Medical Neuroscience Department Theses and Dissertations

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Browsing Medical Neuroscience Department Theses and Dissertations by Subject "Addiction"

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    Assessment of Ethanol and Nicotine Interactions in the Rat Model: Pharmacotherapeutics, Adolescence, and the Mesolimbic System
    (2019-09) Waeiss, Robert Aaron; Truitt, William A.; Hudmon, Andy; Johnson, Philip L.; McBride, William J.; Rodd, Zachary A.
    Alcohol use disorder (AUD) and nicotine dependence often result in serious health problems and are top contributors to preventable deaths worldwide. Co-addiction to alcohol and nicotine is the most common form of polysubstance abuse. Epidemiological studies indicate that more than 80% of individuals diagnosed with AUD concurrently use nicotine. The prevalence of alcohol and nicotine comorbidity may stem from interconnected mechanisms underlying these disorders. A better understanding of how these drugs interact and the biological basis behind the high comorbidity rates could generate key targets for the development of more effective treatments for AUD and nicotine dependence. The following experiments utilized four similar overall groups consisting of vehicle, ethanol (EtOH), nicotine (NIC), and EtOH+NIC. Chapter Two investigated the efficacy of naltrexone and varenicline, the pharmacological ‘gold standards’ for treating AUD and nicotine dependence, on voluntary drug intake by rats selectively bred for high EtOH drinking. The results indicated that the standard treatments for AUD and nicotine dependence were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC co-use/abuse. Chapter Three examined the effects of peri-adolescent EtOH drinking on the ability of NIC infused into the posterior ventral tegmental area (pVTA) to stimulate dopamine release within the nucleus accumbens (NAc) shell during adulthood. The results suggest a cross-sensitization to NIC produced by peri-adolescent EtOH consumption demonstrated by a leftward and upward shift in the dose response curve. Chapter Four investigated the effects of intra-pVTA infusions on NAc shell neurochemistry, EtOH reward within the NAc shell, and the role of brain-derived neurotrophic factor (BDNF) on EtOH reward within that region. The data indicated that only EtOH+NIC significantly increased glutamate, dopamine, and BDNF in the NAc shell. Repeated pretreatment with EtOH+NIC also enhanced EtOH reward in the NAc shell and BDNF infusions were sufficient to recapitulate these findings. Collectively, the data indicate that concurrent exposure to EtOH and NIC results in unique neuroadaptations that promote future drug use. The failure to develop effective pharmacotherapeutics for AUD or nicotine dependence could be associated with examining potential targets in models that fail to reflect the impact of polydrug exposure.
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    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.
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    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.
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    The Enduring Consequences of Prenatal Opioid Exposure
    (2022-02) Grecco, Gregory Giovanni; Sheets, Patrick; Atwood, Brady; Yamamoto, Bryan; McKinzie, David; Yoder, Karmen
    The opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure; however, the long-term effects of opioid exposure on offspring behavior and neurodevelopment remain relatively unknown. I developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. PME produced substantial impairments in offspring growth, sensorimotor milestone acquisition, and activity in an open field. Furthermore, these behavioral alterations were associated with significant disruptions in the primary motor cortex (M1). Notably, layer 5 pyramidal neurons of the M1 displayed significantly increased voltage sag which is primarily mediated by HCN1 channels. Interestingly, the α2-adrenergic receptor, a known modulator of HCN1 channels, displayed significantly increased expression in the M1 of PME animals. The locomotor activity in an open field was significantly reduced following in vivo pharmacological activation of the α2-adrenergic receptor with clonidine in PME offspring suggesting this may be therapeutic target for the hyperactivity associated with prenatal exposure to opioids. Previous work has also described an association between prenatal opioid exposure and alterations in opioid reward-related behavior; however, the effect of PME on alcohol reward remains undetermined. Given the widespread accessibility and usage, alcohol represents the most likely addictive substance the growing population of opioid exposed neonates will encounter as they age. I discovered that PME disrupts conditioned preference for alcohol, enhances the locomotor stimulating effects of alcohol, and increases alcohol consumption in a sex-dependent manner. This alcohol-reward phenotype in PME offspring was associated with altered excitatory neurotransmission and disrupted cannabinoid-mediated long-term depression (CB-LTD) in the dorsolateral striatum, an important substrate involved in compulsive drug use. Further work is required to determine the specific inputs at which CB-LTD is disrupted and if restoring this form of plasticity in PME animals prevents the enhanced alcohol addiction phenotype.