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PloS One 2015Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine...
Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.
Topics: Alcoholism; Case-Control Studies; Cognition Disorders; Demography; Dopamine Plasma Membrane Transport Proteins; Humans; Male; Organotechnetium Compounds; Smoking; Statistics, Nonparametric; Tropanes
PubMed: 26120847
DOI: 10.1371/journal.pone.0131017 -
Brain : a Journal of Neurology Dec 2022Dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual...
Dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behaviour disorder and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism and cognition in DLB. We enrolled 55 patients with probable DLB (15 with prodromal DLB and 40 with DLB) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane PET/CT, 18F-fluorodeoxyglucose PET/CT, 18F-florbetaben PET/CT and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed using general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and longitudinal cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the DLB-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall and Controlled Oral Word Association Test (COWAT)-animal. Path analyses showed that the effect of reduced caudate dopamine on the Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected the Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with the COWAT-animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in DLB, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Lewy Body Disease; Dopamine; Positron Emission Tomography Computed Tomography; Cognition; Brain; Fluorodeoxyglucose F18
PubMed: 35234856
DOI: 10.1093/brain/awac084 -
Journal of Neuroscience Research Oct 2023Dopamine transporter knockout (DAT-KO) rats represent a valuable rodent model for studying the molecular and phenotypical outcomes of the effects of excessive dopamine...
Dopamine transporter knockout (DAT-KO) rats represent a valuable rodent model for studying the molecular and phenotypical outcomes of the effects of excessive dopamine accumulation in the synaptic cleft and the prolonged action of dopamine on neurons. Animals with DAT deficiency are characterized by hyperactivity, stereotypy, cognitive deficits, and impairments in behavioral and biochemical indicators. Several key pathophysiological mechanisms are known to be common to psychiatric, neurodegenerative, metabolic, and other diseases. Among these mechanisms, oxidative stress systems play a particularly important role. One of the main antioxidant systems in the brain is glutathione: specifically, glutathione S-transferase, glutathione reductase, and catalase play a significant role in the regulation of vital oxidative processes, and their dysfunction has been shown in Parkinson's disease, Alzheimer's disease, and other neurodegenerative diseases. The current study aimed to analyze the dynamics of the activity levels of glutathione reductase and glutathione S-transferase in erythrocytes, as well as catalase in the blood plasma, of DAT-deficient, homo- and heterozygous, neonatal and juvenile rats (both male and female). Their behavioral and physiological parameters were evaluated at the age of 1.5 months. For the first time, changes in physiological and biochemical parameters were shown in DAT-KO rats at 1.5 months of postnatal life. The key role of glutathione S-transferase, glutathione reductase, and catalase in the regulation of oxidative stress in DAT-KO rats at the 5th week of life was demonstrated. A positive effect of a slightly increased dopamine level on memory function was shown in DAT-heterozygous animals.
Topics: Rats; Male; Female; Animals; Dopamine Plasma Membrane Transport Proteins; Antioxidants; Catalase; Dopamine; Glutathione; Glutathione Transferase
PubMed: 37394966
DOI: 10.1002/jnr.25228 -
Neuroscience May 2022Under normal conditions, dopamine (DA) clearance after release largely depends on uptake by the DA transporter (DAT). DAT expression/activity is reduced in some...
Under normal conditions, dopamine (DA) clearance after release largely depends on uptake by the DA transporter (DAT). DAT expression/activity is reduced in some neuropsychiatric and neurological disorders. Our aim was to characterize the behavioral, neurochemical and electrophysiological effects of eliminating DAT in a novel knockout rat model we generated using CRISPR/Cas9. Consistent with existing DAT-KO models, our DAT-KO rats displayed increased locomotion, paradoxical calming by amphetamine, and reduced kinetics of DA clearance after stimulated release. Reduced DA kinetics were demonstrated using fast-scan cyclic voltammetry in brain slices containing the striatum or substantia nigra pars compacta (SNc) and in the dorsal striatum in vivo. Cocaine enhanced DA release in wild-type (WT) but not DAT-KO rats. Basal extracellular DA concentration measured with fast-scan controlled-adsorption voltammetry was higher in DAT-KO rats both in the striatum and SNc and was enhanced by L-DOPA (particularly after pharmacological block of monoamine oxidase), confirming that DA release after L-DOPA is not due to DAT reversal. The baseline firing frequency of SNc neurons was similar in both genotypes. However, D2 receptor-mediated inhibition of firing (by quinpirole or L-DOPA) was blunted in DAT-KO rats, while GABA-mediated inhibition was preserved. We have also provided new data for the DAT-KO rat regarding the effects of slowing DA diffusion with dextran and blocking organic cation transporter 3 with corticosterone. Together, our results validate our DAT-KO rat and provide new insights into the mechanisms of chronic dysregulation of the DA system by addressing several unresolved issues in previous studies with other DAT-KO models.
Topics: Amphetamine; Animals; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Levodopa; Rats
PubMed: 35331847
DOI: 10.1016/j.neuroscience.2022.03.019 -
Journal of Chemical Neuroanatomy Apr 2022To investigate the role of the dopamine transporter (DAT) in the ventral tegmental area (VTA) in the recovery from propofol anesthesia in rats.
OBJECTIVE(S)
To investigate the role of the dopamine transporter (DAT) in the ventral tegmental area (VTA) in the recovery from propofol anesthesia in rats.
MATERIALS AND METHODS
A total of 150 Sprague-Dawley (SD) rats were randomly split into a normal control group (NC), saline group (S), propofol anesthesia group (P), adeno-associated viral-NC-mCherry (AAV-NC) group, and AAV-DAT-RNAi (DAT-RNAi) group (n = 30 per group). In rats in the AAV intervention group, AAV was injected into the VTA nucleus via a stereotaxer. The rats in each group were continuously pumped with propofol through the tail vein at a dose of 70 mg/kg/h, and the control group was infused with the same dose of saline at the same speed for 30 min. Immunofluorescence staining was used to observe the expression of c-fos protein in the prefrontal cortex (PFC). The induction and recovery time of propofol anesthesia were recorded based on the time of disappearance of the righting reflex (LORR) and recovery (RORR). The anesthesia depth score was performed on all rats 10 min after starting the administration and 10 min after withdrawal, which represented the depth of anesthesia during anesthesia and the degree of recovery during anesthesia recovery, respectively. electroencephalogram (EEG) was recorded during propofol anesthesia and recovery.
RESULTS
Compared to the NC group, the RORR of the DAT-RNAi group was shortened, and the anesthesia depth score was higher (P < 0.05). In the DAT-RNAi group, during the period of propofol anesthesia, the β wave frequencies increased, the θ wave frequencies decreased, and the expression of c-fos protein in PFC increased and during the recovery from propofol anesthesia, the α wave and β wave frequencies were increased (P < 0.05).
CONCLUSION
Knockdown of the DAT in the VTA region can enhance the activity of PFC neurons and promote the recovery of rats from propofol anesthesia.
Topics: Anesthesia; Animals; Dopamine Plasma Membrane Transport Proteins; Propofol; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Ventral Tegmental Area
PubMed: 35181484
DOI: 10.1016/j.jchemneu.2022.102083 -
Parkinsonism & Related Disorders Oct 2018
Topics: Brain; Constipation; Dopamine Plasma Membrane Transport Proteins; Humans; Parkinson Disease; Primary Dysautonomias; alpha-Synuclein
PubMed: 30181087
DOI: 10.1016/j.parkreldis.2018.08.014 -
Biomolecules Oct 2022Changes in dopaminergic and noradrenergic transmission are considered to be the underlying cause of attention deficit and hyperactivity disorder (ADHD). Atomoxetine...
Changes in dopaminergic and noradrenergic transmission are considered to be the underlying cause of attention deficit and hyperactivity disorder (ADHD). Atomoxetine (ATX) is a selective norepinephrine transporter (NET) inhibitor that is currently used for ADHD treatment. In this study, we aimed to evaluate the effect of atomoxetine on the behavior and brain activity of dopamine transporter knockout (DAT-KO) rats, which are characterized by an ADHD-like behavioral phenotype. Prepulse inhibition (PPI) was assessed in DAT-KO and wild type rats after saline and ATX injections, as well as behavioral parameters in the Hebb-Williams maze and power spectra and coherence of electrophysiological activity. DAT-KO rats demonstrated a pronounced behavioral and electrophysiological phenotype, characterized by hyperactivity, increased number of errors in the maze, repetitive behaviors and disrupted PPI, changes in cortical and striatal power spectra and interareal coherence. Atomoxetine significantly improved PPI and decreased repetitive behaviors in DAT-KO rats and influenced behavior of wild-type rats. ATX also led to significant changes in power spectra and coherence of DAT-KO and wild type rats. Assessment of noradrenergic modulation effects in DAT-KO provides insight into the intricate interplay of monoaminergic systems, although further research is still required to fully understand the complexity of this interaction.
Topics: Rats; Animals; Atomoxetine Hydrochloride; Dopamine Plasma Membrane Transport Proteins; Norepinephrine Plasma Membrane Transport Proteins; Cognition; Norepinephrine; Corpus Striatum
PubMed: 36291693
DOI: 10.3390/biom12101484 -
Addiction Biology Nov 2022As well known, cocaine induces stimulant effects and dopamine transporter (DAT) trafficking to the plasma membrane of dopaminergic neurons. In the present study, we...
As well known, cocaine induces stimulant effects and dopamine transporter (DAT) trafficking to the plasma membrane of dopaminergic neurons. In the present study, we examined cocaine-induced hyperactivity along with cocaine-induced DAT trafficking and the recovery rate of the dopaminergic system in female rats in comparison with male rats, demonstrating interesting gender differences. Female rats are initially more sensitive to cocaine than male rats in terms of both the DAT trafficking and hyperactivity induced by cocaine. Particularly, intraperitoneal (i.p.) administration of 5 mg/kg cocaine induced significant hyperactivity and DAT trafficking in female rats but not in male rats. After repeated cocaine exposures (i.e., i.p. administration of 20 mg/kg cocaine every other day from Day 0 to Day 32), cocaine-induced hyperactivity in female rats gradually became a clear pattern of two phases, with the first phase of the hyperactivity lasting for only a few minutes and the second phase lasting for over an hour beginning at ~30 min, which is clearly different from that of male rats. It has also been demonstrated that the striatal DAT distribution of female rats may recover faster than that of male rats after multiple cocaine exposures. Nevertheless, despite the remarkable gender differences, our recently developed long-acting cocaine hydrolase, known as CocH5-Fc(M6), can similarly and effectively block cocaine-induced DAT trafficking and hyperactivity in both male and female rats.
Topics: Male; Female; Rats; Animals; Dopamine Plasma Membrane Transport Proteins; Cocaine; Sex Factors; Dopamine Uptake Inhibitors; Cell Membrane
PubMed: 36301205
DOI: 10.1111/adb.13236 -
Journal of Affective Disorders Mar 2015Increasing studies have revealed the dopamine transporter (DAT) availability altered in striatum associated with major depression. However, the results remain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Increasing studies have revealed the dopamine transporter (DAT) availability altered in striatum associated with major depression. However, the results remain inconsistent.
METHODS
To assess the alteration of striatal DAT availability in major depression, we performed a meta-analysis based on 12 case-control molecular imaging studies, including a total of 209 depressed patients and 314 healthy controls. Hedges׳ g and corresponding 95% confidence intervals (CIs) for striatal DAT availability in major depression compared with controls were estimated.
RESULTS
Our meta-analysis revealed no evidence for the alteration of striatal DAT availability in major depression (Hedges׳ g=0.09, CI 95% from -0.43 to 0.61, P=0.73). Meta-regression analyses suggested that there were no moderating effects for age, gender, year of publication, sample size, medication exposures and severity of depression on the hedges׳g values for striatal DAT availability.
LIMITATIONS
The results should be treated with caution because of the significant heterogeneity and the potential interference of confounding factors in this meta-analysis.
CONCLUSIONS
Our results showed no altered striatal DAT availability in major depression and indicated that striatal DAT may not implicated in the pathophysiology of major depression.
Topics: Case-Control Studies; Corpus Striatum; Depressive Disorder, Major; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Imaging; Peer Review, Research; Research Report
PubMed: 25497470
DOI: 10.1016/j.jad.2014.11.045 -
Behavioural Brain Research Mar 2020Alcoholism and alcohol use disorders are chronically relapsing conditions which is a major problem in treating alcohol addiction. In a previous study we showed that the...
Alcoholism and alcohol use disorders are chronically relapsing conditions which is a major problem in treating alcohol addiction. In a previous study we showed that the dopamine transporter (DAT) is implicated in voluntary intake and preference. However, its role in modulating ethanol-associated contextual memory remains largely unknown. In this study we have investigated the role of DAT in ethanol-induced conditioned place preference (EtOH-CPP) acquisition and reinstatement in adult male C57BL/6 mice. For this purpose, we used both loss- and gain-of-function approaches to test the effects of central DAT manipulation on EtOH-CPP. We developed a lentiviral-mediated gene transfer approach to examine whether DAT knockdown (shDAT) or overexpression in the nucleus accumbens (Nacc) is enough to impair EtOH-CPP acquisition and reinstatement. In the first experiment, results showed that DAT knockdown blocked, whereas DAT overexpression, exacerbated the acquisition of EtOH-CPP. In the second experiment and after the EtOH-CPP expression, the mice were subjected to a 14-day extinction trials before drug-induced EtOH-CPP reinstatement was induced by a priming injection of 1 g/kg EtOH. Results indicated that reinstatement of EtOH-CPP was considerably decreased after accumbal shDAT injection. However, DAT overexpression significantly increased EtOH-CPP reinstatement. Finally, and following DAT mRNA quantification using RT-PCR, Pearson's correlation showed a strong positive relationship between accumbal DAT mRNA and EtOH-CPP acquisition and reinstatement. These results suggest that DAT expression in the Nacc is involved in the acquisition and retrieval of EtOH contextual memory and that blockade of this transporter can decrease the rewarding properties of EtOH.
Topics: Animals; Central Nervous System Depressants; Conditioning, Classical; Dopamine Plasma Membrane Transport Proteins; Drug-Seeking Behavior; Ethanol; Gene Expression; Gene Knockdown Techniques; Mice; Nucleus Accumbens; RNA, Messenger
PubMed: 31923430
DOI: 10.1016/j.bbr.2020.112475