Daytime sleepiness and the COMT val158met polymorphism in patients with Parkinson disease.

STUDY OBJECTIVE: A preliminary study by our group suggested an association between daytime sleepiness and the catechol-O-methyltransferase (COMT) val158met polymorphism (rs4680) in patients with Parkinson disease (PD). We sought to confirm this association in a large group of patients with PD. DESIGN: Genetic association study in patients with PD. SETTING: Movement disorder sections at 2 university hospitals. PARTICIPANTS: PD patients with and without episodes of suddenly falling asleep matched for antiparkinsonian medication, disease duration, sex, and age, who participated in a previous genetic study on dopamine-receptor polymorphisms. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: In this study, 240 patients with PD (154 men; age 65.1 +/- 6.1 years; disease duration 9.4 +/- 6.0 years) were included. Seventy had the met-met (LL), 116 the met-val (LH), and 54 the val-val (HH) genotype. In the combined LL+LH group (featuring reduced COMT activity), the mean Epworth Sleepiness Scale (ESS) score was 9.0 +/- 5.9 versus 11.0 +/- 6.1 in the HH (high COMT activity) group (P = .047). Forty-seven percent of the LL and LH patients had sudden sleep onset compared with 61% of the HH patients (P = .07). Logistic regression, however, showed that both pathologic ESS scores (i.e., > 10) and sudden sleep onset were predicted by subjective disease severity (P < .001 each) but not by the COMT genotype. CONCLUSIONS: Our previous finding that the L-allele may be associated with daytime sleepiness could not be confirmed in the present study. Altogether, our data do not support a clinically relevant effect of the COMT genotype on daytime sleepiness in PD.

Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates.

Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

Troubles du contrôte des impulsions et maladie de Parkinson [Impulse control disorders and Parkinson's disease].

A variety of behavioral disorders occurring abruptly in patients with Parkinson's disease (PD) has been recently published and attracted considerable attention in the press. Taking the form of pathological gambling, compulsive shopping, addiction to Internet and to other recreational activities, hypersexuality or bulimia, impulse control disorders (ICD) related to PD are probably more frequent than previously appreciated and may have consequences as spectacular as disastrous for the involved patients. ICD are currently viewed as particular adverse reactions to antiparkinsonian medications, notably to dopamine agonists, and, accordingly, tend to improve or disappear when PD therapy is appropriately adjusted.

Dopaminergic modulation of grooming behavior in virgin and pregnant rats

Dopamine receptors are involved in the expression of grooming behavior. The pregnancy-induced increase in self-licking observed in rats is important for mammary gland development and lactation. This study focuses on the role of dopamine receptor subtypes in grooming behavior of virgin and pregnant female rats. General and mammary gland grooming were measured in virgin rats treated with 0.25 mg/kg of the D1-like agonist SKF-81297 and antagonist SKF-83566 and the D2-like agonist lisuride and antagonist sulpiride. The effects of 0.01 and 0.25 mg/kg doses of the same agonists and antagonists were evaluated in pregnant rats as well. In virgin animals both SKF-83566 and sulpiride treatments significantly reduced the time spent in general grooming, while none of the dopamine agonists was able to significantly change any parameter of general grooming. Time spent in grooming directed at the mammary glands was not affected significantly by any of the drug treatments in virgin rats. All drugs tested significantly decreased the frequency of and the time spent with general grooming, while SKF-81297 treatment alone did not significantly reduce the duration of mammary gland grooming in pregnant rats. These data show that in female rats the behavioral effects of D1-like and D2-like dopamine receptor stimulation and blockade differ according to physiological state. The results suggest that dopamine receptors may play specific roles modulating grooming behavior in pregnant rats. Since grooming of the mammary gland during pregnancy may influence lactation, this aspect is relevant for studies regarding the perinatal use of dopamine-related drugs.

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation) in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites.

Pharmacological analysis of 50 kHz vocalizations in the male rat

The production of 50 kHz ultrasonic vocalizations in rats has been associated with both positive social interactions and appetitive behavioural situations. Furthermore, there is significant evidence showing that these vocalizations are controlled by the meso-limbic dopamine system. The purpose of this study was to perform a pharmacological analysis of 50 kHz calls by using dopamine and two dopamine agonists amphetamine and apomorphine, to induce calls. The acoustic parameters of the different call types were compared across each agonist. All three agonists were able to significantly induce more 50 kHz vocalizations compared to the vehicle control. Furthermore, calls elicited by apomorphine had a significantly higher bandwidth compared to those elicited by dopamine and amphetamine. All three agonists also had significantly different pharmacokinetic properties. These observations suggest that the D2 receptor sub-type is involved in the length of call bandwidths.

Síndrome das pernas inquietas: Diagnóstico e tratamento. Opinião de especialistas Brasileiros

This article contains the conclusions of the November 17-18, 2006 meeting of the Brazilian Study Group of Restless Legs Syndrome (GBE-SPI) about diagnosis and management of restless legs syndrome (RLS). RLS is characterized by abnormal sensations mostly but not exclusively in the legs which worsen in the evening and are improved by motion of the affected body part. Its diagnosis is solely based on clinical findings. Therapeutic agents with efficacy supported by Class I studies are dopamine agonists, levodopa and gabapentine. Class II studies support the use of slow release valproic acid, clonazepan and oxycodone. The GBE-SPI recommendations for management of SPI are sleep hygiene, withdrawal of medications capable of worsening the condition, treatment of comorbidities and pharmacological agents. The first choice agents are dopaminergic drugs, second choice are gabapentine or oxycodone, and the third choice are clonazepan or slow release valproic acid.

Efeito das catecolaminas sobre a expansão volêmica sustentada e função renal em coelhos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Approach to the Patient with Persistent Hyperprolactinemia and Negative Sellar Imaging

Hyperprolactinemia is a common cause of menstrual disturbances affecting young women. There is a diversity of causes, from physiological, such as pregnancy, to pharmacological and pathological, such as hypothyroidism. Renal and hepatic failure, intercostal nerve stimulation by trauma or surgery, prolactinomas, other tumors in the hypothalamus-pituitary region, as well as macroprolactinemia can also be considered. Identifying the correct cause is important to establish the correct treatment. Should all these causes be ruled out and pituitary imaging revealed as negative, idiopathic hyperprolactinemia is therefore diagnosed. In symptomatic patients, treatment with dopaminergic agonists is indicated. As for the asymptomatic hyperprolactinemic individuals, macroprolactinemia should be screened, and once it is detected, there is no need for pituitary imaging study or for dopaminergic agonist use. (J Clin Endocrinol Metab 97: 2211-2216, 2012)

Attività autonomica cardiaca e funzioni neurocognitive nei pazienti affetti da sindrome delle gambe senza riposo (RLS): effetto dei farmaci dopamino agonisti in acuto e a lungo termine

Several studies showed that sleep loss/fragmentation may have a negative impact on cognitive performance, mood and autonomic activity. Specific neurocognitive domains, such as executive function (i.e.,prefrontal cortex), seems to be particularly vulnerable to sleep loss. Pearson et al.(2006) evaluated 16 RLS patients compared to controls by cognitive tests, including those particularly sensitive to prefrontal cortical (PFC) functioning and sleep loss. RLS patients showed significant deficits on two of the three PFC tests. It has been recently reported that RLS is associated with psychiatric manifestations. A high prevalence of depressive symptoms has been found in patients with RLS(Rothdach AJ et al., 2000). RLS could cause depression through its adverse influences on sleep and energy. On the other hand, symptoms of depression such as sleep deprivation, poor nutrition or lack of exercise may predispose an individual to the development of RLS. Moreover, depressed patients may amplify mild RLS, making occasional RLS symptoms appear to meet threshold criteria. The specific treatment of depression could be also implicated, since antidepressant compounds may worsen RLS and PLMD(Picchietti D et al., 2005; Damsa C et al., 2004). Interestingly, treatments used to relieve RLS symptoms (dopamine agonists) seem to have an antidepressant effects in RLS depressed patients(Saletu M et al., 2002&2003). During normal sleep there is a well-regulated pattern of the autonomic function, modulated by changes in sleep stages. It has been reported that chronic sleep deprivation is associated with cardiovascular events. In patients with sleep fragmentation increased number of arousals and increased cyclic alternating pattern rate is associated with an increase in sympathetic activity. It has been demonstrated that PLMS occurrence is associated with a shift to increased sympathetic activity without significant changes in cardiac parasympathetic activity (Sforza E et al., 2005). An increased association of RLS with hypertension and heart disease has been documented in several studies(Ulfberg J et al., 2001; Ohayon MM et al., 2002).

[Simultaneous defect of visual fields and loss of libido--a coincidence?]

We present the case of a 60 year old male patient with incidentally detected visual abnormalities. Detailed personal history revealed a hypogonadism that had been present for several years. Further investigations established the diagnosis of an infiltrative macroadenoma. Medical treatment with cabergoline led to a rapid regression of ophthalmologic symptoms and, subsequently, of tumor size. In male subjects symptoms of hypogonadism are often reported only late in the course of the disease, thereby leading to a generally larger tumor size at the point of diagnosis. In contrast to other pituitary tumors that are mainly treated by surgery, medical treatment with dopamine agonists is the principal therapeutic option in prolactinomas.

Actigraphic assessment of periodic leg movements in patients with restless legs syndrome.

The diagnosis of restless legs syndrome (RLS) relies upon diagnostic criteria which are based on history only, and dopaminergic treatment is not normally the first choice of treatment for all patients. It would be worthwhile to identify patients non-responsive to dopaminergic treatment beforehand, because they may suffer from a restless legs-like syndrome and may require alternative treatment. We included retrospectively 24 adult patients fulfilling the four essential criteria for restless legs and 12 age-matched healthy controls. They were investigated by ambulatory actigraphy from both legs over three nights, and patients started treatment with dopamine agonists after this diagnostic work-up. We examined 12 responders to dopaminergic treatment and 12 non-responders and studied the association between response to dopaminergic treatment and the periodic limb movement index (PLMI) as assessed with actigraphy. Demographic characteristics, excessive daytime sleepiness and fatigue at baseline were similar in all three groups. Baseline RLS severity was similar between responders and non-responders [International Restless Legs Severity Scale (IRLS): 25 ± 9 and 24 ± 8]. Group comparisons of PLMI before treatment initiation showed significant differences between the three groups. Post-hoc pairwise comparisons revealed that healthy controls had significantly lower PLMI (4.9 ± 4.5) than responders (29.3 ± 22.7) and non-responders (13.3 ± 11.2). Similarly, the PLMI in responders was lower than in non-responders. PLMI day-to-day variability did not differ between responders and non-responders and there was no correlation between treatment effect, as assessed by the decrease of the IRLS and baseline PLMI. Our retrospective study indicates that actigraphy to assess periodic limb movements may contribute to a better diagnosis of dopamine-responsive restless legs syndrome.

Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease

BACKGROUND: Dopamine agonists (DAs) represent the first-line treatment in restless legs syndrome (RLS); however, in the long term, a substantial proportion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for late DA withdrawal. Polysomnographic features and mechanisms underlining augmentation are unknown. No practice guidelines for management of augmentation are available. METHODS: A clinical case series of 24 consecutive outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA was performed. All patients underwent a full-night polysomnographic recording during augmentation. A switchover from immediate-release DAs (l-dopa, pramipexole, ropinirole, rotigotine) to the long-acting, extended-release formula of pramipexole was performed. RESULTS: Fifty percent of patients presented more than 15 periodic limb movements per hour of sleep during augmentation, showing longer sleep latency and shorter total sleep time than subjects without periodic limb movements. In all patients, resolution of augmentation was observed within two to four weeks during which immediate-release dopamine agonists could be completely withdrawn. Treatment efficacy of extended-release pramipexole has persisted, thus far, over a mean follow-up interval of 13 months. CONCLUSIONS: Pramipexole extended release could be an easy, safe, and fast pharmacological option to treat augmentation in patients with restless legs syndrome. As such it warrants further prospective and controlled investigations. This observation supports the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation.

Autonomic disturbances and cardiovascular reflexes in idiopathic Parkinson's disease

A total of 22 patients suffering from idiopathic Parkinson's disease and 20 age-matched volunteers were questioned about autonomic disturbances and all underwent four non-invasive tests examining cardiovascular reflexes. Significantly more autonomic disturbances were reported by the patients than by the controls. Resting blood pressure was significantly decreased in patients taking dopamine agonists, whereas it was normal in those patients who only received levodopa and anticholinergics. Resting heart rate and resting beat-to-beat variation were normal in the patients, as were the blood pressure response to standing and the postural heart rate response. No pathological response to the Valsalva manoeuvre could be detected. On the other hand, the heart rate variation evoked by deep breathing as well as the blood pressure response and the heart rate response to sustained isometric exercise were significantly diminished in the patients with idiopathic Parkinson's disease. These findings indicate a central disturbance of cardiovascular reflex control, whereas the corresponding peripheral pathways seem to be normal.

A model of increased impulsivity in rats with bilateral parkinsonism treated with Pramipexole

Impulse control disorders (ICD) is a common side effect of the dopaminergic treatment in patients with Parkinson's disease, which is more associated with dopamine agonists than with levodopa. To understand its pathophysiology, reliable animal models are essential. Using the variable delay-to-signal (VDS) paradigm, impulsivity was evaluated in bilateral parkinsonian rats treated with pramipexole (PPX). In this test, rats have to introduce the snout into a nose poke that is signaled by a light (presented at variable delays) triggering the delivery of a food reward after a correct response. Reaching a stable baseline performance, a partial bilateral dopaminergic lesion with 6-OHDA was induced in the dorsolateral striatum (AP: +1mm, L: ±3.4mm, V:-4.7 mm, Bregma). Rats undertook the VDS test under 5 conditions: basal state, 6-OHDA-induced lesion, the effect of two doses of PPX (0,25mg/kg and 3mg/kg; Latin-square design), and the day after the last dose of PPX. Only the acute administration of 3 mg/kg of PPX significantly rised the number of premature responses, indicating an increase of impulsive behavior, in parkinsonian but not in sham rats. Both doses of PPX significantly decreased the accuracy of responding (correct/total number of responses) and increased the incorrect and perseverative (compulsive behavior) responses in both parkinsonian and sham treated groups when compared with saline-treated groups. In conclusion, PPX induced attention deficit (lack of accuracy) as well as compulsive behavior in control and parkinsonian rats, but increased impulsivity only in the parkinsonian animals. This model could constitute a valid tool to investigate the pathophysiology of ICD.