Dopaminergic Link Research Articles

Restless legs syndrome in Korean patients with drug-naïve Parkinson's disease: A nation-wide study

BackgroundRestless legs syndrome is a common neurologic disorder, and there is increasing evidence for a dopaminergic link between Parkinson's disease and restless legs syndrome. However, most previous studies did not take into account the effects of dopaminergic medication. We conducted a nation-wide, cross-sectional study to determine the prevalence and clinical characteristics of restless legs syndrome in Korean drug-naïve Parkinson's disease patients. MethodsOne hundred and fifty-one drug-naïve patients with Parkinson's disease were enrolled from 18 centers in South Korea over the course of one year. Clinical profiles of parkinsonism, restless legs syndrome, psychiatric symptoms, and laboratory data were collected. The findings of subjects with and without restless legs syndrome were compared. ResultsThe prevalence of restless legs syndrome in drug-naïve patients with Parkinson's disease was 16.5%. Subjects with restless legs syndrome had a higher mean Hoehn and Yahr stage and more severe limb parkinsonism, especially tremor. There was, however, no difference in iron metabolism between patients with and without restless legs syndrome. Analysis demonstrated that Beck's depression inventory score was associated with the severity of restless legs syndrome. ConclusionOur study demonstrated an increased prevalence of restless leg syndrome in drug-naïve patients with Parkinson's disease than in the general population. Based on the association between parkinsonism and restless legs syndrome, and the unique characteristics of restless legs syndrome in patients with Parkinson's disease, we suggest that the pathophysiology of restless legs syndrome in Parkinson's disease differs from that in patients without Parkinson's disease.

Prevalence and clinical profile of restless legs syndrome in Parkinson's disease

Parkinson's disease (PD) and restless legs syndrome (RLS) have a dopaminergic link. More insight in the clinical profile of RLS in patients with PD may benefit our understanding of this link. The aims of this study were to evaluate the frequency and clinical profile of RLS in a large cohort of PD patients. In 269 nondemented Caucasian PD patients, the four diagnostic criteria for RLS were administered by a RLS trained researcher. In patients with definite RLS, the severity of these symptoms was assessed. Furthermore, in all patients, relevant motor and nonmotor symptoms in PD were evaluated. Definite RLS was present in 11% of the patients. RLS patients were more often female (69% vs. 32%, P < 0.001), but no other significant differences existed between PD patients with and without RLS. Within the PD patients with RLS, severity of RLS correlated positively with PD severity, motor fluctuations, depressive symptoms, daytime sleepiness, cognitive problems, autonomic symptoms, and psychotic symptoms. This study in a large PD cohort shows that prevalence of RLS is similar to that in the general population, which might be caused by underestimation of RLS due to dopaminergic treatment. No relations were found between the presence of RLS and PD symptoms, but the severity of RLS was related to the severity of PD-related, mainly nondopaminergic, symptoms. It is hypothesized that, nondopaminergic systems, such as the noradrenergic system may play a role in the possible link between PD and RLS.

Individual differences in agentic extraversion: Do they moderate executive functioning through the mesocorticolimbic dopamine system?

Event Abstract Back to Event Individual differences in agentic extraversion: Do they moderate executive functioning through the mesocorticolimbic dopamine system? Timo Berse1*, Jonathan Barenberg1 and Stephan Dutke1 1 University of Muenster, Psychological Institute V, Germany Influential working memory theories postulate a central executive component that monitors and coordinates task-specific processing modules (e.g. [1]). Attempts were made to specify central executive processes (e.g. [6]: updating, shifting, and inhibition). They are considered to be an important factor for learning (e.g. [7]). Neuroimaging studies suggest a brain network sensitive to executive demands consisting of regions in the prefrontal und parietal cortex (e.g. [4]). These structures are innervated by dopaminergic fibres from the mesocorticolimbic dopamine system with dopamine having a neuromodulatory behavior facilitating function [5]. In their psychobiological threshold model Depue and Collins [3] relate individual differences in functional properties of the mesocorticolimbic dopamine system to incentive motivation and the personality trait agentic extraversion encompassing dispositions such as being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals. Recent studies using dopamine challenge paradigms demonstrated an interaction of agentic extraversion and performance in tasks with executive demands (e.g. [8]) providing first evidence for a dopaminergic link between the two [2]. Therefore, we hypothesize that agentic extraversion moderates executive functioning through the mesocorticolimbic dopamine system. This might help to explain differential response to interventions that point at improving executive functions through physical exercise-induced changes in dopamine neurotransmission. Implications for further research and educational contexts will be discussed on the basis of current quasi-experimental studies conducted in our research group.

2.IS.2.3 Depression and Parkinson's disease – The dopaminergic link

2.IS.2.3 Depression and Parkinson's disease – The dopaminergic link

Evidence for a dopaminergic link between working memory and agentic extraversion: An analysis of load-related changes in EEG alpha 1 activity

Several lines of research point to the possibility of a partially overlapping dopaminergic foundation of the trait of agentic extraversion and individual differences in working memory functioning. This study investigates interactive effects of agentic extraversion and dopamine on spectral EEG measures of working memory. Using EEG activity in the alpha 1 band (8–10.25Hz) as a dependent variable, we tested in a randomized double-blind design the effects of the D2-dopamine antagonist sulpiride during the performance of four load-graded n-back working memory tasks in participants high versus low in agentic extraversion. We expected extraversion-related differences in the load-responsivity pattern to be reversed by sulpiride, and the alpha 1 anterior–posterior difference actually depicted this reversal effect. However, in contrast to our expectations this effect was largely due to parietal instead of frontal sites.

Potentiation of the effect of an anesthetic, chloral hydrate, by stress and corticosterone: a behavioral study in the mouse

Many studies have demonstrated that stressors can modify the physiological action of drugs, mainly morphine. The present study investigated the effects of a mild stressor on chloral hydrate (Chl)-induced sedation in mice. For 4 consecutive days, NaCl and Chl-treated mice (300 mg kg −1) were stressed (S) either by a 5 min exposure to a brightly lit inescapable open field, or i.p. injected with corticosterone (Cor) (15 mg kg −1). Then, their spontaneous motor activity was recorded on an actisystem during 20 min and compared with that of the unstressed (US) NaCl and Chl-treated mice. On day 1 and 4, neither stressor nor i.p. administered Cor had any influence on the spontaneous motor activity of NaCl-treated mice. In Chl-treated mice, the spontaneous motor activity was very low. On day 1, it was similar in S mice, Cor-injected mice, and US mice. On the contrary, on day 4, both stress and Cor enhanced the anesthetic-induced hypoactivity, showing that the magnitude of sedation increased. It can then be stated that stressor, provided it was repeatedly administered, potentiated the sedative action of chloral hydrate and that such a potentiation was probably, but not only, Cor-dependent. Given that stress and Chl both produce dopamine overflow, it can be hypothesized that S, potentiates the sedative action of Chl through a dopaminergic link.

Stimulation by nicotine of the spontaneous release of [ 3H]γ-aminobutyric acid in the substantia nigra and in the globus pallidus of the rat

The effect of (−)-nicotine on the spontaneous release of [ 3H]γ-aminobutyric acid ([ 3H]GABA) was studied in vitro in rat substantia nigra (SN) and globus pallidus (GP) slices. In both structures, nicotine (10 −4 M) elicited a transient increase of [ 3H]GABA release lasting no more than 2.5 min. At the peak of the effect, a 18.5% and 25% increase of [ 3H]GABA was observed in GP and SN slices, respectively. At lower concentration (10 −5 M), nicotine produced a small but significant transient increase (+8%) in GP slices whereas this concentration was ineffective in SN slices. Pempidine (10 −5 M) totally antagonized the 10 −4 M nicotine-induced effect in SN and GP. The increase of [ 3H]GABA release elicited by 10 −4 M nicotine was abolished when Ca 2+ concentration in the superfusion medium was lowered from 2.4 to 0.4 mM. To investigate a possible dopaminergic (DA) link in the response, we examined the sensitivity of the nicotine-induced effect to DA D 1 (SCH23390) and D 2 (sulpiride) receptor antagonists. In SN, SCH23390 (10 −6 M) abolished the 10 −4 M nicotine-induced effect. In GP, sulpiride (10 −5 M) failed to modify the response. Moreover, SCH23390 partially reversed the nicotine-induced effect (−37%) in GP. Taken together these results indicate that nicotine differentially modulate the [ 3H]GABA release in SN and GP. In SN, the nicotine-induced [ 3H]GABA release appears to be mediated by DA neurons. IN GP, only a part of the nicotinic response involved a DA link. A possible direct stimulation of nicotinic receptors localized on striato-pallidal terminals is discussed.

The role of reward pathways in the development of drug dependence

In commenting on the discovery of "opiate" receptors, Goldstein (1976) said: "It seemed unlikely, a priori, that such highly stereospecific receptors should have been developed by nature to interact with alkaloids from the opium poppy" (p. 1081). Endogenous opioid peptides and opioid receptor systems have now been identified in invertebrates that are unlikely to have had ancestors exposed to opium poppies (Kavaliers et al., 1983; Kream et al., 1980; Leung and Stefano, 1984; Stefano et al., 1980). Moreover, endogenous opioids play a role in stress-induced feeding in the slug (Kavaliers and Hirst, 1986) just as they play a role in stress-induced feeding in rodents (Lowy et al., 1980; Morley and Levine, 1980). If we are to understand the actions of opiates and other drugs of abuse we must understand them in terms of their abilities to interact with neural systems that evolved in the service of primitive biological functions, long before any serious incidence of addiction itself. The most primitive axes of the biological substrates of behavior are the axes of approach and withdrawal. Addictive drugs appear to be able to activate the mechanisms of approach, which is termed "positive reinforcement" and to inhibit the mechanisms of withdrawal, which is termed "negative reinforcement." Anatomically distinct sets of pathways have evolved to serve these two forms of reward. Activation of the medial forebrain bundle and associated structures serves positive reinforcement and induces forward locomotion. Approach and forward locomotion are the unconditioned responses to positive reinforcing stimuli such as food and sex partners, and approach to environmental objects and positive reinforcement is induced by electrical stimulation of this structure. The locomotor stimulating effects and the positive reinforcing effects of opiates and psychomotor stimulants result from their activation of this mechanism; stimulants activate the mechanism at the level of dopaminergic synapses of the nucleus accumbens, frontal cortex, and perhaps other forebrain structures, while opiates activate the system at two points: at the level of the dopaminergic synapse and at the level of the afferents to the dopaminergic cell bodies. Ethanol, nicotine, caffeine and phencyclidine stimulate both locomotor activity and dopamine turnover, but their sites of interaction with reward pathways have not yet been identified. Benzodiazepines and barbiturates stimulate locomotor activity without stimulating dopamine turnover; they may interact with reward pathways at a synapse efferent to the dopaminergic link in the pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

Action of drugs of abuse on brain reward systems: An update with specific attention to opiates

In addressing the role that the substrate of brain stimulation reward might play in drug abuse, Wise [47] reviewed evidence relating brain stimulation and psychomotor stimulant reward to dopaminergic but not noradrenergic elements identified with brain reward circuitry. He then speculated that one possible mechanism of opiate, ethanol, barbiturate or benzodiazepine reward might involve a specified disinhibition of the dopaminergic element. He suggested that these drugs might have inhibitory actions on locus coeruleus, which in turn might send an inhibitory projection to the dopaminergic link in reward circuitry. This speculation is challenged with respect to ethanol in the companion article [1] and with respect to opiates in the present article. Recent evidence indicates that the rewarding action of opiates is mediated in the region of the dopaminergic cells of the ventral tegmentum and not in the region of the noradrenergic cells of locus coeruleus. Rewarding opiate injections appear to activate the same or a similar dopaminergic link in brain reward circuitry as that thought to be activated through its afferent inputs in the case of brain stimulation reward and activated at its synaptic terminals in the case of psychomotor stimulant reward. Whether other drugs of abuse activate links in brain reward circuitry which function in parallel or in series with the dopaminergic link identified with opiates and stimulants remains an open question.

Inhibitory effects of substantia nigra on impulse transmission from nociceptors

In precollicularly decerebrated cats immobilized with Flaxedil (2 mg/kg, i.v.), a dopamine mechanism played a role in the inhibition produced by brain stem stimulation of nociceptive activated cells in the spinal cord. Lamina V cell activity evoked by natural stimulation (pinch not touch) to the left hind limb or electrical stimulation (0.1 msec pulses at 1/sec) to the left sural nerve exposed at the popliteal fossa was recorded at levels L 6 and L 7. Brain stimulation consisted of 100 msec trains of either single rectangular pulses or 3 pulses/sec for 1 min. The stimulation was delivered to substantia nigra, periaqueductal gray (PAG) and dorsal raphe nucleus via concentric bipolar electrodes. Descending inhibition of the late burst of lamina V cell discharge elicited by mechanical pinch or sural shock could be demonstrated following individual stimulation of the 3 brain stem sites. Nigral-induced inhibition was abolished by injecting tetrabenazine (40 mg/kg, i.v.) or bulbocapnine (20 mg/kg, i.v.); the inhibition was re-established by L-DOPA (20 mg/kg, i.v.) or apomorphine (20 mg/kg, i.v.) indicating that a dopaminergic link has access to the descending inhibitory action on segmental transmission of “pain” impulses. Both nigral and PAG actions were sensitive to methysergide (1 mg/kg, i.v.), while the serotonergic blockade could be overcome by 5-hydroxytryptamine (70 mg/kg, i.v.). We proposed that nigral and PAG actions were relayed in part through the descending raphe system. Through this relay, they exhibit their antinociceptive effects.

Evidence for a possible dopaminergic link in the action of acetylcholine in the rat substantia nigra

The activity of the rat nigro-striatal dopaminergic system has been studied after unilateral injections of hemicholinium-3[HC-3] or carbachol into the substantia nigra zona reticulata. HC-3 produced intense contralateral turning which was antagonized by haloperidol. The dopamine (DA) concentration was reduced and the homovanillic acid (HVA) concentration was increased in the ipsilateral striatum, indicating that removal of the effect of acetylcholine (ACh) from the nigra leads to activation of the nigro-striatal DA pathway. Conversely carbachol produced ipsilateral circling with increased DA concentration and reduced HVA concentration in the ipsilateral striatum. The action of carbachol was antagonized if α-flupenthixol (α-FP) but not β-flupenthixol (β-FP) was added to the carbachol injection solution. This observation suggests that the action of ACh may be mediated by way of an inhibitory DA system. A tentative hypothesis is proposed to explain these observations.