Browsing by Subject "Addiction"

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Amanda Veasy Interview
(2022-02-18) Institute for Diversity & Civic Life; Department of Religious Studies
This interview is with Amanda Veasy, co-founder of One Love Longview, a nonprofit resource center for unsheltered, uninsured, and underserved populations. Amanda talks about the rapid rise of her organization as a response to community needs for accessible mental and physical health care. She describes the changes in her religious experiences over time, including being spurred to leave the church over her unwillingness to condemn the LGBTQ+ community. Amanda also talks about her methods of helping effectively by putting the individual’s desires and consent first and about the strength of her value of southern hospitality.
Astrocytes in alcohol use disorder
(2020-05-08) Erickson, Emma Kerstin; Harris, R. Adron; Mayfield, R. Dayne (Roy Dayne), 1958-; Contreras, Lydia M.; Eberhart, Johann K.; Iyer, Vishwanath R.
Excessive alcohol use causes abundant molecular adaptations throughout the brain, contributing to the pathology of alcohol use disorders (AUDs). Over 50 years of alcohol research has provided insight into brain regions and neurotransmitter systems associated with the development and maintenance of addiction. However, the cellular specificity of alcohol-related functional changes and their contributions to the neurobiology of AUDs remain largely unknown. In addition to neurons, a large percentage of brain space is occupied by glial cells, including astrocytes. Until recently, astrocytes were thought to be simple, passive support cells with no significant impact on behavior. This philosophy has begun to fade with new data demonstrating astrocytes are actively involved in regulating brain function and have the potential to be critical modulators of brain disorders like addiction. In this dissertation, I investigate the role of astrocytes in alcohol-induced molecular adaptations and behaviors. In the first two sections, I present transcriptome signatures of astrocytes isolated from mice subjected to different mouse models of AUD. I identify important biological pathways affected by alcohol that could disrupt cellular function. In the next section, I reveal astrocyte involvement in alcohol consumption and intoxication. Finally, I explore how astrocyte function affects acute behavioral responses to ketamine, a drug with similar molecular pharmacology as ethanol. Altogether, this work uncovers novel roles for astrocytes in behavioral responses to drugs while offering an array of promising astrocyte-specific molecular targets for future interrogation.
Behavioral Health Politics in Texas: Lessons from Austin and the 86th Legislature
(2020-05) Gajewski, Alexander James; Sage, William
How can behavioral health stakeholders engage effectively with Texas' government? To answer this question, my thesis examines three theories of effective advocacy: 1. Effective advocacy attempts to sway public attitudes. 2. Effecive advocacy attempts to change who holds office. 3. Effective advocacy introduces policymakers to new ideas. As the thesis brings nuance to each argument, it also provides readers with a basic understanding of the Texas Legislature, Texas politics, and key actors in state government. Analysis is integrated with narrative vignettes and distilled into seven chapters, each covering one topic in behavioral health policy. These topics include behavioral health lobbying, mental health insurance policy, the Early Childhood Intervention program, the mental health in schools movement, substance use prevention, and the politics of homelessness and comorbid mental illness. Each chapter introduces readers to subfields in public mental health and the political processes relevant to them. Personal experience, secondary research, and a small set of interviews with policy professionals inform the thesis. Ultimately, I hope to empower stakeholders to press the levers of public power and improve Texas' behavioral health care system.
Central amygdala CART modulates ethanol withdrawal-induced anxiety
(2013-08) Salinas, Armando; Morrisett, Richard A.
Cocaine- and amphetamine-regulated transcript (CART), as its name implies, was initially identified as an upregulated transcript in response to psychostimulant administration. Consequently, it has been posited to play a role in psychostimulant abuse and dependence. Spurred on by the finding that a polymorphism in the CART gene was associated with alcoholism, we initiated studies designed to elucidate the role of CART peptide in alcohol dependence. We first investigated the functional significance of CART peptide in alcohol dependence in vivo using a CART KO mouse. We found that CART KO mice had a significant decrease in ethanol consumption that could not be attributed to differences in total intake, taste perception, metabolism, or sensitivity to ethanol. In vitro we found that CART peptide facilitated NMDA receptor-mediated currents in central amygdala neurons. Given the emerging role of CART peptide in anxiety and stress, we decided to examine basal and stress-induced anxiety behaviors in CART KO mice. Under basal and acute stress conditions, CART KO mice did not differ in anxiety-like behaviors from WT mice; however, in response to a stressor, CART KO mice exhibited a potentiated corticosterone response. Using chronic intermittent ethanol exposure (CIE), we tested CART KO and WT mice for common signs of ethanol dependence including an escalation of volitional consumption and the presence of withdrawal-induced anxiety. We further investigated glutamatergic neuroadaptations within the central amygdala of CART KO and WT mice following CIE exposure and early withdrawal. CIE increased ethanol consumption and anxiety-like behaviors in mice of both genotypes but to a lower extent in CART KO mice. Electrophysiologically, CIE enhanced spontaneous excitatory postsynaptic currents in both genotypes and decreased the probability of presynaptic release in WT mice only. We believe that these electrophysiological neuroadaptations contribute to the development of ethanol dependence and may mediate withdrawal-induced anxiety behaviors. Overall, these studies indicate a role for CART peptide in alcohol dependence and specifically in modulating ethanol withdrawal-induced anxiety.
Considerations of the estrous cycle and female gonadal hormones in reward learning and memory
(2021-07-27) Hilz, Emily N.; Lee, Hongjoo Joanne; Monfils, Marie H; Gore, Andrea C; Morikawa, Hitoshi
Reward learning informs adaptive behaviors that allow us to advantageously engage with our environment; however, this learning can become maladaptive in some individuals and result in disordered behaviors like compulsive eating or drug-dependency. While the behavioral and neural substrates of reward learning are well established in males, much less attention has been given to these same systems in females. As females are at increased risk of disordered reward-seeking and female sex steroid hormones are potent modulators of the neural circuitry that underlies reward learning, developing a thorough understanding of how female hormonal states modulate this type of learning will help inform the development of individual-specific therapeutic interventions. In this dissertation, the findings of several studies using rat models of the estrous cycle in both food- and drug-learning are presented. Two aspects of reward learning are explored: renewal of extinguished conditioned food-seeking behavior, and conditioned place preference for amphetamine (AMP). Both paradigms provide novel methodologies for considering endogenous gonadal hormone states as a modulator of female conditioned responding and explore underlying neural mechanisms. Each experiment also considers conditioned orienting behavior as a potential indicator of individual differences in reward learning and memory. The experiments outlined here (1) consider the estrous cycle in the renewal of extinguished food-seeking, (2) examine estrous cycle modulation of immediate early gene Arc mRNA activity following exposure to separate learning contexts in the renewal paradigm, (3) consider conditioned orienting as a predictor of AMP place preference in female rats and, (4) modulate the estrous cycle with hormonal contraceptives to observe subsequent AMP place preference and related response measures. Behaviorally, a consistent result was found wherein the stage of the estrous cycle associated with high endogenous sex steroid hormone levels (i.e., proestrus or P) stimulated female conditioned responding (either increasing the likelihood of renewed food-seeking or contributing to increased drug preference and hedonic drug responsivity). Functionally, P modulated activity in the brain either in dopamine cells or in downstream targets such as the hippocampus and prefrontal cortex. These effects depended on the specific learning windows when cycle-stage was considered. From this research it is apparent that the hormonal state of the female learner contributes to behavioral outcomes.
Dependence of allosteric modulation of glycine receptor function on agonist efficacy
(2017-08-11) Farley, Nicole-Marie Margot Hetzer; Mihic, S. John; Harris, R. Adron; Aldrich, Richard W; Pierce-Shimomura, Jon T; Wilcox, Richard E
The glycine receptor (GlyR) is a ligand-gated chloride channel that mediates inhibitory neurotransmission in the brain and spinal cord. Numerous allosteric modulators act on the GlyR including divalent cations, such as zinc, as well as drugs of abuse including ethanol, inhalants, anesthetics and cannabinoids. GlyRs mediate some of the rewarding effects of addictive drugs and modulate drug related behaviors through activity in the mesolimbic dopamine reward pathway. GlyR activity, however, can differ depending on whether the receptor is activated by the high-efficacy agonist, glycine, or taurine which has much lower efficacy at wild-type GlyRs. As glycine and taurine are believed to activate the GlyR in vivo, it is crucial that we understand receptor function and allosteric modulation of receptors in response to both agonists. We used two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes to study the effects of zinc and ethanol on wildtype glycine receptors activated by glycine or taurine. We determined that the magnitude of allosteric modulation was higher, overall, at taurine-gated receptors and hypothesized that this may be related to the difference in efficacies. Considering that GlyR mutants can affect agonist sensitivity and the response to allosteric modulators, we wondered whether changes in allosteric modulation at mutant receptors could be due to changes in agonist efficacy caused by these mutations. We tested this hypothesis by characterizing ethanol and zinc modulation of taurine currents at GlyR mutants that showed an increase ([alpha]1[superscript W170S]) or decrease ([alpha]1[superscript A52S]) in taurine efficacy. We found that the W170S mutation increases the relative efficacy of taurine to a level that is comparable with glycine and abolishes ethanol enhancement of maximally-effective taurine currents. We determined that the difference in ethanol potentiation of low taurine currents between W170S and WT receptors is due to zinc enhancement of WT currents. Ethanol modulation of these receptors was equal in the presence of tricine. This suggests that ethanol also increases taurine affinity at W170S. A52S, on the other hand, displayed reduced taurine efficacy and increased ethanol modulation. This work provides evidence of a mechanism by which the degree of allosteric modulation of glycine receptor function is dependent on agonist efficacy.
Ethanol experience induces metaplasticity of NMDA receptor-mediated transmission in ventral tegmental area dopamine neurons
(2011-08) Bernier, Brian Ernest; Morikawa, Hitoshi; Harris, R. A.; Aldrich, Richard; Koester, Helmut; Valenzuela, Fernando
Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug-related experiences are formed, resulting in persistent and uncontrollable drug-seeking behavior. However, it is well known that both acute and chronic alcohol (ethanol) exposures impair various types of learning and memory in both humans and animals. Consistent with these observations, both acute and chronic exposures to ethanol suppress synaptic plasticity, the major neural substrate for learning and memory, in multiple brain areas. Therefore, it remains unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. The mesolimbic dopaminergic system is critically involved in the learning of information related to rewards, including drugs of abuse. Both natural and drug rewards, such as ethanol, cause release of dopamine in the nucleus accumbens and other limbic structures, which is thought to drive learning by enhancing synaptic plasticity. Accumulating evidence indicates that plasticity of glutamatergic transmission onto dopamine neurons may play an important role in the development of addiction. Plasticity of NMDA receptor (NMDAR)-mediated transmission may be of particular interest, as NMDAR activation is necessary for dopamine neuron burst firing and phasic dopamine release in projection areas that occurs in response to rewards or reward-predicting stimuli. NMDAR plasticity may, therefore, drive the learning of stimuli associated with rewards, including drugs of abuse. This dissertation finds that repeated in vivo ethanol exposure induces a metaplasticity of NMDAR-mediated transmission in mesolimbic dopamine neurons, expressed as an increased susceptibility to the induction of NMDAR LTP. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5- trisphosphate (IP3) in producing the facilitation of action potential-evoked Ca2+ signals critical for LTP induction. Interestingly, amphetamine exposure produces a similar enhancement of IP3R function, suggesting this neuroadaptation may be a common response to exposure to multiple drugs of abuse. Additionally, ethanol-treated mice display enhanced learning of cues associated with cocaine exposure. These findings suggest that metaplasticity of NMDAR LTP may contribute to the formation of powerful memories related to drug experiences and provide an important insight into the learning component of addiction.
Friends with benefits : on documenting the struggle of a friend
(2016-08) Onsando, Weslie; Garrison, Andrew; Spiro, Ellen; Straubhaar, Joseph
Selené is a 24-minute documentary film about a 24-year-old drug addict’s struggle to reconcile her addictions with her faith in God. The following report gives an account of the documentary’s conception and actualization. It also highlights the filmmaker’s intention and reflection throughout the creative process. Supplementary materials include the original proposal for the film as well as screenshots from the completed documentary.
Habit-forming : reading Infinite jest as a rhetoric of humility
(2011-05) Gerdes, Kendall Joy; Davis, D. Diane (Debra Diane), 1963-; Cvetkovich, Ann
In this project, I argue that David Foster Wallace's 1996 novel Infinite jest (or IJ) is both about recovering from addiction through humility, and also it produces that humility in some of its readers by making us feel ourselves to be addicts to a certain kind of reading: a reading to find closure, certainty, and resolution. But, in frustrating the desires for closure, certainty, resolution, etc., IJ denies readers the satisfaction of completing the fix. It is precisely this denial that prompts readers to re-read, repeating the structure of addiction--but also destructuring it, by installing habits of reading that pleasure in the failure to close, the uncertainty, the impossibility of resolution--habits which I treat as humility. Following a thread in the performative theory of J.L. Austin, Jacques Derrida, and Eve Kosofsky Sedgwick, I clear space for reconceptualizing the performative utterance through an unusual example of a performative utterance: I take IJ to be the utterance of humility. Drawing on Avital Ronell's "narcoanalysis" in Crack wars, I argue that IJ's performative or substantializing work is in exploiting one kind of habit (addiction) in order to replace it with another (humility). The rhetorical transformation (to humility) effects itself through IJ's performative formation (in the reader) of the humbled habit. This project is a reading of a performative utterance (IJ) that produces a rhetorical effect, which effect is the formation of the habit of humility.
Hate the sin, blame the sinner : the effects of language on attitudes toward substance use disorders
(2020-06-23) Tinlin, Charles Ryan; McGlone, Matthew S., 1966-
The reported study aims to explain the role syntactic choices, such as noun form, can have on the perceived persuasiveness of arguments related to opioid use disorders. In addition to these syntactical choices, the author was also interested in how semantic differences, such as argument frames, can influence persuasiveness. Participants (N=764) were exposed to one of eight op-ed style essays using different argument frames (health crisis vs. moral crisis), different noun forms referred to as actor nouns (addicts) and activity nouns (addiction), and different diagnostic labels (addiction vs. abuse). This study found that argument frames and nominal form can influence audience perceptions of agency and responsibility in people living with opioid use disorders. These differing perceptions of agency appeared to influence the persuasiveness of essays prescribing differing degrees of punishments for individuals’ living with substance use disorders.
Hijacking Our Own Attention Controls to Curb Capitalistic Surveillance
(2021-05) Hilder, Jordan O'Dowd
There is currently a lacuna within the law with regard to the legality of the ethics of creating software with features that initiate and perpetrate addictive behavioral patterns: users are engaged in a perpetual scroll that allows for extensive free data mining that benefits the profit motives of corporations. The user is the product: in essence, the user’s attention is being mined, as the longer a user spends scrolling, the more profitable to a corporation he/she is. Internet companies are only concerned with how to best initiate, motivate and perpetrate addictive behaviors as strategies to mine data and in turn, optimize profits, and take no pains to protect or care for vulnerable populations that fall prey to the woes of addiction. This data is shared with corporations, institutions, and government agencies and used to modify behavioral changes and to classify, differentiate, and hierarchize individuals as they see fit. Knowledge is power. We no longer own our own data. We no longer own our own attention. Ethicists understand the need for enacting and enforcing policies and regulations that limit the data mining of Big Tech and limit the addictive potential of platform and app designs. In this paper, I examine the relationship between knowledge and power and its relevance and implications for the infiltration of surveillance as a mechanism of power in educational practices with the aim of increasing user conformity. I discuss the development of an app that helps redirect the obsessive-compulsive feedback loop of addictive thinking that benefits corporations and institutions into thinking patterns that help users control usage and break addiction, and in turn, generate positive physical, mental and socio-cultural benefits. Finally, I evaluate the positive and negative social implications of using attention distraction blocker apps.
Karen Thompson Interview
(2020-10-06) Institute for Diversity & Civic Life
This interview is with Karen Thompson, Pastor of Uprising Austin. Karen was an avid church go-er in Pflugerville and involved in youth work. She came out as lesbian during the process of becoming a minister and was eventually ordained in Metropolitan Community Churches, creating a safe space for the LGBTQ community. Speaking on the pandemic, Karen moved into the church for three months to make sure the food and clothes delivery services to Austin’s unsheltered population were able to continue. Now, Karen is in the process of founding a daycare for deaf infants and children as well as children from low socioeconomic backgrounds.
Loss of control and phenomenology in mental disorder
(2021-08-16) Evans, Amanda Lea; Montague, Michelle; Strawson, Galen; Sosa, Ernest David; Bayne, Tim; Pickard, Hanna
Any insights we can hope to gain with respect to what is going on with our mental lives and our agency will almost certainly require a close examination of the “worst-case scenarios”, since it is when things break down that the joints of the phenomena are revealed. This is a philosophical intuition of mine that pervades everything I work on, and the papers that make up this dissertation are no exception. In keeping with this guiding sentiment, this dissertation tackles three philosophical issues related to the so-called “loss of control” that occurs in mental disorder, and it does so in a way that places the phenomenology of agency at the forefront in some way or other. In my first paper on the sense of agency in anorexia nervosa (AN), I try to resolve an apparent discrepancy between the phenomenology of anorexics in the grip of their disorder and the psychological and neurological data that purport to describe what they are undergoing. I provide a solution to this apparent incongruency by offering an account of the sense of agency in AN that grants sincerity to anorexic testimony while also being able to explain why the relevant experiences of agency come to be illusory. Then, in my second paper, I broaden my scope to include not just AN but also substance use disorder (SUD). After outlining the debate surrounding the question of whether addiction ought to be categorized as a form of akrasia, I show that the phenomenon at issue is far more complex than either side has supposed. I then propose a “horseshoe model” of loss of control that is able to capture the complexity that is brought in by examining the similarities and differences between SUD and AN. Finally, in my third paper, I pursue a question that arises from the exposition of the horseshoe model introduced in the previous paper. The question is, roughly, “Why is one ‘half’ of the horseshoe model associated with the phenomenology of loss of control while the other “half” is associated with the phenomenology of extreme self-control?”. This line of inquiry ultimately leads to an understanding of how one’s pathological desires can be experienced quite differently depending on the content of one’s self-image. Taken together, it is my hope that these papers can contribute to the philosophical goal of unearthing the realities of our mental lives and our agency by examining the fault lines formed by psychopathology.
Maintaining relationships during recovery : expanding inconsistent nurturing as control theory
(2020-12) Kearns, Kyle; Dailey, René M.; Donovan, Erin; Vangelisti, Anita; Holleran Steiker, Lori
Inconsistent nurturing as control theory has illuminated how those who wish to support their romantic partners' substance use disorder (SUD) recovery may use different communicative strategies to do so. However, loved ones have an interest in maintaining their relationship with the recovering individual, a goal that may compete at times with efforts to help them avoid relapse. Thus, research is needed to establish the connection between influence behaviors and relationship quality, as well as that between relationship quality and relapse. The present study gathered data from 149 romantic partners of individuals in recovery from problematic substance use. Data was collected again two weeks (n = 108) and four weeks (n = 85) after the initial survey. Results indicate that punishing one's partner for substance use-related behavior led to lower relationship quality, while reinforcing the substance use or reinforcing alternative behavior (such as attending treatment or sober activities) was related to increased relationship quality. Further, higher relationship quality was associated with lower rates of relapse later in the study. Finally, participants who indicated they had reached a point of frustration in their relationships had lower relationship quality and may experience the effects of reinforcing alternatives slightly differently. Implications for both theory and practice are discussed.
Medial prefrontal cortical extracellular dopamine responses after acutely experimenter-administered or orally self-administered ethanol
(2012-12) Schier, Christina Joanne; Gonzales, Rueben Anthony
Dopamine signaling in the prefrontal cortex is thought to play a role in ethanol abuse. However, little is known about how ethanol affects dopamine signaling in the region. There are a few rodent studies regarding the matter, but both the pharmacological effects of ethanol and the effects of self-administered ethanol on extracellular dopamine in the medial prefrontal cortex remain unclear. The goal of the studies conducted for this dissertation is to clarify these relationships. To accomplish this, we monitored both dialysate dopamine and ethanol concentrations in the medial prefrontal cortex of Long Evans rats while an experimenter administered or a rat operantly self-administered ethanol. In naïve rats, dopamine dose-dependently increased after the intravenous infusions of a 10% ethanol solution, while no changes were noted after saline infusions. In rats trained to orally self-administer drinking solutions, dopamine transiently increased at the initiation of consumption in both ethanol-plus-sucrose- and sucrose-solution-consuming rats. Dopamine concentrations remained significantly elevated for the entire 21-minute drinking period in the ethanol-plus-sucrose-consuming group and for the first seven minutes of the drink period in the sucrose-consuming group. Additionally, in the ethanol-plus-sucrose-consuming group, dialysate ethanol concentrations were lowest at the initiation of drinking and then slowly increased, peaking 35 minutes after drinking commenced. Taken together, these data suggest that the mesocortical dopamine system is responsive to acute, intravenous and repeatedly, orally, self-administered ethanol. It appears that direct pharmacological effects of ethanol were responsible for the dopamine increase after acute, ethanol administration. Furthermore, while is it possible that the direct pharmacological effects of ethanol also bolstered the dopamine response seen after ethanol self-administration, we cannot firmly conclude by what mechanism ethanol elicited the differences. Overall, our clarifying and novel results support a role for the mesocortical dopamine system in ethanol abuse, which deserves continued investigation. In addition to completing the two aforementioned data studies, we also published the methods we use to monitor dialysate ethanol concentrations, in a specific brain region, during ethanol self-administration in a video-methods journal. The methods are presented in both a detailed written protocol, as well as a video demonstrating how to perform the procedures.
Molecular pathways in alcohol consumption and dependence : emphasis on gut-brain and neuroimmune signaling
(2021-12-03) Grantham, Emily Kathleen; Harris, R. Adron; Mayfield, R. Dayne (Roy Dayne), 1958-; Messing, Robert O; Fonken, Laura; Davies, Bryan
Alcohol use disorder (AUD) is a chronic, relapsing brain disease with few effective treatment options. Chronic alcohol abuse leads to cellular and molecular changes throughout the brain and body. These molecular adaptations, such as gene expression changes, drive the pathophysiology of AUD. Therefore, it is critical to profile and understand gene expression changes underlying the various components of AUD, such as voluntary alcohol consumption, alcohol dependence, and stress-induced alcohol consumption. Microarray and transcriptome studies have revealed neuroimmune signaling as a consistent and significant molecular pathway involved in the regulation of alcohol consumption and dependence, though the mechanisms for how this pathway modulates behavior are unclear. In addition, given the limited availability of FDA-approved therapies for AUD, novel approaches to targeting the brain are necessary. One promising approach for therapeutic development involves targeting anti-inflammatory signaling via the gut-brain axis. In the first part of this dissertation, I describe transcriptome changes caused by chronic alcohol exposure and stress in critical stress- and addiction-related brain regions, the nucleus of the solitary tract (NTS) and bed nucleus of the stria terminalis (BNST). Results from these experiments identify neuroimmune signaling, specifically type I interferon signaling, as an important dependence-related signaling pathway across the brain. Next, I show that pharmacologically manipulating type I interferon signaling affects addiction-related behaviors depending on the timing of drug administration. Finally, I take advantage of the neural connection between gut and brain to develop a novel drug delivery system that targets neuroimmune signaling and has the potential to reduce alcohol consumption. Altogether, this work provides new information about molecular drivers of alcohol dependence and consumption and lays a foundation for novel therapeutic development in the future.
My sister Sarah
(2013-05) Chatelain, Elizabeth Marie; Kelban, Stuart
"My Sister Sarah" is a 25-minute long documentary film about my sister, Sarah Chatelain, a recovering methamphetamine addict from Fargo, North Dakota. Utilizing a combination of family home videos, Super 8 film and verité footage of Sarah's contemporary life, "My Sister Sarah" relates Sarah's journey with drug addiction from childhood through recovery. This report contains the process of creating the film: its inception, production and completion.
Neuroimmune signaling in alcohol abuse
(2022-10-06) Warden, Anna Senia Britta; Harris, R. Adron; Mayfield, R. Dayne; Hofmann, Hans; Messing, Robert O; Ehrlich, Lauren IR
Chronic alcohol use produces vast changes in gene expression and function across peripheral organs and the brain. These ethanol-induced adaptations eventually lead to alcohol dependence and alcohol use disorder (AUD), depending on both genetic and environmental factors. Recent evidence suggests that the interplay between brain, behavior and immune response plays a crucial role in the transition from alcohol misuse to dependence and the development of AUD. Previous work has connected neuroimmune signaling to regulation of alcohol behaviors. This dissertation seeks to address two major gaps in knowledge in our field: (1) which innate immune signaling pathway mediates alcohol behaviors; (2) when microglia, the primary immune cell in the brain, are casual regulators of alcohol behaviors. I apply immunological, pharmacological, and network-based approaches to gain mechanistic insight into how neuroimmune signaling regulates alcohol abuse. In this dissertation I provide evidence that neuroimmune signaling regulates alcohol abuse. First, I developed a viral innate immune model of excessive drinking. I demonstrated that toll-like receptor 3 (TLR3) mediates alcohol consumption in a sex- and genotype-specific manner, dependent upon the duration of innate immune activation. Using RNA-sequencing and bioinformatics, I further defined the transcriptomic and cell type-specific perturbations that regulate neuroimmune-induced escalations in alcohol intake—microglial immune response and the extracellular matrix. Further characterization of peripheral immune cell recruitment demonstrated that plasmacytoid dendritic cells may be an important cell type in this model. I also found that although microglia are implicated in alcohol abuse and dependence, microglia depletion does not change many alcohol behaviors. Instead, transcriptomic analysis implicated astrocytes in regulation of acute and voluntary drinking. Whereas, microglia regulated context-specific behaviors. The final component of this dissertation examined how we can leverage gene expression information to predict novel therapeutic compounds to treat alcohol abuse. I applied transcriptome-based computational approaches to predict compounds that regulate excessive drinking. Top predictions were validated in vivo, reinforcing a role for type I interferon signaling, the extracellular matrix and anti-inflammatory drugs in alcohol abuse. The results of this dissertation further our understanding of how neuroimmune signaling regulates alcohol abuse and proposes several new therapeutic targets to treat excessive drinking.
Repeated social stress induces metaplasticity in ventral tegmental area dopaminergic neurons
(2015-12-02) Stelly, Claire Elizabeth; Morikawa, Hitoshi; Harris, Robert A; Monfils, Marie; Mauk, Michael; Wilson, Charles
Learned associations between environmental cues and drug reward are critical for reinforcing drug use and triggering relapse. Effective prevention and treatment of substance use disorders requires a detailed understanding of the synaptic plasticity mechanisms underlying these associations as well as their modulation by experience, environment, and genetic differences. Stressful experience increases susceptibility to addiction in humans and hastens the development of addiction-related behaviors in rodent models. The facilitating effects of stress persist beyond the duration of the stressful experience, suggesting that stress causes persistent cellular adaptations that promote drug-related learning processes. The data presented in this dissertation demonstrate that stress, via glucocorticoid receptor (GR) signaling, induces metaplasticity of N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). NMDAR-mediated transmission in these neurons is of particular importance as it is required for burst firing and subsequent phasic dopamine release, which is both necessary and sufficient for learning of reward-predictive cues. Repeated exposure to social defeat stress induces a persistent, PKA-dependent increase in the sensitivity of inositol 1,4,5-triphosphate (IP3) receptors. This sensitization of IP3Rs augments metabotropic glutamate receptor (mGluR) -dependent calcium (Ca²⁺) signaling, which then enhances induction of long-term-potentiation of NMDAR transmission (NMDAR-LTP). Repeated social defeat stress also enhanced acquisition of cocaine conditioned place preference (CPP), a form of associative learning driven by drug reward, and this effect required GR signaling as well. This dissertation provides the first demonstration of stress-induced metaplasticity in VTA DA neurons. These findings may illuminate one mechanism by which stress increases vulnerability to addiction, a chronic, relapsing disorder that is perpetuated by powerful memories of stimuli associated with drug reward.
Smoke signals : patterns of agency assignment in smoking initiation and cessation narratives
(2017-05) Wartel, Max Aaron; McGlone, Matthew S., 1966-; Vangelisti, Anita; Ballard, Dawna; Banas, John
This research sought to describe and understand patterns of linguistic agency assignment in smoking cessation narratives. To this end, a corpus of these narratives gathered from an online twelve step cessation program, Voices of Nicotine Recovery (VONR), was constructed and an objective scheme for coding linguistic agency assignment in ex-smokers’ cessation narratives was developed. When discussing smoking and addiction, speakers have the option of linguistically assigning agency (i.e., the capacity for action) to themselves, others, inanimate objects, or to abstract concepts like addiction. Patterns of agency assignment may provide insight into conceptions of efficacy and responsibility for addictive behaviors. The author predicted patterns of linguistic agency based on the dominant disease model of addiction, cessation programs based in this model, and extant findings concerning self-efficacy and nicotine addiction. The author hypothesized that ascription of agency would vary during the stages of addiction such that personal agency would decline and non-personal and non-human agency would increase following addiction. Findings were consistent with predictions concerning increases in non-human agency following nicotine addiction relative to pre-initiation levels. However, observed patterns of agency assignment were not consistent with other predictions based in the disease model. It was also hypothesized that following the expected decrease in personal agency ascription after smoking initiation, personal agency assignment would then increase leading to cessation attempts. During quit attempts, personal agency assignment was expected to decrease before rising following successful cessation to its highest post-initiation levels. As predicted, the highest post-initiation levels of personal agency assignment were observed following cessation. However, the data were inconsistent with expected patterns of linguistic agency for other stages. These findings suggest that the study of linguistic agency in addiction narratives may contribute to an improved understanding of how addiction operates and the extent to which the disease model is predictive of the way in which recovering nicotine addicts view their addiction and cessation. Findings, implications, and additional areas of research are discussed.