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1.
Neurochemical features of idiopathic restless legs syndrome.
Jiménez-Jiménez, FJ, Alonso-Navarro, H, García-Martín, E, Agúndez, JAG
Sleep medicine reviews. 2019;:70-87
Abstract
The most important traditional hypotheses of the pathogenesis of idiopathic restless legs syndrome (iRLS) involve dopaminergic dysfunction and iron deficiency. However, a possible role of other neurotransmitter or neuromodulators, mainly glutamate, gamma-hydroxybutyric acid (GABA), and adenosine have been suggested in recent reports. Moreover, iron deficiency in experimental models (which causes sensorimotor symptoms resembling those of RLS) is able to induce changes in dopaminergic, glutamatergic and adenosinergic neurotransmission, thus suggesting its crucial role in the pathogenesis of this disease. Relationship between iRLS and opiates, oxidative stress and nitric oxide, and with vitamin D deficiency has also been reported, although data regarding these variables should be considered as preliminary. In this review, we focus on studies relating to neurochemical findings in iRLS.
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2.
Mean Diffusivity in the Dopaminergic System and Neural Differences Related to Dopaminergic System.
Takeuchi, H, Kawashima, R
Current neuropharmacology. 2018;(4):460-474
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Abstract
BACKGROUND The mean diffusivity (MD) parameter obtained by diffusion tensor imaging provides a measure of how freely water molecules move in brain tissue. Greater tissue density conferred by closely arrayed cellular structures is assumed to lower MD by inhibiting the free diffusion of water molecules. METHODS In this paper, we review studies showing MD variation among regions of the brain dopaminergic system (MDDS), especially subcortical structures such as the putamen, caudate nucleus, and globus pallidus, in different conditions with known associations to dopaminergic system function or dysfunction. The methodologies and background related to MD and MDDS are also discussed. RESULTS Past studies indicate that MDDS is sensitive to pathological derangement of dopaminergic activity, neural changes caused by cognitive and pharmacological interventions that are known to affect the dopaminergic system, and individual character traits related to dopaminergic function. CONCLUSION These results suggest that MDDS can be one useful tool to tap the neural differences related to the dopaminergic system.
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3.
THE RESTLESS LEGS SYNDROME (REVIEW).
Japaridze, G, Kasradze, S, Maisuradze, L, Popp, R, Wetter, T
Georgian medical news. 2018;(285):74-81
Abstract
The restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common sleep related neurological disorder with prevalence between 1 and 10%, increasing with age. Women are more frequently affected than men. RLS is characterized by an urge to move the legs accompanied by uncomfortable and unpleasant sensations in the legs, worsening of complaints during periods of rest, improvement by movement and an increase of symptoms in the evening or at night. In addition, affected patients may also suffer from severe sleep disorders and negative effects on daily activities. There is often a history of RLS among first-degree relatives, especially with the primary form. Among other, comorbidities or causal factors are iron deficiency, terminal renal insufficiency, pregnancy, polyneuropathy, or psychotropic drugs. The etiology of primary (idiopathic) RLS has not been clarified yet; however, genetic factors and dysfunctional dopaminergic neurotransmission as well as alterations of central iron metabolism play an important role. In addition to non-pharmacological treatment such as lifestyle modifications or behavioral strategies, levodopa, dopamine agonists, or anticonvulsants are effective. Opioids may be used in otherwise refractory forms. In the case of secondary or comorbid RLS, treatment of the underlying disease is necessary.
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4.
Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.
Kaasinen, V, Vahlberg, T
Annals of neurology. 2017;(6):873-882
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Abstract
A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882.
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Dopamine dysregulation syndrome in Parkinson's disease: a systematic review of published cases.
Warren, N, O'Gorman, C, Lehn, A, Siskind, D
Journal of neurology, neurosurgery, and psychiatry. 2017;(12):1060-1064
Abstract
OBJECTIVES Dopamine dysregulation syndrome (DDS) is an uncommon complication of the treatment of Parkinson's disease, characterised by addictive behaviour and excessive use of dopaminergic medication. DDS may frequently go unrecognised or misdiagnosed. We aimed to clarify current understanding of presentation, risk factors, comorbidities and management of DDS. METHODS Case reports were identified through a systematic search of databases (PubMed, Embase) with the following terms: dopaminergic dysregulation syndrome, hedonistic homeostatic dysregulation, dopamine/levodopa addiction. RESULTS We reviewed 390 articles, identifying 98 cases of DDS. Early-onset Parkinson's disease (67%) and male gender (83%) were common. DDS presented with significant physical and social impairment, actions to enable or prevent detection of overuse, as well as mood, anxiety and motor fluctuations. All DDS cases met DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) substance use disorder criteria. Past substance and psychiatric history was present in 15.3% and 10.2% of cases. Comorbid impulse control disorders (61%), psychosis (32%) and panic attacks (14%) were common. A large variety of management strategies were used; only 56% of cases resolving. Sodium valproate was successful in 5/5 cases. The response to deep brain stimulation varied. CONCLUSIONS Given the functional impairment, medical and psychiatric consequences and the difficulties of treatment, early identification of DDS should be a priority.
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Human Laboratory Studies on Cannabinoids and Psychosis.
Sherif, M, Radhakrishnan, R, D'Souza, DC, Ranganathan, M
Biological psychiatry. 2016;(7):526-38
Abstract
Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids.
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[Nicotine and caffeine: influence on dopaminergic transmission].
Napierała, M, Bogusiewicz, J, Enko, J, Florek, E
Przeglad lekarski. 2016;(10):791-4
Abstract
Dopamine plays an important role in the neuronal regulation of motivation / reward, voluntary movements, cognitive processes and the process of addiction. Disorders of the production and release of dopamine can be the base of the pathomechanism of many diseases. Both nicotine and caffeine are psychomotor stimulants. Caffeine, through inhibition of adenosine, increases the activity of the dopaminergic system, and it shows the reinforcing and the psychomotor effect. Nicotine gets its reinforcing and psychostimulant effects from blocking dopamine uptake and increasing synaptic dopamine release. Nicotine and caffeine affect the release of the dopamine. It is believed that the interaction of these substances may be a synergistic effect on pain perception, voluntary movement functions or behavioral traits.
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Catechol-O-methyltransferase, dopamine, and sleep-wake regulation.
Dauvilliers, Y, Tafti, M, Landolt, HP
Sleep medicine reviews. 2015;:47-53
Abstract
Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsy-cataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants.
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9.
Somatodendritic dopamine release: recent mechanistic insights.
Rice, ME, Patel, JC
Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2015;(1672)
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Abstract
Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K(+) channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca(2+) dependence of release and the potential role of exocytotic proteins.
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Targeting the glutamatergic system to treat pathological gambling: current evidence and future perspectives.
Pettorruso, M, De Risio, L, Martinotti, G, Di Nicola, M, Ruggeri, F, Conte, G, Di Giannantonio, M, Janiri, L
BioMed research international. 2014;:109786
Abstract
Pathological gambling or gambling disorder has been defined by the DSM-5 as a behavioral addiction. To date, its pathophysiology is not completely understood and there is no FDA-approved treatment for gambling disorders. Glutamate is the principal excitatory neurotransmitter in the nervous system and it has been recently involved in the pathophysiology of addictive behaviors. In this paper, we review the current literature on a class of drugs that act as modulating glutamate system in PG. A total of 19 studies have been included, according to inclusion and exclusion criteria. Clinical trial and case series using glutamatergic drugs (N-acetylcysteine, memantine, amantadine, topiramate, acamprosate, baclofen, gabapentin, pregabalin, and modafinil) will be presented to elucidate the effectiveness on gambling behaviors and on the related clinical dimensions (craving, withdrawal, and cognitive symptoms) in PG patients. The results have been discussed to gain more insight in the pathophysiology and treatment of PG. In conclusion, manipulation of glutamatergic neurotransmission appears to be promising in developing improved therapeutic agents for the treatment of gambling disorders. Further studies are required. Finally, we propose future directions and challenges in this research area.