2006 — 2007 |
Szumlinski, Karen Kathleen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Homer Proteins, Glutamate and Alcoholism @ University of California Santa Barbara
[unreadable] DESCRIPTION (provided by applicant): Alterations in accumbens glutamate neurotransmission are implicated in the long-term behavioral consequences of repeated alcohol administration. Thus, molecular candidates contributing to individual vulnerability to chronic alcohol-induced changes in brain and behavior are likely those regulating plasticity at glutamate synapses. This project will test the over-arching hypothesis that genetic vulnerability to alcohol reward is related to the capacity of alcohol to augment the expression of the Homer family of post-synaptic scaffolding proteins involved in modulating plasticity at glutamatergic synapses. In vivo microdialysis will be conducted in the nucleus accumbens of two strains of mice that differ in their propensity to voluntarily consume alcohol [C57BL/6 (high) and DBA/2J (low)] to examine for strain differences in basal and alcohol induced changes in extra cellular glutamate. An examination of drinking behavior while pharmacologically manipulating extra cellular glutamate levels will establish a causal relationship between accumbens glutamate and the propensity to consume alcohol in these strains (Specific Aim 1). Immunoblotting will be employed to assess for strain differences in accumbens Homer2 protein content and the effects of manipulating Homer2 protein expression will be assessed on drinking behavior to confirm an active role for this protein in alcohol consumption (Specific Aim 2). It is expected that a strain difference will exist with [unreadable] respect to basal and alcohol-induced alterations in glutamate transmission and accumbens levels of [unreadable] Homer2. Moreover, it is expected that the genetic propensity to consume large amounts of alcohol will be amenable to changes in accumbens levels of extra cellular glutamate, as well as alterations in accumbens Homer protein expression. The results of these studies will provide insight into the role for Homer proteins in genetic vulnerability to alcohol reward and will increase our understanding of the cellular mechanisms mediating the neural plasticity underlying individual vulnerability to alcoholism. [unreadable] [unreadable] [unreadable]
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0.958 |
2006 — 2008 |
Szumlinski, Karen Kathleen |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mglur-Homer Interactions in Excessive Drinking @ University of California Santa Barbara
Current theories of alcoholism posit that alcohol-induced neuroadaptations within limbic structures in the brain, including the nucleus accumbens (NAC), contribute to the transition from recreational alcohol drinking to excessivealcohol consumption. Recently, the Group 1 metabotropic glutamate receptor (mGluR)- associated scaffolding protein Homer2 was identified as an active and necessary cellular mediator of alcohol-induced neural plasticity in mice. Constitutively expressed Homer proteins facilitate Group 1 mGluR- stimulated intracellular signaling and cluster Group 1 mGluRs within the postsynaptic density, co-localizing these receptorswith other proteins implicated in synaptic plasticity, such as PI3K (phosphatiylionsitol-3 kinase). Homer2 deletion reduces the function and the expression of Group 1 mGluRs in the NAC in vivo and the alcohol-avoiding and -intolerant behavioral phenotype of Homer2 knock-out (KO) mice resembles that produced by the pharmacological blockade of Group 1 mGluRs. Collectively, these observations suggest that Group 1 mGluR-Homer signaling is an important cellular mediator of excessive alcohol consumption. To test this hypothesis directly, this proposal will employ in vivo pharmacological and genetic approaches to characterizethe role for Group 1 mGluR-Homer signaling within the NAC in regulating excessive alcohol consumption within the scheduled high alcohol consumption (SHAC) murine model (Aim 1). Immunohistochemical and immunoblotting approaches will be employed to determine the role for Homer2 n regulating the effects of sustained, excessivealcohol consumption upon the synaptic architecture of NAC neurons, as well as the formation, subcellular localization and function of mGluR-Homer signaling complexes (Aim 2). Finally, to relate genetic variance in excessive alcohol drinking to mGluR-Homer-PI3K expression and signaling within the NAC, immunoblotting the total protein content and membrane localization of members of the mGluR-Homer-PI3K signaling cascade will be compared between mouse lines selectively bred for high SHAC and SLAC (Scheduled Low Alcohol Consumption) phenotypes. The results of these studies will further our understanding of the cellular mechanisms involved in regulating the transition from recreational to excessive alcohol drinking and provide greater insight into the etiology of alcoholism and its treatment.
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0.958 |
2008 — 2012 |
Szumlinski, Karen Kathleen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Homer-Mediated Signaling and Cocaine Addiction @ University of California Santa Barbara
[unreadable] DESCRIPTION (provided by applicant): Repeated cocaine exposure induces persistent, maladaptive changes in mesocorticolimbic glutamate transmission that are central to an addicted phenotype. Thus, likely molecular candidates contributing to the neuropathology of cocaine addiction are those regulating mesocorticolimbic glutamate transmission. Over the past 5 years, the Homer family of post-synaptic scaffolding proteins has emerged as a critical regulator of cocaine-induced changes in mesocorticolimbic glutamate and behavior that likely have relevance for the molecular underpinnings of hallmark features of addiction, such as relapse. A Homer1 polymorphism is significantly associated with cocaine addiction in humans and repeated cocaine administration, including excessive cocaine self-administration, alters mesocorticolimbic Homer mRNA and protein expression. Behavioral genetic studies indicated that a cocaine-induced increase in prefrontal cortex (PFC) Homer2 protein levels is sufficient, while a reduction in nucleus accumbens (NAC) Homer2 protein levels is both necessary and sufficient, for the expression of cocaine-seeking behavior, as assessed using place-preference paradigms. This project will extend these earlier data through a functional examination of the role for cocaine-induced changes in Homer2 expression within the dorsal and ventral PFC-NAC glutamate projections upon cocaine- paired cue-induced drug-seeking and associated changes in NAC glutamate during immediate, intermediate or protracted withdrawal from a period of excessive (40-60+ mg/kg/day) cocaine intake. Based on our previous immunoblotting and behavioral neurogenetics data, it is hypothesized that that excessive cocaine intake produces a time-dependent increase in PFC and decrease in NAC mGluR-Homer signaling pathways that underlie the intensification of drug-seeking during protracted withdrawal. Specific Aim 1 of this proposal will employ immunoblotting and in vivo microdialysis to test the specific hypothesis that the time- dependent intensification of cocaine-seeking during withdrawal from excessive cocaine self-administration is associated with time-dependent increases in PFC and decreases in NAC Homer-mediated signaling pathways within the dorsal mesocorticolimbic circuit, resulting in abnormal mesocorticolimbic glutamate release. Specific Aim 2 will employ site-directed viral-mediated gene delivery to examine the functional consequences of augmenting and preventing cocaine-induced changes in Homer2 within PFC-NAC projections for cocaine- paired cue-induced drug-seeking and NAC glutamate transmission. It is anticipated that the results obtained will greatly increase our understanding of the role for Homer2 in regulating excitatory glutamate transmission within the ventral and dorsal mesocorticolimbic subcircuits as it relates to time-dependent increases in relapse vulnerability. Such knowledge will point to cocaine-induced alterations in Homer2 regulation of both pre- and post-synaptic aspects of PFC-NAC glutamate transmission as critical neuroadaptations regulating the propensity to relapse during protracted withdrawal, which has high relevance for understanding addiction neuropathology and its treatment with glutamate-targeting pharmacotherapies. Repeated cocaine administration induces persistent, maladaptive changes in the excitatory neurotransmitter glutamate within the dorsal and ventral mesocorticolimbic subcircuits and these neuroadaptations are central to relapse vulnerability during cocaine withdrawal. Thus, an understanding of the molecular mechanisms involved in the protracted effects of excessive cocaine intake upon mesocorticolimbic glutamate transmission will assist in the identification of novel therapeutic targets for the treatment of addiction, as well as assist in screening "at risk" individuals or predicting individual treatment outcomes. To this end, this project will employ a combination of behavioral, neurochemical, genetic and immunological approaches to examine the role for Homer2-mediated signaling pathways within the dorsal and ventral mesocorticolimbic subcircuits in the intensification of cocaine-seeking observed during protracted withdrawal from excessive cocaine self- administration. [unreadable] [unreadable] [unreadable]
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0.958 |
2010 — 2014 |
Szumlinski, Karen Kathleen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Regulation of Cea Glutamate and Binge Drinking @ University of California Santa Barbara
Abstract/Project Summary Binge alcohol drinking is the most prevalent form of alcoholism within the United States yet the neurobiology of binge drinking is not well-understood. A significant body of functional data from my laboratory demonstrates that alcohol-induced increases in mGluR5/Homer2 pathway activity (via PI3K and PKC¿) within the nucleus accumbens (NAC) shell as important for the propensity to consume alcohol in murine models of binge alcohol drinking. The NAC shell shares cytoarchitectural, anatomical and functional features with other members of the extended amygdala subcircuit, including the central nucleus of the amygdala (CeA) - a brain region highly implicated in the neurobiology of alcoholism. Homer2 is enriched in the CeA and its levels are up-regulated in concert with those of mGluR1/5 in models of chronic alcohol drinking. Preliminary functional data indicates that, as observed for the NAC shell, inhibiting CeA mGluR5, as well as PI3K, activity reduces binge alcohol drinking in mice, a finding consistent with existing reports for a reduction in limited access alcohol intake upon CeA PKC¿ knock-down. Such data point to an important role also for mGluR5-mediated signaling through both PI3K and PKC¿ within the CeA in the regulation of, and perhaps genetic vulnerability to, binge drink. This project will expand upon these recent observations and employ our combination of behavioral pharmacological and genetic approaches to test the over-arching hypothesis that idiopathic or alcohol-induced increases in mGluR-mediated signaling through its ¿q subunit to PKC¿ and its ¿¿ subunit to PI3K within extended amygdala structures, notably the CeA, is important for the manifestation of, and genetic vulnerability to, binge alcohol drinking. Aim 1 of this proposal will employ a combination of pharmacological and genetic approaches to test the specific hypothesis that intact signaling through the mGluR5-Homer2-PI3K and mGluR5-Homer2-PKC¿ pathways within the CeA is necessary and/or sufficient for maintaining excessive alcohol intake in mice. Aim 2 will relate these functional studies to the short- and long-term effects of a history of binge drinking upon the expression and activational state of mGluR5-mediated signaling pathways within extended amygdala structures and their prefrontal cortical interconnected regions. Aim 3 will relate basal and alcohol-stimulated mGluR5-Homer2-kinase pathway activation to genetic propensity to binge drink, using several animal models. It is anticipated that the results obtained will greatly increase our understanding of the role for mGluR/Homer2-mediated signaling within the extended amygdala regulates the maintenance of, and vulnerability to, excessive alcohol drinking. Such knowledge will point to alcohol-induced alterations in mGluR5/Homer-mediated regulation of post-synaptic aspects of glutamate transmission within extended amygdala structures and their prefrontal cortical interconnections as critical neuroadaptations regulating the propensity to binge drink, which has high relevance for understanding of alcoholism vulnerability and its treatment with glutamate-targeting pharmacotherapies.
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0.958 |
2016 — 2020 |
Szumlinski, Karen Kathleen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Adolescent Alcohol and Anxiety @ University of California Santa Barbara
? DESCRIPTION (provided by applicant): Binge alcohol drinking is the most prevalent form of alcoholism in the United States, with high rates of binge drinking reported in adolescents and young adults. This is concerning as adolescence/early adulthood is a period of robust neurodevelopment during which forebrain glutamate neurons establish their connectivity with subcortical structures within the extended amygdala that regulate emotionality and motivated behavior. Thus, binge drinking during this critical period is likely to grossly perturb the developmental trajectories of glutamate systems within the extended amygdala, which may contribute to the high prevalence of comorbid affective and alcohol use disorders. Indeed, an early history of alcohol abuse is reported to advance significantly the onset of psychiatric symptoms of affective disorders in humans. Consistent with the human condition, alcohol-naïve male and female adolescent mice are hyper-reactive to stressors and voluntarily binge drink greater amounts of alcohol, than their adult counterparts. Also consistent with the human condition, adolescent-onset binge drinkers are insensitive to the hang-over-related anxiogenic state produced by early alcohol withdrawal, but their stressor reactivity incubates during protracted withdrawal. Thus, it is hypothesized that developmental differences exist in alcohol-induced perturbations within the extended amygdala neural circuitry underpinning emotionality, which impact the manifestation of negative affect during alcohol withdrawal. The present proposal seeks to answer a number of research questions pertaining to the impact of excessive voluntary binge alcohol intake on affective behavior as a function of the interactions between age of binge drinking onset X duration of alcohol abstinence using a novel, but well-validated, murine model. As age of drinking onset X sex interactions are reported for affective and alcohol use disorder comorbidity, Aim 1 will carefully control early life experiences and alcohol exposure to characterize the ontogeny of binge drinking-induced negative affect in both male and female subjects. These studies will chart how the manifestation of withdrawal-induced changes in affect vary as a function drug abstinence, potentially vary with reproductive cycle and relate to subsequent binge drinking. Aim 2 will employ immunoblotting procedures to identify subject factor interactions in the biochemical correlates of alcohol withdrawal-induced hyper-anxiety and binge drinking. Aim 3 will then employ behavioral neuropharmacological approaches to determine the functional relevance of alcohol withdrawal- induced changes in glutamate neurotransmission within the central nucleus of the amygdala for subject factor interactions in anxiety and depression measures. The results of these studies will provide novel insight into the neurobiological impact of adolescent binge drinking upon excitatory neurotransmission within a neural circuit critical for emotionality and motivated behavior and will determine the relevance of such changes for affective and alcohol use disorder comorbidity. Such information will not only further our understanding of the molecular mechanisms regulating individual differences in excessive alcohol intake, but provide greater insight into the etiology of alcoholism-affective disorder comorbidity to direct more effective treatment.
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0.958 |
2021 |
Szumlinski, Karen Kathleen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Incubated Drug-Craving and Neurochemical Interactions @ University of California Santa Barbara
Psychomotor-stimulant Use Disorder (PUD) is a chronic relapsing disorder, characterized by a high propensity for relapse even during protracted abstinence. In both humans with PUD & animal models, the intensity of cue- elicited drug craving & drug-seeking behavior increases or ?incubates? during protracted withdrawal. The neurochemical underpinnings of drug craving & its incubation are not well understood. Drug cue-induced increase in metabolic hyperactivity within the prefrontal cortex (PFC) is correlated with the intensity of drug- craving in humans. Consistent with this, we have reported a link between the magnitude of drug-seeking in a rat model of cocaine-taking & a number of abnormalities in glutamate (GLU) transmission within the ventromedial aspect of the PFC (vmPFC). Notably, incubated cocaine-seeking is associated with a time-dependent increase in the capacity of drug-predictive cues to increase GLU levels, primarily within the prelimbic (PL) subregion. We theorize this cue-elicited rise in GLU might underpin cue-elicited increases in metabolic hyperactivity observed within PFC of PUD patients. Importantly: (1) the increased GLU responsiveness to drug-predictive cues is selective for rats with a cocaine-taking history; (2) the magnitude of the GLU increase predicts the vigor of cocaine-seeking behavior; & (3) neuropharmacological inhibition of GLU transmission within the PL eliminates cocaine-incubated responding. Intriguingly, the incubated cue-responsiveness of vmPFC GLU is inversely related to cue-elicited changes in vmPFC dopamine (DA). This inverse neurochemical relation has led to the over-arching hypothesis to be tested in this proposal: the incubation of cue-elicited drug-seeking behavior results from dysregulated GLU-DA interactions w ithin the PL subregion of the vmPFC . Aim 1 of this proposal employs neuropharmacological approaches to systematically target & dissect the relative contribution of postsynaptic AMPA & NMDA GLU receptor subtypes to the manifestation of incubated cocaine-seeking & examine for the generalization of pharmacological effects to a highly prevalent psychomotor-stimulant, methamphetamine (MA), as well as the non-drug reinforcer, sucrose. It is hypothesized in Aim 1 that the incubation of COC craving is driven by GLU-mediated activation of ionotropic GLU receptors within vmPFC. Aim 2 will employ a combination of in vivo microdialysis & neuropharmacological approaches to examine the role for D1- & D3-type DA receptors & their regulation of GLU, DA & GABA release within the vmPFC in incubated cocaine-, MA- & sucrose-seeking. It is hypothesized in Aim 2 that the incubation of cue- elicited GLU release, cellular hyperactivity & drug-seeking reflect time-dependent anomalies in DA signaling within PL. The proposal presents a series of theoretically innovative experiments designed to address the biobehavioral underpinnings of incubated craving, which will advance our basic understanding of the neurobiology of relapse.
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0.958 |