Browsing by Subject "Addiction"

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Behavioral and neurobiological consequences of intermittent exposure to addictive drugs.
(2010-02) Rothwell, Patrick Eldredge
These studies were undertaken to better understand how repeated exposure to addictive drugs leads to adaptations in brain function and behavior related to the development of addiction. They are predicated on evidence that the mere presence of a drug in the body is not the sole determinant of adaptation - rather, the pattern of drug exposure is a key variable, with intermittent exposure making the brain reward system increasingly sensitive to drugs and leaving individuals susceptible to relapse. These experiments were designed to examine whether events occurring during the offset of drug action may contribute to the unique effects of intermittent drug exposure. The first series of experiments develops a set of behavioral measures that can be used to resolve and quantify a state of acute withdrawal caused by the offset of drug action. The second series of experiments utilizes these measures to investigate whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization - a specific consequence of intermittent drug exposure related to adaptations in the brain reward system. The final series of experiments describes a specific synaptic adaptation in a key component of the brain reward system (the nucleus accumbens) that is caused by intermittent drug exposure, related to the development of psychomotor sensitization, and reversed by experiences linked to relapse. The results of these studies suggests new and provocative interactions between neural circuits mediating reward and aversion, which may help identify and explain forms of neural plasticity that underlie the development of drug addiction.
Characterizing specific henetic and environmental influences on alcohol use
(2012-09) Irons, Daniel Edward
Although both genetic and environmental influences, as well as the interplay between them, are clearly important to the development of alcohol use and related psychopathology, the effects of many of the particular genetic variants and environmental risk factors responsible have not yet been confirmed. We conducted three studies with the goal of moving beyond abstract estimates of genetic and environmental variance to the assessment of whether specified risk factors were causally implicated in the development of alcohol-related behaviors and problems. First, in a longitudinally assessed sample of 356 adopted adolescents and young adults of East Asian descent, we examined the progression over time of the relationship between a functional polymorphism in the alcohol metabolism gene aldehyde dehydrogenase 2 (ALDH2) and multiple measures of drinking behavior. We found that the protective effect of the less-functional ALDH2 variant increased between mid-adolescence and early adulthood, and that non-biological parental alcohol use, but not sibling alcohol use, nor deviant peer affiliation, moderated the effect of the gene. In a second study, using a community-based sample of 7224 individuals assessed in early and middle adulthood, we employed multiple methods to conduct a comprehensive examination of the effects of markers in GABA system genes on measures of alcohol use and related symptomatology. We tested not only the potential effects of individual markers, but also their effects in aggregate, and at the whole-gene and system-wide levels. None of these methods produced results indicative of an effect of GABA system variants on measures of alcohol use or misuse. We conducted a third study with a sample of 1512 twins, longitudinally assessed from early adolescence into adulthood, to determine whether adult alcohol use and misuse, as well as other adult outcomes, could be attributed to the causal effect of alcohol exposures in early adolescence. We used two separate techniques to adjust for potentially confounding factors. First, we used a propensity score design to adjust for the potentially confounding effects of a number of measured background covariates. Second, we used the cotwin control design to adjust for confounding due to unmeasured factors (including genetic influences) shared between twins in pairs discordant for early alcohol exposure. The results of both methods applied in this third study were generally consistent with there being a causal effect of early alcohol exposures on the later development of adult alcohol problems and other related adult outcomes, but contrasting the two methods indicated that exposure effect estimates from the propensity score application were likely to be biased by unmeasured confounding variables. In summary, we have first substantially elaborated upon the effects of a genetic variant known to influence alcohol-related behaviors (in the ALDH2 gene); next, despite thorough investigation, we have found no evidence for the effects of a second set of purported genetic influences (GABA system genes); and finally, we provided evidence that early alcohol exposure likely exerts a genuinely causal influence on later alcohol-related problems and other adult outcomes.
Chemogenetic Inhibition of Ventral Tegmental Area Dopamine Neurons Does Not Affect Cue-elicited Alcohol Seeking
(2023-09-23) Liao, Isaac; Remde, Paige; Richard, Jocelyn M
Alcohol use disorder (AUD) is characterized by an impaired ability to control alcohol use despite negative consequences. Individuals with AUD often have significant physiological and subjective reactions to presentations of cues associated with alcohol availability. Alcohol-predictive cues evoke a conditioned motivational state that elicits alcohol-seeking behaviors, which can then drive other aspects of addiction, such as compulsive drinking and relapse. Previous rat studies found that dopamine neurons in the ventral tegmental area (VTA) play a key role in cue-elicited reward seeking (Halbout et al., 2019). A recent study showed that chemogenetic inhibition of VTA dopamine neurons reduces alcohol seeking in a Pavlovian paradigm (Valyear et al., 2020), where alcohol and cues were delivered simultaneously. However, it remains controversial to what extent the activity of VTA dopamine neurons encodes the motivational properties of alcohol-predictive cues. Here, we tested whether cue-elicited alcohol seeking is reduced when VTA dopamine neurons are chemogenetically inhibited. Fifteen TH-Cre-positive rats (females = 8, males = 7) were intermittently exposed to 15% ethanol. They underwent training to associate an auditory cue with alcohol. Cue-elicited alcohol seeking is measured by port entry probability and latency in response to cues. After training, the rats received hM4Di-DREADD or control virus infusion surgery to suppress VTA dopamine neurons bilaterally. They were then given ligand or vehicle injections and tested responses to cues under extinction and test conditions. After the tests, their brain tissues were examined for viral and cFos expressions. Overall, chemogenetic inhibition of VTA dopamine neurons has no effect on cue-elicited alcohol seeking. Such a diverging result may be driven by task differences between Pavlovian and operant conditioning. This suggests that different neural systems may underlie the conditioned motivational state evoked by a cue depending on the time of the cue’s presentation relative to reward delivery.
Chronic morphine treatment-modulated trafficking of AMPA receptors: a potential mechanism for drug addiction
(2012-08) Kam, Yuet Fong
Morphine is the benchmark analgesic for treating chronic pain. However, its clinical uses are hindered by its highly addictive nature, as chronic treatment with the drug will produce physical and psychological dependence upon the cessation of use. Drug craving is the main driving force for relapse after prolonged periods of abstinence, and represents an enormous challenge for the treatment of drug addiction. Since addiction is a long-term behavioral alteration, it is believed that addictive drugs produce reorganization of specific neural circuits and adjustment of synaptic strength. The underlying mechanisms of these neural adaptations may represent a promising target for prevention and/or treatment of addiction, but the detailed mechanisms of these processes remain unclear. Therefore, the main goals of this work are to delineate signaling pathways controlling morphine-induced neural adaptations and investigate their functional role in opiate addictive behaviors. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are postsynaptic glutamate receptors, and are responsible for mediating most excitatory synaptic transmission under normal conditions. More importantly, the dynamic localization of AMPA receptors plays a critical role for modifying synaptic strength and synaptic morphology. Here, I hypothesized that regulation of AMPA receptor trafficking by morphine treatment underlies the drug-induced neural modulation implicated in the addiction process. Hence, the first part of this dissertation research examined whether and how chronic exposure to morphine modulates trafficking of surface GluR1 (a subunit of AMPA receptors) in primary hippocampal neurons. Using live-cell imaging techniques together with biochemical studies, I demonstrated that chronic exposure to morphine induced a significant loss of synaptic and extrasynaptic GluR1 by internalization. In mechanistic studies, I found that the GluR1 internalization was attributed to dephosphorylation of the receptor subunit at Ser845 following morphine treatment, but it did not result from altered neural network or NMDA receptor activation. Moreover, dephosphorylation of GluR1 at Ser845 was found to require morphine-evoked calcineurin activation. Therefore, calcineurin-dependent dephosphorylation of AMPA receptor and subsequent AMPA receptor internalization provides a novel mechanism for opioid-induced neural adaptations. The second part of this dissertation research attempted to link morphine's effects on GluR1 phosphorylation and endocytosis to addictive behavior, especially formation of memory for the environmental context of the drug experience, because recall of this memory by encountering the drug-paired cues triggers relapse to drug seeking. In this approach, a mutant mouse line was used, in which GluR1 at Ser845 was mutated to Ala (S845A) leading to an absence of morphine-induced GluR1 endocytosis. A behavioral test, conditioned place preference (CPP), was carried out to assess the ability of morphine to produce a positive association with environmental cues. I found that S845A mice were significantly slower to acquire morphine-induced CPP when compared to wild types (WT). This decreased sensitivity to morphine CPP in mutants was neither related to contextual memory deficits or abnormal locomotor activity, as there was no difference between WT and S845A mice in the contextual memory acquisition in the Morris water maze test or locomotion with or without morphine injection. To examine the persistence of morphine-associated contextual memory in the mutant mice, I also performed extinction tests on mice conditioned with 10 mg/kg morphine for four sessions, by which both WT and S845A mice exhibited similar CPP responses. Interestingly, a prolonged extinction was observed in S845A mutant mice, suggesting the S845A mutation either impaired the learning of the new conditioning or prolonged the retention of the old conditioning. Nevertheless, these results suggest that an alteration in GluR1 phosphorylation at Ser845 and subsequent receptor endocytosis/insertion are involved in acquisition and extinction of morphine CPP. Altogether, the present findings indicate that calcineurin-mediated GluR1-S845 dephosphorylation is required for morphine-induced internalization of GluR1-containing AMPA receptors, providing a molecular basis for the drug-induced neural modulation. This work also suggests that this regulation of GluR1 phosphorylation and trafficking by morphine is involved in the modulation of the drug-associated contextual memory, which reflects the involvement of AMPA receptor trafficking in the mechanisms underlying opiate-seeking behaviors.
Decision making gone awry: Dorsal striatum, decision-making, and addiction
(2015-02) Regier, Paul
Millions of people use addictive substances, such as alcohol and cocaine, however only a subset of individuals become dependent on these types of substances. Addiction can be thought of as a maladaptive decision-making process, driven by distinct neural regions. As behavior shifts from goal-directed to habit-based behavior, control of this behavior by corticostriatal circuits shifts from the associative circuit, which includes the dorsomedial striatum, to the sensorimotor circuit, which includes dorsolateral striatum. Once behavior becomes more habit-based, and control shifts to the sensorimotor corticostriatal circuit, actions become difficult to devalue. Thus, behavior becomes difficult to change. In this dissertation, I explore a behavioral shift to habit-based behavior as one potential way addiction can occur. I focus on the dorsomedial and the dorsolateral striatum and the role of these two regions in goal-directed and habit-based behavior, respectively, and the role of these two regions in drug-seeking behavior. In addition, I discuss the dorsomedial and dorsolateral striatum in relation to animal models of drug addiction that differentially seek drugs, and I discuss these two regions as potential biomarkers of addiction treatment. Finally, I relate previous research as well as my own research, presented throughout the dissertation, to human drug use and consider how analogues of dorsal striatum in the human brain might play a role in human addiction and addiction treatment. In all, consideration of addiction as a maladaptive decision-making process as well as understanding the neural correlates of this process may help to generate new ways of perceiving, studying, and treating addiction.
Drug Regimes: Addiction, Biopolitics, American Literature, 1820-1940
(2019-07) McGillicuddy, Brendan
"Drug Regimes" traces the development of the disease concept of addiction from the early American Republic into the inter-war period. In this work, struggles against alcoholism, both individual and social, are used to frame and explore larger issues of national conflict occurring around race, gender, and political economy. Each chapter discusses a literary text that exemplifies a particular "drug regime" - a mode of the governance of health, both individual and public - and analyzes this text as a mode of extrapolating a political theory of drug conflict.
A Dual Investigation of Questions in Drug Addiction: Exploring the Role of Neuroinflammation in Opioid Withdrawal and A Novel Measure of Reward-Seeking Behavior in Rodents
(2016-08) Kennedy, Bruce
Substance abuse disorders are extremely disruptive to the lives and relationships of those who suffer from them and are a burden on society and the healthcare system. Effective treatments are currently lacking and our understanding of the neurobiology driving addictive behaviors remains incomplete. The following animal studies aimed to advance the drug addiction field by 1) investigating neuroimmune interactions as a potential mechanism in opioid withdrawal in mice as well as 2) introducing a novel behavioral test in order to expand the repertoire of tools available to researchers investigating drug or reward-seeking behaviors in rats. Microglia, the immune cells of the brain have been recently recognized as being important contributors in a wide variety of neuropsychiatric disorders, including drug addiction. Although current views support a microglia role in the physical drug dependence experienced by opioids addicts, it is thought that the emotional effects of withdrawal, such as anxiety and depression, are better predictors of relapse. In the first series of experiment, a genetic mouse model lacking the key microglia immune receptor TLR4 was used to determine the involvement of this protein in the molecular and behavioral responses to opioid withdrawal, in particular those related to negative emotions. Although technological advances in behavioral testing techniques have improved our ability to model drug addiction in rodents, the low-tech behavioral assays used most frequently have remained largely unchanged over the last several decades. The second set of experiments introduced and validated a novel behavioral task based on the classic measure of reward, conditioned place preference. In the modified test, objects rather than contexts were used as a conditioned cue, which potentially allows for greater flexibility and opens up new ways of analyzing conditioned approach, a commonly used measure for assessing the reward value of a given substance.
Endogenous modulation of addiction: chronic pain and the NMDA/NOS cascade.
(2010-07) Wade, Carrie Lynn
Opioid treatment for chronic pain is controversial due to abuse potential and perceived addiction potential. Because of perceptions of addiction from chronic opioid treatment for pain it is important to clearly understand the biological bases for a number of factors related to opioid therapy in the context of chronic pain, including the effectiveness of opioid treatment under distinct conditions chronic pain and alterations in the effectiveness of opioid treatment under distinct conditions of chronic opioid pharmacotherapy. One way to approach this question is to study the changes that occur with chronic pain and see how those changes parallel those that occur with opioid addiction. Our approach to address the questions raised above is to apply a combination of rodent models of pain and opioid self-administration. In the first phase of this study we examine changes in oral fentanyl self-administration under distinct conditions of chronic pain including inflammatory pain, neuropathic pain and an idiopathic pain model of sickle cell anemia. The second set of studies examines the potential for an endogenous modulator of the NMDA/NOS cascade to interact with adverse opioid events such as tolerance and addiction. We observed that mice with inflammatory pain, neuropathic pain and sickle cell anemia had differential fentanyl self-administration profiles following induction of mechanical hyperalgesia. In the second set of studies we observed that agmatine reduced opioid-induced tolerance and abolished self-administration behaviors. We also found that endogenous agmatine may have a neuroprotective effect on these opioid effects.
Enhancing the efficacy of a nicotine vaccine
(2013-03) Cornish, Katherine E.
Tobacco addiction is the leading cause of preventable death worldwide. Many people continue to smoke cigarettes despite clear detrimental health effects. Available smoking cessation therapies are only partially effective, making new treatment approaches necessary to increase smoking cessation rates. Immunization against nicotine features a different mechanism of action than currently available medications. As a pharmacokinetic antagonist, immunization against nicotine alters distribution, metabolism, and clearance of nicotine to attenuate nicotine-induced behavior in animal models. Nicotine vaccines in clinical trials show efficacy but are limited by the modest and highly variable nicotine-specific antibody (NicAb) concentrations produced. This thesis focuses on ways to improve efficacy of a nicotine vaccine by combining it with additional forms of immunotherapy. The first aim of this thesis examined the effects of supplementing vaccination against nicotine with individualized doses of Nic311, a nicotine-specific monoclonal antibody. Compared to either immunotherapy alone, combining active and passive immunization produced greater alterations in nicotine pharmacokinetics and nicotine-induced behavior using a locomotor activity model. Only small doses of Nic311 were necessary to supplement vaccine-generated NicAb concentrations to a previously effective threshold. This decreased cost and use of typically expensive monoclonal antibodies, potentially increasing viability of this approach in a clinical setting. The second aim of this thesis examined the effects of concurrent administration of two immunologically distinct nicotine immunogens in a bivalent vaccine over a range of vaccine formulations and immunization conditions. Immunogens were co-administered in a bivalent vaccine without compromising immunogenicity of either immunogen when delivered subcutaneously in alum, but not when delivered intraperitoneally in Freund's adjuvant. When combined in alum, immune responses elicited by the two immunogens were largely independent of one another. This suggests that subjects who responded poorly to one immunogen may have responded better to the second, immunologically distinct immunogen in the bivalent vaccine. These results indicate that the bivalent vaccine strategy is a feasible way to increase antibody concentrations above what can be achieved using one immunogen alone, but integrity of the response is highly dependent on vaccine formulation and administration conditions.
Gay Bar Culture and Drinking in the Lesbian, Gay, Bisexual, Trans, Queer, Intersex, Asexual and Two-Spirited Community
(2024-04-10) Dolan, Eleanor; Ostrander, Nomi
Gay bars have long been a staple of the Lesbian, Gay, Bisexual, Trans, Queer, Intersex, Asexual and Two-Spirited (LGBTQIA2S+) community. They were often the only spaces for LGBTQIA2S+ individuals to meet others, connect with their community, and engage in activism (Escoffier, 1997). Yet today the LGBTQIA2S+ community engages in disproportionately high levels of drinking (National Institute on Drug Abuse, 2017). This study examines the impact of gay bar culture of drinking in the LGBTQIA2S+ community through a survey of 60 participants from Minnesota who identify as members of the LGBTQIA2S+ community. The majority of participants reported no change in their drinking behavior between LGBTQIA2S+ and non-LGBTQIA2S+ spaces. Yet many expressed a need for more sober LGBTQIA2S+ spaces. Participants also expressed feeling safe in LGBTQIA2S+ spaces and enjoying their time in them. More research is required on the need for sober LGBTQIA2S+ spaces and the benefits they bring.
Greed-OxyContin-Addiction-Death
(2022) Hilleboe, Cody J
A supporting paper to fulfill the Master of Fine Arts degree requirements Submitted to the Graduate Faculty of the Department of Art University of Minnesota By Cody Hilleboe In partial fulfillment of the requirements of the Master of Fine Arts Degree in Art 2022 Committee: Rotem Tamir Christina Schmid Emily Jordan Jensen Tetsuya Yamada
Methadone population pharmacokinetics: toward understanding the dose-response relationship in the treatment of opiate addiction
(2013-01) Bart, Gavin Bryce-Samuel
Methadone is a synthetic opiate agonist that is highly effective in the treatment of opiate addiction. When given as a long-term therapy, methadone maintenance reduces morbidity and mortality associated with opiate addiction. It is thus considered an “essential” medication by the World Health Organization. The benefits of methadone maintenance in the treatment of opiate addiction are well established. Predicting treatment response for a given individual, however, remains difficult. While methadone dose is generally associated with treatment outcome, large interstudy and interindividual variability in plasma concentrations of methadone have made it difficult to link dose response to pharmacokinetic parameters. This thesis explores characteristics of methadone maintained patients and develops a population pharmacokinetic model that identifies variables associated with methadone pharmacokinetic parameters. Chapter 1 provides a general review of the three Food and Drug Administration approved pharmacotherapeutic agents for the treatment of opiate dependence. Chapter 2 reviews the clinical pharmacology of methadone as used in the treatment of opiate dependence. Chapter 3 introduces us to the Hmong and their paradoxically exceptional treatment outcome in methadone maintenance on lower doses of methadone than their non-Hmong counterparts. This retrospective study helps form the hypothesis that their better treatment outcome is related to greater methadone exposure.The results of this population pharmacokinetic study and the psychosocial differences between Hmong and non-Hmong are presented in Chapters 4 and 5, respectively. We found that the lower methadone dose requirement is explained by higher apparent bioavailability of methadone in Hmong. Other influences on methadone pharmacokinetics, more specifically clearance, include age, body mass index, and single nucleotide polymorphisms in the ABCB1 and CYP2B6 genes. While the potential for culture to influence methadone treatment outcome is acknowledged, there remain sufficient grounds to hypothesize a significant biological (i.e., pharmacokinetic and/or pharmacodynamic) influence.
mGluR5 Structural Plasticity in the Nucleus Accumbens: Characterization, Mechanism, and Sex Differences
(2017-10) Gross, Kellie S
The group I metabotropic glutamate receptors, mGluR1 and mGluR5, are important modulators of neuronal signaling and plasticity. One specific way that group I mGluRs appear to influence excitatory neurotransmission is through the remodeling of neuronal structure by inducing changes to dendritic spines. However, group I mGluR spine remodeling has only been studied in an extremely limited number of regions and cell types, leaving the contribution of this mechanism to plasticity in many systems unknown. Group I mGluRs, especially mGluR5, have been associated with the synaptic plasticity in the reward circuitry of the brain that is believed to underlie addiction. Structural changes in this circuitry, particularly in the nucleus accumbens (NAc) are strongly correlated with the development and maintenance of addiction. Yet a potential relationship between mGluR5 signaling and spine plasticity in the NAc has not been directly studied. Here, the effects of mGluR5 signaling on spine plasticity in medium spiny neurons of the NAc are characterized, with particular attention on the sex differences and hormonal regulation of these effects. Activation of mGluR5 signaling is found to decrease spine density in the NAc with sex differences in subregion specificity. Additionally, primary gonadal hormones are found to trigger mGluR5 signaling to produce structural modulation in the NAc, with previous evidence implicating mGluR5 in estradiol-induced spine changes in this region in females, and research here finding a similar, novel role for androgen signaling in males. The mechanisms of mGluR5-mediated spine plasticity are also explored. Endocannabinoid signaling was found to be required for mGluR5-induced spine decreases in the male NAc, and spine changes were found to be correlated with a change in NAc F-actin content. Collectively, these results indicate that mGluR5 signaling results in structural plasticity in a region that is critical to reward in a sex-dependent manner, suggesting that the activity of this receptor might contribute differently to both natural and pathological motivated behavior in males and females.
Neuroligin-3 Modulates Opioid-Evoked Changes in Behavior and Brain Function
(2022-05) Brandner, Dieter
Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 is a postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of neuroligin-3 alters responses to chronic morphine in male mice. Constitutive neuroligin-3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure, as well as a change in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of neuroligin-3 from cells expressing the Drd1 dopamine receptor, whereas the reduction in psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. In the absence of neuroligin-3 expression, dopamine neurons within the ventral tegmental area showed diminished activation following chronic morphine exposure, as measured by in vivo calcium imaging with fiber photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of neuroligin-3: dopamine neurons lacking neuroligin-3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioral sensitivity to opioids, and further suggests that neuroligin-3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.
Relevance of inhibitory G protein-dependent signaling in prelimbic pyramidal neurons to cocaine-related behavior
(2022-01) Rose, Timothy
Drugs of abuse share the ability to enhance DA levels within the mesocorticolimbic system. This increased DA neurotransmission triggers persistent adaptations throughout the brain that are believed to underlie the detrimental behaviors that define addiction. For example, chronic cocaine exposure causes a suppression of inhibitory G protein-dependent signaling mediated by the GABAB receptor (GABABR) and G protein-gated inwardly rectifying K+ (GIRK/Kir3) channel in pyramidal neurons of the prelimbic cortex (PL), a cell population important for executive function. As GIRK-dependent signaling is crucial for tempering excitatory input in neurons, the loss of this “inhibitory brake" may drive neuronal hyperexcitability and foster the development of addiction-related behavior. The goal of this thesis is to examine the contribution of GIRK channels in PL pyramidal neurons to behaviors that may be relevant to addiction, and to further understand the regulatory mechanisms that control inhibitory signaling mediated by GABABRs and GIRK channels.To test the prediction that a loss of GIRK channel activity in pyramidal neurons promotes neuronal hyperexcitability, we employed a viral genetic approach to selectively ablate a critical GIRK channel subunit (GIRK1) in PL pyramidal neurons. GIRK channel ablation blunted GABABR-GIRK currents in, and elevated the excitability of, PL pyramidal neurons – electrophysiological outcomes that closely resemble the effects of repeated cocaine exposure. To examine the behavioral consequences of elevated PL pyramidal neuron excitability, we used complementary viral approaches to model the impact of acute (chemogenetic) and persistent (GIRK channel ablation) excitation of PL pyramidal neurons on PL-dependent behaviors, including acute cocaine-induced locomotion and trace fear conditioning. We found that GIRK channel ablation enhanced the motor-stimulatory effect of cocaine, but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the ventral tegmental area, a brain region important for reward behavior. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice. Withdrawal from prolonged cocaine exposure has been correlated with negative affective behaviors, as well as formation of persistent drug-related memories that drive drug-seeking behavior. Therefore, we next modeled the impact of viral-mediated GIRK, or GABABR, ablation in PL pyramidal neurons on mood-related behaviors and cocaine conditioned place preference (CPP). While GIRK ablation did not impact anxiety- or depression-related behavior, the manipulation impaired the extinction of cocaine CPP in male mice. In contrast, GABABR ablation was without effect. Since an impairment in extinction may result in prolonged drug-seeking behavior, we next assessed whether strengthening GIRK channel activity could enhance the extinction of cocaine CPP. As predicted, overexpression of GIRK2 in PL pyramidal neurons facilitated extinction of cocaine CPP in male mice. Together, these findings highlight a unique, sex-specific role for GIRK channels in PL pyramidal neurons in tempering cocaine conditioned responding. Despite established links between GIRK channel plasticity and disease, the basic mechanisms that regulate GIRK-dependent signaling in PL pyramidal neurons are not fully understood. One important regulator of GIRK channel activity is the regulator of G protein signaling (RGS) protein, and specifically RGS6 and RGS7 (RGS6/7). RGS6/7 facilitate the termination of inhibitory G protein-dependent signaling, and are thus critical for maintaining the high temporal resolution of GABABR-GIRK signaling. While both RGS6/7 are expressed in the PFC, little is known about their functional roles in the PL. After establishing that RGS6/7 are coexpressed in most PL pyramidal neurons, we next examined their contribution to synaptically-evoked and baclofen-activated GABABR-GIRK currents using constitutive RGS6–/– and RGS7–/– mice. We found that RGS6/7 differentially regulate GIRK channel activity; RGS6 regulates the amplitude, while RGS7 regulates the kinetics and sensitivity, of GIRK-dependent signaling. These shed light on the functional compartmentalization mechanisms that are critical for ensuring high temporal resolution of neuronal inhibitory G protein-dependent signaling. Overall, the work in this thesis suggests that GIRK-dependent signaling in PL pyramidal neurons represents an “inhibitory brake” on cellular excitability that is critical for excitation/inhibition balance and optimal behavioral function. Although the weakening of this inhibition following repeated cocaine exposure may promote neuronal hyperexcitability and addiction-related behavior, therapeutic interventions that restore inhibitory tone may confer resilience to these effects.
Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of male and female rats
(2023-04) Liu, Shirelle
Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied.In this study, Next-Generation RNA-sequencing (RNA-seq) was employed followed by quantitative chromatin immunoprecipitation to investigate changes in gene expression and their regulation in adult male and female rats’ dorsomedial prefrontal cortex (dmPFC) after a regimen of daily injection of morphine (5.0 mg/kg; 10 days). Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors. A complementary behavioral study evaluated the effects of the same morphine injection regimen on locomotor activity, pain sensitivity, and somatic withdrawal signs. Behaviorally, repeated morphine injection induced locomotor hyperactivity and hyperalgesia in both sexes. 90% of differentially expressed genes (DEGs) in morphine-treated rats were upregulated in both males and females, with a 35% overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Chromatin immunoprecipitation revealed enrichment of H3 acetylation, a transcriptionally activating chromatin mark. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males. The results cohere with findings from previous studies based on a priori gene selection. This study also reveals novel genes and molecular pathways that are upregulated by repeated morphine exposure, with some common to males and females and others that are sex-specific.
Review of The Warmest December by Bernice McFadden
(Voices from the Gaps, 2005) Malmberg, Jacob
A rodent model of phenotypic variation in sweet preference, addiction vulnerability, and pharmacological treatment sensitivity
(2013-01) Holtz, Nathan Alexander
Sweet preference is a stable, genetically-mediated trait that is associated with vulnerability to drug dependence in both human and non-human animals. For instance, rats that have been selectively bred for high intake of a saccharin solution (HiS) are more drug-prone than rats bred for low saccharin intake (LoS). The experiments detailed in this review investigated whether the HiS and LoS phenotypes would display differential effects of pharmacological agents on cocaine self-administration and cocaine-seeking behavior. Treatment effects (e.g., baclofen, progesterone, allopregnanolone, or histamine) were examined between the HiS and LoS rats during the following phases: escalation during long access (LgA) to the drug [Experiments 1 (baclofen) and 3 (progesterone)], including pre- and post-escalation short-access (ShA) periods, dose-response assessment, and cocaine-primed reinstatement of extinguished drug-seeking behavior [Experiments 2 (baclofen) and 4 (allopregnanolone)]. The last experiment investigated the effect of pharmacological treatment of steady-state cocaine self-administration; specifically, we used a punishment paradigm in which histamine was added to the i.v. cocaine self-administration solution (Experiment 5). We found that baclofen and progesterone decreased cocaine intake in LoS animals but increased cocaine intake in HiS animals. Baclofen attenuated cocaine-primed reinstatement of drug-seeking behavior in both HiS and LoS rats equally. In contrast, allopregnanolone potentiated low-dose cocaine-primed reinstatement in LoS rats, whereas it attenuated this response following moderate-dose cocaine priming injections in the HiS rats. Histamine was equally effective in punishing cocaine self-administration in both phenotypes; however, LoS rats exhibited a delay in reaching baseline levels of self-administration following histamine punishment. By demonstrating that phenotypic variance in sweet preference can predict treatment sensitivity in substance-dependent individuals, these data can inform more effective, personalized treatment strategies.
Shelter for good?: examining the ethical issues of housing first for homeless substance abusers
(2013-08) Barrett, Tyler Dane
In the past fifteen years, the guiding philosophies used in addressing chronic homelessness have undergone a radical shift in approach. Whereas nearly all shelters once stipulated substance addicted or mentally ill residents must undergo treatment for chemical dependency and mental illness prior to admittance, in recent years many cities across the United States and abroad have adopted a "housing first" model. This approach treats housing as a basic human right and allows homeless individuals immediate and indefinite access to shelter and related resources without requirements of treatment, sobriety, or abstinence. This paper examines the establishment, proliferation, and evolution of housing first programs, their efficacy and the empirical research that has been collected in recent years, and the persisting ethical dilemmas and considerations that need to be addressed.

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