Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.
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PMID:Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers. 1869 Jan 17

Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment. Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood, but brain dopamine systems have been implicated. Here, we test whether one night of sleep deprivation changes dopamine brain activity. We studied 15 healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/D3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects were tested twice: after one night of rested sleep and after one night of sleep deprivation. The specific binding of [11C]raclopride in the striatum and thalamus were significantly reduced after sleep deprivation and the magnitude of this reduction correlated with increases in fatigue (tiredness and sleepiness) and with deterioration in cognitive performance (visual attention and working memory). In contrast, sleep deprivation did not affect the specific binding of [11C]cocaine in the striatum. Because [11C]raclopride competes with endogenous dopamine for binding to D2/D3 receptors, we interpret the decreases in binding to reflect dopamine increases with sleep deprivation. However, we cannot rule out the possibility that decreased [11C]raclopride binding reflects decreases in receptor levels or affinity. Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment.
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PMID:Sleep deprivation decreases binding of [11C]raclopride to dopamine D2/D3 receptors in the human brain. 1871 3

There is growing evidence that hepatitis C virus (HCV)-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy fatigue persists in about one third of the patients. Many patients, in addition, report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning ability as characteristic for HCV-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebral serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilisation compatible with alterations of the dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in lymphoid tissue. Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain (probably in microglia) and to infect brain cells, especially astrocytes.
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PMID:Hepatitis C virus infection and the brain. 1913 Jan 96

Patients with hepatitis C virus (HCV) infection frequently show neuropsychiatric symptoms. This study aims to help clarify the neurochemical mechanisms behind these symptoms and to add further proof to the hypothesis that HCV may affect brain function. Therefore, 15 patients who reported increasing chronic fatigue, mood alterations, and/or cognitive decline since their HCV infection underwent neurologic and neuropsychological examination, magnetic resonance imaging, (18)F-fluoro-deoxy-glucose positron emission tomography of the brain, and single photon emission tomography of striatal dopamine and midbrain serotonin transporter (SERT) availability. None of the patients had liver cirrhosis. Patients' data were compared with data of age-matched controls. In addition, regression analysis was performed between cognitive deficits, and mood and fatigue scores as dependent variables, and cerebral glucose metabolism, dopamine, or SERT availability as predictors. Patients showed significant cognitive deficits, significantly decreased striatal dopamine and midbrain SERT availability, and significantly reduced glucose metabolism in the limbic association cortex, and in the frontal, parietal, and superior temporal cortices, all of which correlated with dopamine transporter availability and psychometric results. Thus, the study provides further evidence of central nervous system affection in HCV-afflicted patients with neuropsychiatric symptoms. Data indicate alteration of dopaminergic neurotransmission as a possible mechanism of cognitive decline.
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PMID:Cerebral glucose utilisation in hepatitis C virus infection-associated encephalopathy. 2162 58

Whether dopamine (DA) release is compensated during the presymptomatic phase of Parkinson's disease (PD) is controversial. Here we use in vivo voltammetry in the parkinsonian rat and an electrical stimulation protocol established to fatigue nigrostriatal dopaminergic (DAergic) neurons to investigate the plasticity of DA-release mechanisms. Amplitudes of evoked voltammetric signals recorded in intact rat striata decreased with repetitive, high-frequency stimulation (60 Hz, every 5 min/60 min). Strikingly, DA levels were maintained during an identical "fatiguing" protocol in 6-hydroxydopamine-lesioned (<40% denervation) striata in the absence of enhanced DA synthesis. In contrast, more severely lesioned striata (>55% denervation) also appeared to sustain DA release, however, this was demonstrated in the presence of enhanced synthesis. Sustained release was replicated in intact animals after irreversible blockade of the dopamine transporter (DAT) via RTI-76, implicating neuronal uptake as a trigger. We further demonstrate through kinetic analysis that lesions and compromised uptake target a "long-term" (time constant of minutes) presynaptic depression, which underlies the maintenance of release. Taken together, our findings identify a denervation-induced maintenance of DA release that was independent of activated synthesis and driven by altered uptake. This novel neuroadaptation may contribute to early preclinical normalization of function and help resolve discrepant findings regarding compensatory changes in DA release during progression of the parkinsonian state.
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PMID:Functional reorganization of the presynaptic dopaminergic terminal in parkinsonism. 2178 43

Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons associated with intracellular Lewy inclusion bodies. The result is poverty of movement, increased muscle rigidity, and tremor at rest and on posture. Midbrain/nigral structural abnormalities can be demonstrated in vivo with both transcranial sonography (TCS) and diffusion tensor magnetic resonance imaging (DTI) while positron emission tomography (PET) and single photon emission computed tomography (SPECT) ligands exist to demonstrate dopamine terminal dysfunction. These radiotracers are markers of dopamine storage capacity, vesicular monoamine and dopamine transporter availability. While loss of putamen dopaminergic function leads to motor disability, Lewy bodies not only target dopamine neurons but have also been observed in serotoninergic, noradrenergic, and cholinergic neurons. As a consequence, non-dopaminergic neurotransmission is also impaired resulting in non-motor symptoms including sleep disturbance, fatigue, depression, dementia, and autonomic dysfunction. PET and SPECT ligands exist to interrogate the function of monoaminergic and cholinergic neurons. Cortical and limbic Lewy body disease is seen in more advanced PD and this can be detected with FDG PET as abnormal covariance between levels of resting brain metabolism in these regions. Additionally, widespread microglial activation can be detected in PD with PET. This review discusses the role of structural and functional imaging for understanding parkinsonian syndromes and aiding in their diagnosis and management.
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PMID:Imaging biomarkers in Parkinson's disease. 2189 6

Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o-methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary.
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PMID:Dopaminergic polymorphisms associated with time-on-task declines and fatigue in the Psychomotor Vigilance Test. 2243 94

Parkinson's disease (PD) affects about 1 % of the population over the age of 60 years and is characterized by a combination of rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait (FoG). However, the clinical spectrum also spans a wide range of non-motor symptoms, such as depression, apathy, cognitive disorders, sleepiness, fatigue and pain. Given that the loss of dopamine in the striatum is the primary pathochemical hallmark in PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission. The currently licensed dopaminergic treatments for PD modulate all the key steps in the dopamine transmission except the most powerful determinant of extracellular dopamine concentrations: the presynaptic dopamine transporter (DaT). Methylphenidate is a CNS stimulant that blocks the DaT and the noradrenaline (norepinephrine) transporter in the striatum and the prefrontal cortex in particular. Here, we report on and discuss the main open-label studies and randomized controlled trials on the effect of methylphenidate on severe gait disorders (e.g. the FoG) and non-motor symptoms in advanced PD. The various pharmacodynamic effects of methylphenidate mean that the drug may have significant value in the treatment of PD. However, there is a lack of randomized controlled trials in this field. Furthermore, more rigorous selection of the types and doses of the associated dopaminergic treatments is required because these parameters may profoundly influence the mechanisms of action of methylphenidate and the clinical outcomes. Pharmacogenetic tools could be of use in better defining study patients as a function of their dopaminergic metabolism and drug responsiveness.
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PMID:Methylphenidate : a treatment for Parkinson's disease? 2316 Sep 37

Drugs that are able to shift effort-related decision making in intact rats towards high-effort response options are largely unknown. Here, we examined the effects of two candidate drugs, MRZ-9547 and its l-enantiomer MRZ-9546 on progressive ratio (PR) responding using two different tasks, a standard PR task that involves increasing ratio requirements and a PR/chow feeding choice task in which animals can lever press for preferred food pellets under a PR schedule or approach freely available less preferred lab chow. Furthermore, we assessed the mechanisms of action of both drugs using in vitro-assay methods and in vivo-microdialysis. Results reveal that MRZ-9547 is a selective dopamine transporter (DAT) inhibitor that moderately stimulated striatal dopamine release. MRZ-9546 was a much less potent DAT inhibitor. Furthermore, MRZ-9547 dose dependently increased the tendency to work for food reinforcement both in the standard PR task and the PR/chow feeding choice task, MRZ-9546 was considerably less active. Relative to MRZ-9547, other DAT-interfering drugs had only moderate (methylphenidate) or marginal (modafinil, d-amphetamine) stimulant effects on PR responding in either task. Collectively, our data demonstrate that the DAT inhibitor MRZ-9547 can markedly stimulate PR responding and shift effort-related decision making in intact rats towards high-effort response options. An analysis of effort-related decision making in rodents could provide an animal model for motivational dysfunctions related to effort expenditure such as fatigue, e.g. in Parkinson's disease or major depression. Our findings suggest that DAT inhibitors such as MRZ-9547 could be potentially useful for treating energy-related symptoms in neurological or neuropsychiatric disorders.
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PMID:The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats. 2496 69

The current report assessed the effects of low-level proton irradiation in inbred adult male Fischer 344 and Lewis rats performing an analog of the human Psychomotor Vigilance Test (PVT), commonly utilized as an object risk assessment tool to quantify fatigue and sustained attention in laboratory, clinical, and operational settings. These strains were used to determine if genetic differences in dopaminergic function would impact radiation-induced deficits in sustained attention. Exposure to head-only proton irradiation (25 or 100 cGy) disrupted rPVT performance in a strain-specific manner, with 25 cGy-exposed Fischer 344 rats displaying the most severe deficits in sustained attention (i.e., decreased accuracy and increased premature responding); Lewis rats did not display behavioral deficits following radiation. Fischer 344 rats displayed greater tyrosine hydroxylase and dopamine transporter levels in the frontal cortex compared to the Lewis rats, even though radiation exposure increased both of these proteins in the Lewis rats only. Tyrosine hydroxylase was decreased in the parietal cortex of both rat strains following radiation exposure, regardless of proton dose. Strain-specific cytokine changes were also found in the frontal cortex, with the Lewis rats displaying increased levels of putative neurotrophic cytokines (e.g., CNTF). These data support the hypothesis that basal dopaminergic function impacts the severity of radiation-induced deficits in sustained attention.
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PMID:Deficits in Sustained Attention and Changes in Dopaminergic Protein Levels following Exposure to Proton Radiation Are Related to Basal Dopaminergic Function. 2665 10


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