study was conducted on 207 Parkinson's disease patients (79 taking dopamine agonists) and 230 healthy controls. The outcome measures were the presence of current impulse control disorders and punding symptoms, based on clinical criteria after application of the Minnesota Impulsive Disorders Interview for screening. ResultsThe frequency of impulse control disorders in Parkinson's disease patients vs. Healthy controls was 16.9% vs. 15.2% (p = 0.631). Punding was more frequent in Parkinson's disease patients (p = 0.028); however, impulse control disorders were more frequent in medicated Parkinson's disease patients taking dopamine agonists than in medicated patients not taking dopamine agonists (p = 0.001) and healthy controls (p = 0.014). ConclusionsParkinson's disease itself does not lead to the development of impulse control disorders. Dopaminergic agonist treatment may trigger the disorder in susceptible individuals. Punding may be more prevalent in Parkinson's disease patients.

Punding in Parkinson's disease: To a better understanding of a common phenomenon between Parkinson's disease and addictions

IntroductionPunding is a stereotypical motor behaviour characterized by a repetitive, excessive and non-goal oriented activity that causes an important loss of time. Since its first description in psychostimulant addicts, data on punding has only derived from studies on Parkinsonian patients treated with dopaminergic drugs. Little is known in the literature about Parkinsonian patient's characteristics who suffer from punding.ObjectiveWe propose to study characteristics of Parkinsonian “punders” in order to investigate the pathophysiology of this phenomenon.MethodsIn this retrospective study, we use the “Ardouin Scale of Behavior in Parkinson's disease” database. This database was initially used to design a global scale to detect changes in mood and behavior of Parkinson's disease (PD) patients. We compared different variables between Parkinsonian patients who suffer from punding with non-punder Parkinsonian patients.ResultsEighty of the 258 patients were identified as punders. In univariate analysis, the punder and non-punder groups differed statistically with regard to the age of diagnostic of PD, hypersexuality and dopaminergic agonist treatment. In multivariate analysis, the punder and non-punder groups only differed statistically with regard to dopaminergic agonist treatment (P = 0.05).ConclusionDopaminergic agonist treatments appear to be more represented among patients with punding in our sample. Impulse control disorders (ICD) are known to be more common in patients treated by dopamine agonists. Punding could be considered as the most severe form of ICD that is linked to psychomotor stimulation and reward mechanisms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Restless leg syndrome in patients with spinal cord injury

BackgroundThe presence of restless leg syndrome (RLS) in patients with spinal cord injury (SCI) is not well established. We studied the frequency and severity of RLS in a population of patients with SCI and the effect of treatment with dopaminergic drugs when clinically indicated. MethodsConsecutive patients with SCI admitted to an out-patient clinic of a neurorehabilitation hospital (n:195) were evaluated for the presence of RLS between February 2013 and May 2014. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS rating scale. Information on gender, age, time since SCI, level and severity of SCI, was obtained. ResultThe mean age was 54.7 ± 15.6 years (range: 22–81 year); with time since SCI: 16.9 ± 11.4 years (range: 1–50 years). Thirty-five of 195 patients (17.9%) presented RLS. Twenty-two out of 154 (14.3%) patients with cervicothoracic SCI and 13 out of 41 (31.7%) patients with lumbosacral SCI presented RLS. Restless leg symptoms were mild in 2 patients, moderate in 10 patients, severe in 12 patients and very severe in 11. Ten patients received dopaminergic agonist treatment with a significant reduction in RLS severity scale from 29.1 ± 5.9 to 10.2 ± 7.9. DiscussionRLS occurs frequently in SCI patients and responds to dopaminergic treatment. Physicians have to be aware of this diagnosis to avoid unnecessary suffering in this patient population.

Restless legs syndrome in patients with sequelae of poliomyelitis.

No studies have examined the association between RLS and the sequelae of poliomyelitis (PM). We studied the frequency and severity of RLS in a group of consecutive patients with the sequelae of poliomyelitis (PM) and the effect of treatment with dopaminergic drugs. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS rating scale. Information on sex, age, age at onset, site affected by PM, disease duration of PM, and history of post-polio syndrome (pPS) was obtained in a cohort of 52 PM patients. The mean age was 55.9 ± 6.5 years; 39 patients had post-polio syndrome (75%). RLS was diagnosed in 21 (40.4%) patients. Sixteen of the 21 patients (76.2%) with RLS had pPS, which was similar to the non-RLS group (74.2% patients with pPS). RLS symptoms were very severe in 5 patients, severe in 13, moderate in 2 and mild in 1. Nineteen of the 21 patients with RLS had symptoms predominantly in the more affected lower limb (90% of patients). Sixteen patients received dopaminergic agonist treatment with a significant reduction in their scores on the RLS severity scale from 28.3 ± 4.7 to 6.9 ± 7.3 (p < 0.001). RLS occurs frequently in patients with PM, both in those with and without pPS, and responds well to treatment with dopaminergic drugs.

Circadian Perinatal Photoperiod Has Enduring Effects on Retinal Dopamine and Visual Function

Visual system development depends on neural activity, driven by intrinsic and light-sensitive mechanisms. Here, we examined the effects on retinal function due to exposure to summer- and winter-like circadian light cycles during development and adulthood. Retinal light responses, visual behaviors, dopamine content, retinal morphology, and gene expression were assessed in mice reared in seasonal photoperiods consisting of light/dark cycles of 8:16, 16:8, and 12:12 h, respectively. Mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity, but only transient changes were observed for scotopic measures. Dopamine levels were significantly lower in short photoperiod mice, and dopaminergic agonist treatment rescued the photopic light response deficits. Tyrosine hydroxylase and Early Growth Response factor-1 mRNA expression were reduced in short photoperiod retinas. Therefore, seasonal light cycles experienced during retinal development and maturation have lasting influence on retinal and visual function, likely through developmental programming of retinal dopamine.

Spontaneously Hypertensive Rats: Possible Animal Model of Sleep-Related Movement Disorders

ABSTRACT Clinical experience suggests that restless legs syndrome (RLS), periodic leg movement (PLM), and attention-deficit hyperactivity disorder (ADHD) may co-occur in both children and adults. The purpose of the present study was to provide an electrocorticography and electromyography evaluation of the spontaneously hypertensive rat (SHR) to investigate the potential of this rat strain as an animal model of RLS–PLM. Initial work focused on evaluating sleep patterns and limb movements during sleep in SHR, having normotensive Wistar rats (NWR) as control, followed by comparison of two treatments (pharmacological–dopaminergic agonist treatment and nonpharmacological–chronic physical exercise), known to be clinically beneficial for sleep-related movement disorders. The captured data strengthen the association between SHR and RLS–PLM, revealing a significant reduction on sleep efficiency and slow wave sleep and an increase on wakefulness and limb movements for the SHR group during the dark period, as compared to the NWR group, effects that have characteristics that are strikingly consistent with RLS–PLM. The pharmacological and nonpharmacological manipulations validated these results. The present findings suggest that the SHR may be a useful putative animal model to study sleep-related movement disorders mechanisms.

Secondary deterioration of visual field during cabergoline treatment for macroprolactinoma

During dopaminergic agonist treatment for macroprolactinoma, tumour shrinkage can be accompanied by secondary deterioration of the visual field in rare instances. The aim of the present study was to evaluate the incidence of symptomatic or asymptomatic delayed visual loss associated with chiasmal herniation during long-term cabergoline treatment of macroprolactinomas and to report our experience of its management. The study included 28 patients (11 women and 17 men) aged 14-85 years treated for macroprolactinoma with cabergoline at our centre from 1997 to 2006. Chiasmal herniation was observed at MRI in five out of the 28 cases. A systematic visual field evaluation revealed visual field worsening, during cabergoline treatment, in three out of these five patients. In two asymptomatic patients, secondary deterioration of visual field occurred 2.5 years and 4 years, respectively, after cabergoline treatment initiation. In the third case, cabergoline treatment resulted in a paradoxical worsening of an initial visual defect. In all three cases, visual fields improved after cabergoline withdrawal although chiasmal herniation persisted. Visual field remained normal in the two other patients. Our results suggested that chiasmal herniation associated with delayed visual field defect is not a rare feature during cabergoline treatment of macroprolactinomas. It should be assessed by systematic visual field evaluation and treated by adaptation of medical treatment.

Alpha‐synuclein aggregation and cell death triggered by energy deprivation and dopamine overload are counteracted by D2/D3 receptor activation

Progressive degeneration and intraneuronal Lewy bodies made of filamentous alpha-synuclein (alpha-syn) in dopaminergic cells of the nigrostriatal system are characteristics of Parkinson's disease (PD). Glucose uptake is reduced in some of the brain regions affected by PD neurodegenerative changes. Defects in mitochondrial activity in the substantia nigra have been observed in the brain of patients affected by PD and substantia nigra lesions can induce the onset of a secondary parkinsonism. Thus, energy starvation and consequently metabolic impairment to dopaminergic neurons may be related to the onset of PD. On this line, we evaluated the effect of nutrient starvation, reproduced 'in vitro' by glucose deprivation (GD), in primary mesecephalic neuronal cultures and dopaminergic-differentiated SH-SY5Y cells, to evaluate if decreased glucose support to dopaminergic cells can lead to mitochondrial damage, neurodegeneration and alpha-syn misfolding. Furthermore, we investigated the effect of dopamine (DA) treatment in the presence of a DA-uptake inhibitor or of the D(2)/D(3) receptor (D(2)R/D(3)R) agonist quinpirole on GD-treated cells, to evaluate the efficacy of these therapeutic compounds. We found that GD induced the formation of fibrillary aggregated alpha-syn inclusions containing the DA transporter in dopaminergic cells. These alterations were accompanied by dopaminergic cell death and were exacerbated by DA overload. Conversely, the block of DA uptake and D(2)R/D(3)R agonist treatment exerted neuroprotective effects. These data indicate that glucose starvation is likely involved in the induction of PD-related pathological changes in dopaminergic neurons. These changes may be counteracted by the block of DA uptake and by dopaminergic agonist treatment.

Effects of the dopamine agonist piribedil on prefrontal temporal cortical network function in normal aging as assessed by verbal fluency

Normal aging has been associated with impaired performance in verbal fluency suggesting a prefrontal temporal cortical network (PFTCN) deficiency. In this study, we investigated the effects of a 2-month treatment period with a dopaminergic agonist (DA) on PFTCN function. Forty healthy, elderly volunteers were assessed on semantic and phonemic verbal fluency after two months of a placebo or a DA treatment (i.e. piribedil 50 mg/day) in a double-blind crossover design. Protocols were scored considering clustering, (i.e. production of words within semantic or phonemic categories, depending on the integrity of temporal lobe), and switching (i.e. the ability to shift between clusters, depending on frontal lobe functioning). Results revealed no significant main effect of the DA treatment on either verbal fluency variables but showed a significant interaction with working memory capacities, with high-capacity span subjects improving phonemic switching on DA whereas low-capacity span subjects performed more poorly on the drug than off. These data are consistent with the literature and confirm the crucial link between working memory capacities and dopamine agonist effects. The present study also provides evidence that pharmacological remediation of age-related cognitive decline has to be taken into consideration.

Dopamine-Dependent Desensitization of Dopaminergic Signaling in the Developing Mouse Striatum

The dynamics of dopamine receptor signaling efficacy were characterized in developing mice by measuring striatal c-Fos expression after dopaminergic agonist treatment at postnatal day 4 (P4) to P18. Control mice and mutant mice, in which dopamine production is inactivated in dopaminergic neurons by gene targeting, were treated with saline; a synthetic dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA) methyl ester; a direct dopamine D(1) receptor agonist, N-allyl-SKF 38393; or a dopamine reuptake inhibitor, cocaine. L-DOPA methyl ester treatment failed to induce striatal c-Fos immunoreactivity in control and mutant mice deficient in dopamine production at P4 and P6 compared with saline treatment. However, at P10 through P18 it induced abundant c-Fos expression in mutants. At these later stages, c-Fos expression remained at basal levels in control mice after L-DOPA methyl ester treatment. Control and mutant mice responded to D1 receptor agonist administration to a similar degree at P4 and P6, but the responses were greatly enhanced in mutants at later stages. Cocaine treatment elicited expression in control mice at P10 through P18 but not at P4 and P6. Mutant mice were largely unresponsive to cocaine treatment. The results suggest that striatal dopamine receptors are capable of transducing extracellular signals at P4 and P6, but dopaminergic neurotransmission begins thereafter. Dopaminoceptive neurons appear to reduce their sensitivity to dopamine as dopaminergic terminals innervate the striatum and functional neurotransmission begins.

Restoration of brain protein synthesis in mature and aged rats by a DA agonist, piribedil.

Brain ageing affects numerous cerebral metabolic pathways such as cerebral glucose consumption or protein synthesis rate. The pharmacological effect of a mixed D1-D2 dopaminergic agonist, piribedil, on this last metabolism is reported. Cerebral Protein Synthesis Rate (CPSR) was measured by the [35S]L-methionine autoradiographic procedure in 38 main brain regions of 11 and 26-month-old Wistar rats after a 2-month treatment per os at 9 and 30 mg/kg/day with piribedil. Mean decrease of CPSR was -21% during the 15-month ageing we followed, with important local variations. Mean CPSR increased with the two treatments, +25% in mature and +35% in aged rats. Treatments restored CPSR of aged rats to the exact mature subjects levels in quite all the brain regions. No dose-effect or asymetrical modification was statistically revealed for the two treatments. Metabolic increases involved particularly central brain gray structures, especially some DA-targeted brain nuclei concerned with behaviour and learning. This effect argued for a general metabotrophic effect of D1-D2 dopamine stimulation of the brain. The original pattern of local ageing of brain protein synthesis in rat was also incidentally reported. This was the first direct report of a wide and effective metabolic activation of CPSR in the brain during ageing by a curative dopaminergic agonist treatment.

Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy

We studied mitochondrial respiratory chain function in skeletal muscle taken from 27 patients with idiopathic Parkinson's disease (PD; 21 Dopa-treated PD patients and 6 de novo patients), 5 patients with multiple system atrophy (MSA) and from 43 age-matched controls in order to determine the occurrence of mitochondrial respiratory chain abnormalities in parkinsonian syndromes. In our control subjects, we found a significant age-related decrease in the activity of respiratory chain complex I. As compared to carefully age-matched control subjects, activity of complex (NADH: ubiquinone reductase) was significantly lower in muscle mitochondria from patients with PD and MSA and a mean remaining activity < 30% of controls was observed. Mean activities of complexes III (ubiquinol:cytochrome c reductase) and IV (cytochrome c oxidase) were also lower in PD patients than controls, but a low activity (remaining activity < 30% of controls) was observed in only 5 PD patients for complex I and III or I and IV. No deficit in complex II activity (succinate: ubiquinone reductase) was observed. Our results support the hypothesis of a wide-spread mitochondrial complex I deficiency in PD and MSA as compared to age-matched controls, who showed age-related deficiency. This deficit can be found in de novo PD patients as well as in treated patients. The observed respiratory enzyme chain deficiency could not be explained by the dose and duration of l-Dopa or dopaminergic agonist treatment, the severity of the disease, anxiety or depression since no significant correlation was found between these parameters and enzyme complexes activities.