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Browsing by Subject "dopamine"

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  • Hyry, Saimi (2022)
    The aim of the study. Spontaneous eye blink rate (sEBR) is a behavioral index that has been linked to frontostriatal dopaminergic activity. Reduced or increased dopaminergic activity due to clinical conditions tends to be associated with lower or higher sEBR, respectively, and sEBR can be modulated by pharmacological agents that affect dopamine signaling. Consequently, sEBR could serve as an easily accessible method of assessing brain dopaminergic tone indirectly in humans. It might be preferable to more expensive and invasive techniques such as positron emission tomography. However, it remains unclear whether variations in dopaminergic genes predict sEBR. In this cross-sectional study, the relationship between sEBR and dopaminergic genotype was examined in two samples. Two genetic polymorphisms were focused on: the COMT Val158Met polymorphism and the A1 allele of the Taq1A polymorphism. It was hypothesized that the COMT Val158Met polymorphism is associated with higher sEBR, and that the A1 allele of the Taq1A polymorphism is associated with lower sEBR. As BMI and diet have been linked with altered striatal dopamine function, the possible association between BMI, diet, and sEBR was studied exploratively. Methods. Data from three cross-sectional studies was used in this study: The intervention study (n = 31) is an experimental study that examines the effect of acute phenylalanine/tyrosine depletion on cognitive measures. The GREADT study (n = 86) focuses on the effects of genotype and diet on dopamine tone. The BEDOB study (n = 69) investigates neurocognitive mechanisms in obesity and binge eating disorder. Similar methodologies were used in the GREADT and the BEDOB studies, which is why these datasets were combined for the analyses. Blink rates were measured using an infrared eye tracking system. The participants completed the Dietary Fat and free Sugar Questionnaire (DFS) to assess how much they consumed saturated fat and refined sugar. In the GREADT/BEDOB sample, the associations between the polymorphisms, BMI, DFS-score, and sEBR were examined with univariate analyses of variance. In the intervention study sample, a generalized linear mixed model was run to check whether sEBR changed in the intervention and whether the genotypes, BMI, or DFS-score affected sEBR. Results. No influence of the genotypes was found on sEBR in either of the samples. BMI had a significant effect on sEBR in the GREADT/BEDOB sample. The association was significant in the overweight/obese group but not in the normal weight group. DFS-score did not influence sEBR in either of the samples. Conclusions. The results of this study converge with those of authors suggesting caution in using sEBR as a proxy for central dopamine functioning of healthy humans. In future studies, particular attention should be paid to methodological considerations when studying sEBR.
  • Laukkanen, Heidi (2022)
    The aim of the study. Working memory (WM) is a cognitive function that relies on the neurotransmitter dopamine. WM has multiple subfunctions: maintaining relevant information, ignoring distractors, and updating the information when needed. Information maintenance and ignoring irrelevant stimuli are associated with brain activity in the prefrontal cortex and updating information with the striatum. A connection between polymorphisms within the dopaminergic genes COMT (COMT Val158Met polymorphism) and DRD2/ANKK1 (Taq1A polymorphism), and WM performance has been established in previous studies, and these genes seem to impact dopamine signaling in the prefrontal cortex and striatum, respectively. The present study investigates associations between dopaminergic gene polymorphisms and WM performance. The main research questions include the main effects and interactions that the genes have to WM on performance overall and WM stability and flexibility in particular. The study investigates also whether obesity, diet, and age affect WM performance, as there are indications for these from previous studies. Methods. Data from three separate cross-sectional studies with a total of 244 participants was used. A computer-based visual working memory task was used to assess the WM performance measures accuracy and reaction time. Other measurements included blood measures, Body Mass Index (BMI), and the Dietary Fat and free Sugar Questionnaire (DFS). Results and conclusion. In WM accuracy analyses, there was a significant main effect for the task condition as well as interactions between the COMT*task condition and COMT*Taq1A*task condition. In the three-way interaction analysis for WM accuracy, the most beneficial combination was Met/Met & A1- in the task condition measuring the stability, and Val/Met & A1+ in the task condition measuring the flexibility. This result gives support for established knowledge about how Met/Met combined with A1- is beneficial especially for WM stability and maintenance. Also, the inverted-U shape theory and previous studies' results of A1+ being beneficial in executive functions updating tasks, give support to the result regarding WM flexibility. In the three-way interaction reaction time analysis, the combination of Val/Met & A1+ was the fastest in every task condition. However, the significant differences were mainly between A1- and A1+ genotypes when combined with Val/Met and between Met/Met and Val/Met genotypes when combined with A1-. The two-way interaction between COMT Val158Met and task condition did not remain significant in pairwise comparisons. In reaction time analyses, COMT Val158Met and Taq1A had a significant main effect where reaction times followed the order: Met/Met < Val/Val < Val/Met, with Val/Met being significantly slower than the others and in Taq1A A1+ < A1-, with a significant difference. Adding age, BMI, and DFS to the analyses did not affect the significant/non- significant main effects or interactions in the analyses. The results of this thesis converge with the previous knowledge about these genotypes having an interacting effect on working memory stability and flexibility. However, these effects are complex to interpret as the results and their directions differed between the task conditions and outcome measurements. In the main outcome variable (accuracy), the result regarding the WM stability is well in line with previous literature about the Met/Met & A1- combination being beneficial to WM performance, and the result about Val/Met & A1+ being beneficial for WM flexibility gets preliminary support from executive function studies, but also opens new research avenues regarding the WM flexibility subfunction.
  • Montonen, Heidi (2013)
    Literature review: The plasma membrane DA transporter (DAT) belongs to the family of Na+/ClÙÄÉ≠ dependent neurotransmitter transporters. DAT is the primary mechanism for clearance of dopamine from the extracellular space and transporting it back to the presynaptic nerve terminals. There's a great interest in the DAT and its regulation as its substrate, dopamine, mediates a wide array of physiological functions e.g. locomotor activity, cognition and the control of motivated behaviors. With selective transport DAT limits the intensity and the duration of dopaminergic signal. Its function is regulated by several kinases, phosphatase and protein-protein interactions. The altered expression of DAT may be related to several neurological diseases such as Parkinson's disease, addiction and ADHD. To study DAT's function, several genetically modified mouse lines including DAT knockout mice, DAT knockdown mice and DAT knock in mice with elevated DAT levels have been generated. Experimental part: Glial cell line-derived neurotrophic factor (GDNF) plays important role in the survival and function of dopaminergic neurons, learning, memory and synaptic plasticity. More recently, several studies have shown that GDNF can also negatively regulate the actions of abused drugs. The aim of this study was to investigate GDNF's role and mechanism of action in plasticity and function of the dopaminergic neurons projecting to striatum. For that purpose, we used in vivo microdialysis in freely moving mice. We chose two different mouse lines: MEN2B mice with constitutive active Ret-signaling and elevated striatal dopamine concentrations, and GDND-cKO mice that lack GDND in the central nervous system. Microdialysis guide cannula was implanted in the dorsal striatum in the stereotaxic surgery and the mice were allowed to recover for 5-7 days. The concentrations of dopamine and its metabolites DOPAC and HVA and also 5-HIAA were determined from the samples by highperformance liquid chromatography. Microdialysis was performed twice for every mouse on days 1 and 4. Between microdialysis days, the mice were given amphetamine 1 mg/kg i.p. on days 2 and 3. In the microdialysis experiment, the mice received amphetamine stimulation (100 µM/60 min) via microdialysis probe. The placements of microdialysis probes were verified from fixed brain sections after the experiments. Amphetamine increased the dopamine output in both mouse lines, but there were no statistically significant differences in striatal dopamine concentrations between genotypes neither after acute nor chronic administration. However, there was a difference between the dopamine outputs in days 1 and 4 in both MEN2B and GDNF-cKO mice: The striatal dopamine concentrations were significantly lower on the second microdialysis day. This may be a sing from tolerance to the drug. However, without more research, it is not possible, by this experiment, to draw direct conclusions of GDNF's role in addiction and in plasticity in striatum. It is possible that the differences between genotypes are too small to be seen with microdialysis. Development of compensatory mechanisms in mice cannot be ruled out either. Effects may also vary between different brain areas.
  • von Bagh, Anna (2022)
    Objectives. Motivational contexts exert a profound influence on behavior biasing actions in sometimes detrimental ways. In Pavlovian bias, reward-predicting conditioned cues elicit approach behavior while aversively associated cues elicit withdrawal, with capacity to impact instrumental goal-driven behavior. Similar bias has been suggested to be produced by instrumental learning. Motivational biases have been linked to dopaminergic system but the precise role of dopamine in their modulation is unclear. The present study investigated genetically driven variation in Pavlovian and instrumental learning biases by comparing task performance in subjects carrying different variants of two dopaminergic SNPs, COMT Val108/158Met and DRD2/ANKK1Taq1A. Associations with BMI, diet, age and gender were studied. All subjects were expected to show motivational bias while no direct hypotheses were made concerning genotypic or lifestyle-mediated effects due to exploratory nature of the study. Methods. 160 subjects completed a probabilistic Go/NoGo learning task in an experimental within-subject design. Generalized mixed-model logistic regressions were used to predict differences by genotype in Go responding with and without covariants. Differences by genotype in computationally modelled latent bias estimates were studied with linear regression. Results and Conclusions. Confirming expectations, an overall effect of motivational bias and a general bias towards active responding were found. Relative to Val/Met and A1+, carriers of COMT Val/Val and Taq1A A1- variants showed superior learning of correct Go responses, indicating enhanced instrumental bias. BMI was inversely associated with learning rate while diet, age and gender did not explain variance. Results partly contradict previous findings and highlight the mixed nature of research regarding associations between dopaminergic SNPs and motivational biases.
  • Renko, Juho-Matti (2012)
    Review of the literature: The purpose of the review is to go through what is known about mechanisms of actions of different neurotrophic factors (GDNF, neurturin, CDNF and MANF) and how they are transported within the brain. Neurotrophic factors are endogenous and secreted proteins which have a pivotal role in the development and maintenance of neurons. They support the survival of neurons and they can help them to recover from different injuries. Due to these functions neurotrophic factors might be beneficial for the treatment of neurodegenerative disorders like Parkinson's disease. There are a great deal of studies that clearly show the neuroprotective and neurorestrorative function of GDNF and neurturin on dopaminergic neurons. They are also studied in clinical studies with Parkinson's patients but the results have been partly contradictory. The signalling route of GDNF and neurturin via RET tyrosinekinasereceptor is fairly well known but the other mechanisms of action of these factors needs to be studied further. CDNF and MANF constitute a novel, evolutionarily conserved family of neurotrophic factors. They are shown to have neuroprotective and neurorestrorative actions on dopaminergic neurons both in vitro and in vivo in a rodent model of Parkinson's disease. The mechanisms of action of CDNF and MANF are not quite clear at the moment. There are two different domains in their structure both of which are likely to carry different functions. The N-terminal domains of these proteins are close to saposins, lipid and membrane binding proteins, some of which are shown to have neurotrophic and anti-apoptotic effects. The C-terminal domain of MANF, in turn, is structurally close to the SAP-domain of Ku70-protein which binds Bax in the cytoplasm and thus inhibits apoptosis mediated by Bax. CDNF and MANF might protect neurons both via intracellular mechanisms and extracellularly acting like a secreted neurotrophic factor. CDNF and GDNF are transported retrogradially from striatum to substantia nigra. MANF, unlike the others, is transported from striatum to the frontal cortex. MANF and CDNF are shown to have better diffusion properties in the brain parenchyma than GDNF. Experimental part: We studied, by means of microdialysis, the effects of CDNF, MANF and GDNF on the dopaminergic neurotransmission of naive rats within the striatum. Neurotrophic factors (10 µg) and PBS as a negative control were injected into the left striatum in stereotaxic surgery. After this rats recovered one week before the first mircodialysis. The second mircodialysis was performed three weeks after the surgery. The samples were collected from the left striatum of freely moving rats. During the microdialysis neurotransmission was stimulated by replacing the perfusion solution with hypertonic potassium solution and with amphetamine solution. The concentration of dopamine, DOPAC, HVA and 5-HIAA was measured from the dialysate samples. In vivo TH-activity experiment was carried out for three rats in each group. NSD1015 was injected i.p.after which rats were decapitated and their striatums were dissected. The concentration of L-DOPA, dopamine and metabolites on the treated and untreated hemisphere were analyzed from the tissue samples. The amount of L-DOPA in the striatum after NSD1015-treatment indicates how active TH-enzyme is. There were no significant differences in the concentrations of dopamine and metabolites during the baseline. MANF and CDNF increased the release of dopamine from the nerve terminals compared to GDNF and PBS one week after the surgery. Three weeks after the surgery there was still significant increase in the release of dopamine in MANF group compared to GDNF group. Also the dopamine-DOPAC-turnover was increased significantly in MANF group compared to GDNF and PBS groups one week after the surgery. DOPAC/HVA -ratio was significantly smaller in GDNF group than in other groups one week after the surgery. These findings suggest that MANF potentiates dopaminergic neurotransmission most drasticly. The effects of MANF seem to last longer time than the effects of other neurotrophic factors. CDNF seems to increase the release of dopamine from the nerve terminals as well. The potentiation of dopaminergic neurotransmission could be due to increased biosynthesis of dopamine or due to the potentiation of the function of nerve terminals. In the results of the TH-activity experiment there was a trend according to which L-DOPA is synthesized less after the neurotrophic factor treatment that after the PBS treatment. This suggests that neurotrophic factors might decrease the activity of TH-enzyme.
  • Kinnunen, Marja (2015)
    Histamine is a monoamine structured signal molecule, which takes part in many functions of living organisms. It was first found in brain approximately 70 years ago. Neuronal histamine regulates for example biological rhythms, energy metabolism and thermoregulation. In the 1980's, H3-receptor was recognized in the brain. Neuronal histamine regulates functions of other transmitters for example gamma-aminobutyric acid, glutamate, acetylcholine, noradrenaline and dopamine. Currently, the interactions of histamine and dopamine are not well characterized. Though, it is known that histaminergic fibers innerviate almost every dopaminergic area of the brain. There are also several H3-receptors in the striatum and in the limbic system. These brain areas are important for the rewarding effect of dopamine. The aim of the experimental part of this Master's thesis was to examine the location of histaminergic and dopaminergic nervous systems in mouse brain by using immunohistochemistry. Primary antibodies that were produced in rabbit (anti-histamine (HA)) and in mouse (anti-tyrosine hydroxylase (TH)), and secondary anti-rabbit and anti-mouse anti-bodies, that were produced in goat and conjugated with fluorophores, were used in the study. The samples were imaged with a confocal microscope. The primary aim was to find out, in which addiction related brain areas, histamine and dopamine cells and fibers are located and how they are situated in relation to each other. H3-receptor antagonists have been shown to decrease the consumption and rewarding effect of alcohol in animal models. Therefore, it was examined if non-imidazole structured H3-receptor antagonist also inhibits the rewarding effect of amphetamine, and if it decreases the locomotor activity induced by amphetamine. JNJ-39220675, a neutral antagonist of H3-receptor, and behavioral paradigm of conditioned place preference (CPP) were used in the experiment. CPP was also used to find out if D2-receptor agonist quinpirole cause reward or aversion. The effect of JNJ-39220675 on quinpirole's place preference and change in locomotor activity was also investigated. The interactions of these two pharmacological ligands were also examined in a separate locomotor activity experiment. C57BL/6J mice were used in all experiments. The results show that there are possible synaptic connections of histaminergic and dopaminergic system in substantia nigra, supramammillary nucleus, dorsomedial hypothalamic area and ventral periaqueductal grey area. Also, histaminergic nerve fibers innerviate to the dorsal striatum, which regulates motor functions, and to the ventral striatum, which is a part of the rewarding system of the brain. Hence, it is possible that histamine regulates the actions of dopa-mine in these brain areas. The behavioral experiments showed that JNJ-39220675 inhibits acutely increased locomotor activity caused by amphetamine, and decreases desensitation of decreased locomotor action caused by repeated dose of quinpirole. However, JNJ-39220675 did not have any effect on the rewarding effect of amphetamine, which causes strong sensitization. Also, JNJ-39220675 did not have an effect on quinpirole's aversive action. It remains to be seen, if H3-receptor is a potential target for new medicines in the treatment of different brain diseases and addiction in the future.
  • Huynh, Thi Le Hang (2010)
    In the written part of my master -thesis I discuss about GDNF signalling and more specifically how the changes in the GDNF/GFRα1/Ret signaling affect the nigrostriatal dopaminergic neurons in different mutant mice. In the animal models of Parkinson's disease the neuroprotective and neurorestorative effects of exogenous GDNF are very clear which raises hope for use of GDNF in treatment of Parkinson's disease. In intact animals GDNF stimulates the function of nigrostriatal dopaminergic system. Revealing the role of GDNF/GFRα1/Ret signaling in development, maintenance and protection of nigrostriatal dopaminergic system will certainly help in search for treatment of neurodegeneration in Parkinson's disease. In knockout mouse models GDNF/GFRα1/Ret signaling is not crucial for prenatal nigrostriatal dopaminergic neuron development, but it has been shown that it plays an important role in the early postnatal development. Also, it was shown that reduced GDNF/GFRα1/Ret signaling compromises nigrotriatal dopaminergic system in heterozygous GDNF/GFRα1/Ret knockout mice. However the physiological roles of endogenous GDNF and its signalling in the nigrostriatal dopaminergic neurons are not very well understood. In the experimental part of my master -thesis I studied how reduced endogenous GDNF signaling affects the dopaminergic system after 6-OHDA induced neurotoxicity in the conventional heterozygous GDNF mice. Besides that I examined the effects of elevated endogenous GDNF on dopaminergic system of 7 days old so-called GDNF hypermorphs mice. The effects of reduced endogenous GFRα1 levels on dopaminergic system of 20 days old GFRα1 hypomorphs have also been studied. The obtained date showed that mice with the reduced levels of endogenous GDNF are not more susceptible to the 6-OHDA induced neurotoxicity than the wild type littermates. Elevated endogenous GDNF levels did not affect early postnatal development of the nigrostriatal dopaminergic system in GDNF hypermorphs mice as revealed by normal intensity of TH staining in striatum and normal number of TH-positive cells in the substantia nigra pars compacta. Reduced levels of endogenous GFRα1 levels did not affect monoamine levels in the striatum of GFRα1 hypomorph mice.
  • Tulenheimo, Tapio (2023)
    Aims. In our everyday activities, we need to make a great number of decisions, like choosing a high-rewarded but effortful or low-rewarded but rather effortless task. This value-based decision-making is regulated by the dopaminergic system. Recent technological advances have made it possible to measure in real-time the neural activity of dopaminergic brain regions and thus enabled training to self-regulate those regions. The present study aims to investigate the effect of self-regulation of dopaminergic brain regions on value-based decision-making – specifically effort discounting – and how stress moderates the relationship between neural activity and value-based decision-making. Methods. Using real-time functional magnetic resonance imaging (rt-fMRI), 74 participants (34 females, age M= 22.5) were trained to self-regulate dopaminergic midbrain regions. During the subsequent test session participants up- or down-regulated dopaminergic midbrain regions before performing the value-based decision-making task. Participants were faced with a choice to either accept to perform the N-back task and get a higher reward or refuse and get a lower reward. Acute and chronic stress was measured before and after the experiment using questionnaires. Linear mixed model analyses were performed to investigate the effects of self-regulation and stress on decision-making behavior. Results and conclusions. Upregulation of dopaminergic midbrain activity significantly increased the probability of choosing the effortful task and decreased effort discounting. Downregulation of the dopaminergic midbrain was not significantly affecting decision-making. Chronic stress was not significantly affecting decision-making. Acute stress had a significant main effect on decision- making and interacted with the self-regulation of dopaminergic midbrain activity by increasing effort discounting. Taken together, upregulation of the dopaminergic midbrain is an effective way to decrease effort discounting, and acute stress can have a negative impact on value-based decision-making.