2012 — 2016 |
Rodd, Zachary Aaron |
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. |
Biological Basis of Conditioned Cues Effects On Etoh-Seeking @ Indiana Univ-Purdue Univ At Indianapolis
DESCRIPTION (provided by applicant): Alcoholism is a chronic disorder characterized by repeated episodes of relapse to alcohol consumption. Potential precipitators of relapse include cues paired with past alcohol use. Subsequent exposure to these stimuli could induce a state of alcohol craving that results in reinstatement of alcohol us. The goals of this proposal are to determine the biological bases of how conditioned cues elicit or inhibit drug-seeking. The long- range objectives of this study are to determine the neurocircuits that regulate the modulation of EtOH-seeking by conditioned cues. The overall hypotheses are that there are two distinct systems that integrate environmental cues that promote or inhibit EtOH-seeking, and that each system is comprised of separate neurocircuits and neurotransmitter systems. These hypotheses will be tested primarily using the alcohol- preferring (P) rat, which demonstrates high alcohol drinking behavior and robust EtOH-seeking and relapse behaviors. Proposed experiments will determine the effects of environmental cues (conditioned excitation and conditioned inhibition) on the expression of context-induced seeking. Proposed experiments will determine the neurochemical consequences of exposure to conditioned cues that promote or inhibit EtOH-seeking. In addition, the proposed experiments will identify the neurotransmitter characteristics of neurons activated by presentation of cues that promote or inhibit EtOH-seeking. Further experiments will determine the effects of altering activity at candidate receptors in discrete brai regions on the ability of conditioned cues to alter EtOH- seeking. Understanding the complex factors that underlie EtOH-seeking behaviors and the ability of environmental cues to potentiate or suppress EtOH-seeking will contribute toward the development of therapeutic strategies to reduce 'craving' and alcohol relapse. PUBLIC HEALTH RELEVANCE: The long-range goals of this project are to better understand the biological basis of alcohol craving and how environmental cues can later alter the expression of alcohol craving. Understanding these neurocircuits of drug-seeking will assist in the development of treatment strategies to reduce alcohol drinking and prevent relapse.
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0.924 |
2013 — 2014 |
Rodd, Zachary Aaron |
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.) |
Preclinical Assessment of Deep Brain Stimulation For the Treatment of Alcoholism @ Indiana Univ-Purdue Univ At Indianapolis
DESCRIPTION (provided by applicant): Attempts to develop efficacious pharmacotherapeutics for the treatment of alcoholism have, to date, not obtained this goal. Pharmacological treatment for alcoholism has been limited by efficacy of the compounds and lack of compliance by patients to employ the compounds. Recent human studies have indicated that a neurosurgical procedure, deep brain stimulation (DBS), is effective at reducing alcohol consumption in alcoholics with a co-morbid psychological treatment (e.g. depression). The study of neurosurgical treatment of alcoholism is a developing area of research, and findings obtained from detailed research examining the effects of DBS on alcohol consumption could augment the use of the procedure as a treatment for alcoholism, provide neuroanatomical information to illuminate the biological bases for the efficacy of DBS treatment, and/or allow for an integration of pharmacological and neurosurgical intervention for the treatment of alcoholism. The overall objectives of this proposal are to establish a wireless DBS treatment in rodents, determine the effects of DBS within the nucleus accumbens shell (AcbSh) on alcohol consumption in rats consuming pharmacologically relevant levels of EtOH, and to elucidate the biological consequences of DBS within the AcbSh and other brain regions. The nucleus accumbens shell (AcbSh) is a site where ethanol (EtOH; Engleman et al., 2009), cocaine (Rodd et al., 2005), and other drugs of abuse can produce reinforcing effects. The AcbSh is also a target site of DBS for the treatment of psychological disorders. Preliminary data indicate that our research group has developed a prototype wireless DBS system for use in rodents. In addition, direct DBS stimulation of the AcbSh selectively reduced EtOH consumption in alcohol-preferring (P) rats. The overarching hypotheses of the project are that; a) the development of a wireless DBS system is possible which would provide readily translatable technology for human DBS treatment, b) DBS within the AcbSh will be efficacious at reducing alcohol consumption, EtOH-seeking, and EtOH relapse drinking, and c) neuroadaptations produced by DBS within the AcbSh will provide targets for the development of pharmacotherapeutics for the treatment of alcoholism. The application will further develop the highly novel and clinically relevant wireless DBS system (Aim 1). In addition, the application will examine the effects of DBS within the AcbSh on multiple animal models of EtOH use in the P rat (Aim 2). To clarify the biological basis of the efficacy of DBS on EtOH consumption, the expression of genes within the AcbSh will be determined following DBS treatment and alterations in neurochemical levels within the medial prefrontal cortex (mPFC) will be determined during DBS treatment (Aim 3). This is a highly significant project that will provide important information on the development of wireless DBS, the efficacy of DBS treatment for alcoholism, and the biological consequences of DBS treatment within the AcbSh.
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0.924 |
2015 — 2019 |
Rodd, Zachary Aaron |
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. |
7/8 Nadia Uo1 Adolescent Alcohol and Neurocircuitry Mediating Ethanol Reinforcement @ Indiana Univ-Purdue Univ At Indianapolis
? DESCRIPTION (provided by applicant): The vast majority of American children begin consuming alcohol prior to high school graduation and episodes of heavy ethanol consumption increase over time (Johnson et al., 1999, 2009). A family history of alcoholism increases the risk that adolescent alcohol consumption is associated with adult alcoholism (Agrawal et al., 2009). Periadolescent ethanol consumption by alcohol-preferring (P) rats increases the reinforcing properties of EtOH in the posterior ventral tegmental area (pVTA) during adulthood (Toalston et al., 2014). NADIA- generated research has indicated that adolescent intermittent ethanol (AIE) exposure results in persistent alterations in neuroimmune factors, choline acetyltransferase (ChAT), increased anxiety, and changes in histone acetylation altering neurocircuitry (Vetreno et al., 2014; Sakharkar et al., 2014). As a new component of the NADIA Consortium, the long-range objectives of this study are to determine the effects of AIE on the motivational, reinforcing and anxiolytic properties of EtOH during adulthood within the pVTA and central nucleus of the amygdala (CeA). The impact of a genetic predisposition to high alcohol consumption on the effects of AIE will be determined by making assessments in P rats. The overall hypothesis is that AIE results in lasting neurotransmitter system, epigenetic, and structural alterations in regions critical for motivation, reinforcement, and anxiety. The goals of the application are 1) to assess alterations in the reinforcing properties of EtOH in the pVTA and CeA produced by AIE, 2) to evaluate the neurochemical response to EtOH in the pVTA induced by AIE, 3) to determine if histone deacetylase (HDAC) inhibitor treatment reverses the alterations produced by AIE, 4) to determine the impact of AIE on probabilistic decision-making. In Aim 1, we will test the hypothesis that AIE induced neuroadaptations within the pVTA alter EtOH reinforcement and the neurochemical response to EtOH during adulthood. In Aim 2, we will test the hypothesis that AIE induced neuroadaptations within the pVTA can be reversed by site specific administration of HDAC inhibitor during adulthood. In Aim 3, we will test the hypothesis that AIE induced neuroadaptations within the CeA alter the reinforcing and anxiolytic properties of EtOH during adulthood. In Aim 4, we will test the hypothesis that AIE has altered the probabilistic decision-making (an animal model of impulsivity) during adulthood. This is a highly significant project that will attempt to elucidate the complex factors that underlie the effects of AIE on adult EtOH usage.
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0.924 |