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Item Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats(Elsevier, 2016-10) Ding, Zheng-Ming; Ingraham, Cynthia M.; Rodd, Zachary A.; McBride, William J.; Psychiatry, School of MedicineRepeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the ‘EtOH’ than ‘Water’ groups (e.g., 150 mg% EtOH: to ~ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the ‘Water’ than ‘EtOH’ groups (e.g., 200 μM sulpiride: to ~ 190–240 vs 150–160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the ‘Water’ (to ~ 150–180% and 180–230% of baseline, respectively) but not the ‘EtOH’ groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA.Item Alterations of the serotonergic system in the dopamine deficient striatum of the weaver mutant mouse(1993) Stotz, Elizabeth HansenItem Analysis of Galvanic Skin Response: Potential Relationships to Stimulus Responsivity and Brain Dopamine Signal(2014-04-11) Chumin, Evgeny; Albrecht, Daniel; Yoder, KarenFibromyalgia is a chronic pain disorder that presents itself with no apparent medical explanation for the pain. Functional alterations of neurotransmitters such as dopamine (DA) have been implicated in fibromyalgia neuropathology. It is not known how central dopamine function in pain is associated with objective peripheral measurements that are thought to be associated with the presence of pain and stress. Galvanic skin response (GSR), is a physiological measure of nervous system activation. GSR could potentially give insight to novel aspects of DA function. In this study, GSR was recorded from fibromyalgia patients (FM) and healthy controls (HC) while they underwent scanning with [18F]-fallypride (FAL) Positron Emission Tomography (PET). FAL is a D2/D3 DA receptor antagonist that is sensitive to changes in DA levels in the brain. Given the involvement of DA in cognitive processes, FAL PET can be used to examine baseline DA activity as well as changes from baseline during cognitive load tasks. Relationships between GSR and working memory load, acute pain, and DA function were studied and compared between FM and HC.Item Assessment of the dopamine system in addiction using positron emission tomography(2014) Albrecht, Daniel Strakis; Hutchins, Gary D.; Saykin, Andrew J.; Kareken, David A.; Yoder, Karmen K.; Grahame, Nicholas J.Drug addiction is a behavioral disorder characterized by impulsive behavior and continued intake of drug in the face of adverse consequences. Millions of people suffer the financial and social consequences of addiction, and yet many of the current therapies for addiction treatment have limited efficacy. Therefore, there is a critical need to characterize the neurobiological substrates of addiction in order to formulate better treatment options. In the first chapter, the striatal dopamine system is interrogated with [11C]raclopride PET to assess differences between chronic cannabis users and healthy controls. The results of this chapter indicate that chronic cannabis use is not associated with a reduction in striatal D2/D3 receptor availability, unlike many other drugs of abuse. Additionally, recent cannabis consumption in chronic users was negatively correlated with D2/D3 receptor availability. Chapter 2 describes a retrospective analysis in which striatal D2/D3 receptor availability is compared between three groups of alcohol-drinking and tobacco-smoking subjects: nontreatment-seeking alcoholic smokers, social-drinking smokers, and social-drinking non-smokers. Results showed that smokers had reduced D2/D3 receptor availability throughout the striatum, independent of drinking status. The results of the first two chapters suggest that some combustion product of marijuana and tobacco smoke may have an effect on striatal dopamine concentration. Furthermore, they serve to highlight the effectiveness of using baseline PET imaging to characterize dopamine dysfunction in addictions. The final chapter explores the use of [18F]fallypride PET in a proof-of-concept study to determine whether changes in cortical dopamine can be detected during a response inhibition task. We were able to detect several cortical regions of significant dopamine changes in response to the task, and the amount of change in three regions was significantly associated with task performance. Overall, the results of Chapter 3 validate the use of [18F]fallypride PET to detect cortical dopamine changes during a impulse control task. In summary, the results reported in the current document demonstrate the effectiveness of PET imaging as a tool for probing resting and activated dopamine systems in addiction. Future studies will expand on these results, and incorporate additional methods to further elucidate the neurobiology of addiction.Item Blockade of Striatal Dopamine D1 Receptors Reduces Quinine-Resistant Alcohol Intake(2019-05) Houck, Christa A.; Grahame, Nicholas J.; Boehm, Stephen L.; Logrip, Marian L.; Hopf, F. WoodwardDrinking despite aversive consequences, or compulsive drinking, is a criterion of alcohol use disorder and can be modeled in rodents by adding bitter quinine into alcohol. Previous studies have shown the development of quinine-resistant ethanol (EtOH) drinking following a drinking history, but used animals that achieved relatively low blood alcohol levels. Selectively bred crossed High Alcohol Preferring (cHAP) mice average over 250 mg/dl during a two-bottle choice procedure. Compulsive drinking is hypothesized to be D1-receptor mediated via the dorsolateral striatum (DLS). We hypothesized that 2 weeks of free-choice EtOH would lead to quinine resistance and intra-DLS infusion of a D1-antagonist, SCH23390, would attenuate quinine-resistant alcohol drinking with no effect on non-conflicted EtOH drinking. Infusion of SCH23390 into the DMS would not affect quinine-resistant drinking. cHAP mice had guide cannulae placed in the DLS or DMS and had either two weeks (2W) of EtOH and water two-bottle choice or were EtOH naïve (0W). Mice were infused with either SCH23390 or saline immediately prior to one 10% EtOH and water test day and SCH23390 did not disturb alcohol drinking. The following day, we adulterated the EtOH with 0.32-g/L quinine (0.89 mM), and mice received the same microinjection. For animals cannulated in the DLS, 2W history group infused with saline drank more quinine-adulterated EtOH than the 0W saline mice. While SCH23390 infused 0W animals looked no different from saline treated mice, it attenuated quinine + EtOH intake in the 2W animals to the level of 0W animals. Interestingly, DMS-cannulated mice demonstrated similar behavior, with SCH23390 reducing EtOH + quinine consumption, while leaving EtOH consumption undisturbed. Quinine resistance following 2 weeks of free-choice EtOH consumption is attenuated by acute administration of a D1-antagonist in the DLS, suggesting that an alcohol history induces compulsivity and that dopamine contributes to this behavior. This is unique to compulsive drinking, as non-conflicted EtOH drinking was unaffected.Item Constructing a new nigrostriatal pathway in the Parkinsonian model with bridged neural transplantation in substantia nigra(Society for Neuroscience, 1996-11-01) Zhou, Feng C.; Chiang, Yung H.; Wang, Yun; Anatomy and Cell Biology, School of MedicineThe physical repair and restoration of a completely damaged pathway in the brain has not been achieved previously. In a previous study, using excitatory amino acid bridging and fetal neural transplantation, we demonstrated that a bridged mesencephalic transplant in the substantia nigra generated an artificial nerve pathway that reinnervated the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats. In the current study, we report that a bridged mesencephalic transplant can anatomically, neurochemically, and functionally reinstate the 6-OHDA-eradicated nigro-striatal pathway. An excitatory amino acid, kainic acid, laid down in a track during the transplant generated a trophic environment that effectively guided the robust growth of transplanted neuronal fibers in a bundle to innervate the distal striatum. Growth occurred at the remarkable speed of approximately 200 microm/d. Two separate and distinct types of dopamine (DA) innervation from the transplant have been achieved for the first time: (1) DA innervation of the striatum, and (2) DA innervation of the pars reticularis of the substantia nigra. In addition, neuronal tracing revealed that reciprocal connections were achieved. The grafted DA neurons in the SNr innervated the host's striatum, whereas the host's striatal neurons, in turn, innervated the graft within 3-8 weeks. Electrochemical volt- ammetry recording revealed the restoration of DA release and clearance in a broad striatal area associated with the DA reinnervation. Furthermore, the amphetamine-induced rotation was attenuated, which indicates that the artificial pathways were motor functional. This study provides additional evidences that our bridged transplantation technique is a potential means for the repair of a completely damaged neuronal pathway.Item Cortical Connectivity in Alcoholism(2019-09) Chumin, Evgeny Jenya; Kareken, David A.; Dzemidzic, Mario; Goñi, Joaquín; Harezlak, Jaroslaw; Lapish, Christopher C.; Yoder, Karmen K.Alcoholism carries significant personal and societal burdens, and yet we still lack effective treatments for alcohol use disorders. Several lines of research have demonstrated disruption of major white matter (WM) tracts in the brains of detoxified alcoholics. Additionally, there are several reports of alterations in the dopaminergic system of alcoholics. A better understanding of the relationships of brain structure and function in the alcoholic brain is necessary to move toward more efficacious pharmacological interventions. In this dissertation, there are three main chapters. First, reduced WM integrity was reported in a sample of individuals with active alcohol use disorder (AUD). This is a relatively understudied population, which is believed to represent a less severe phenotype compared to the in-treatment samples that are typically studied. Second, higher WM integrity was reported in a sample of college-age, active AUD. In a subsample of these individuals, graph theory measures of structural brain network connectivity were shown to be altered in cigarette-smoking social-drinking controls and smoking AUD subjects, compared to nonsmoking healthy individuals. Finally, a novel multimodal approach that combines diffusion weighted imaging and [11C]raclopride positron emission tomography identified differential relationships between frontostriatal connectivity and striatal dopamine tone in active AUD versus social-drinking controls. This suggests that aberrations in frontostriatal connectivity may contribute to reported differences in dopaminergic function in AUD. In summary, these results show that similar to detoxified/in-treatment alcoholics, active AUD samples present with WM integrity alterations, and changes in both structural connectivity and frontostriatal structure/function relationships.Item Definition of the mesostriatal dopamine deficit in the weaver mutant mouse and reconstruction of the damaged pathway by means of neural transplantation(1987) Triarhou, Lazaros ConstantinosItem Differential dopamine function in fibromyalgia(Springer, 2016-09) Albrecht, Daniel S.; MacKie, Palmer J.; Kareken, David A.; Hutchins, Gary D.; Chumin, Evgeny J.; Christian, Bradley T.; Yoder, Karmen K.; Radiology and Imaging Sciences, School of MedicineApproximately 30% of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [18F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and eleven female controls completed study procedures. Subjects received one FAL PET scan while performing a “2-back” task, and one while performing a “0-back” (attentional control, “baseline”) task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.Item Differential effects of acute ethanol on the dopaminergic and serotonergic systems in rat brain(1987) Khatib, Samir A.