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Animal Models Core

Rat Animal Models And Gene Testing Core

Richard Bell, Ph.D.
Indiana University School of Medicine
Institute of Psychiatric Research

2 U01 AA013522          27 September 2001 - 31 August 2016

The long-range goals of the Rat Animal Models Core (RAMC) are to better understand the molecular neurobiological events underlying the development and maintenance of excessive ethanol (EtOH) drinking, and how these neurobiological events contribute to the long-range consequences of excessive EtOH drinking. The overall hypotheses to be tested are that (a) a number of neurobiological events, associated with excessive EtOH drinking, occur within the extended amygdala (E-AMYG); (b) the use of excessive drinking procedures, outlined below, in alcohol-preferring, P, and high alcohol-drinking, HAD-1 and HAD-2 rats enables the detection of these events; (c) site-specific lesioning of structures [accumbens-shell (ACBsh), central amygdala (Ce-AMYG), and bed nucleus of the stria terminalis (BNST)], within the E-AMYG, alter the development and/or maintenance of excessive drinking; and (d) experience with these excessive drinking procedures, by P and HAD rats, results in behavioral and/or physiological alterations associated with criteria for a valid animal model of alcoholism (i.e., expression of intoxication, tolerance, and withdrawal signs, and changes in the amount of ethanol consumed and/or pattern of ethanol consumption). Excessive drinking is defined as repeatable and sustainable blood EtOH concentrations (BECs) in the range of 100 to 150 mg% or higher over a chronic period. Three protocols of excessive drinking induction will be used to reflect (a) binge-like drinking during the dark cycle [drinking-in-the-dark-multiple scheduled access (DIDMSA)], with rats receiving three 1-hr access periods spaced 2 hrs apart across the dark cycle; (b) dependence-induced excessive drinking using a prolonged repeated alcohol deprivation (PRAD) procedure, with rats receiving 6 weeks of initial EtOH access followed by multiple cycles of 2 weeks of deprivation from and 2 weeks of re-exposure to EtOH access; and (c) withdrawal-induced, via EtOH vapor inhalation, (excessive) drinking, with a 3 bottle-choice test procedure (WID-3BC) used to measure intake after each cycle of exposure to and withdrawal from EtOH vapor inhalation. Overall, the results of this project will provide valuable information on the complex molecular neurobiological changes that contribute to the development and consequences of excessive alcohol drinking, and aid in the development of interventions for the prevention, and/or treatment of alcohol abuse and alcoholism.

Mouse Target Assessment Core,

Amanda J. Roberts, Ph.D.
Molecular and Integrative Neurosciences Department (MIND)
The Scripps Research Institute

2U01 AA013523     27 September 2001 - 31 August 2016

Alcoholism is characterized by increased ethanol intake, loss of control over ethanol intake, and compulsive ethanol taking. Progress in understanding the neurobiological basis of excessive ethanol drinking depends on the combined development and use of molecular and neuropharmacological tools for understanding the mechanisms of ethanol actions and animal models that allow interpretation of these advances in the context of ethanol addiction. The primary goal of the Mouse Animal Models Core is to provide well characterized and validated behavioral models of excessive ethanol consumption to INIA investigators. This Core has been completely designed around the specific needs of the INIA-West group and has developed from intense discussions and contact with everyone. Inherent in the goal of the Core is that it allows for both the standardization of these models and the pooling of resources. This Core will service twelve INIA investigators studying each of the two domains (Binge and Dependence, see below) and their three levels of analysis (neurocircuitry, cellular, and molecular). In this way, the Core shares the responsibility of making this consortium highly integrated and multidisciplinary and establishes economies of scale. Individual laboratories can focus on their own expertise and will not be required to establish these models in their own laboratories. One of the most innovative aspects of this Core is the application of its neuroadaptive models to the many genetic models (transgenics, knockouts, selectively bred mice) being studied and/or produced by INIA investigators. This will allow for a comprehensive study of the combined impact of genes and environment on the process of ethanol addiction and represents a major strength of the present application. In addition, these models will be extended to additional strains such as those used in the production of knockout and transgenic strains and those commonly used in ethanol research. Finally, this Core will examine phenotypic correlates of excessive alcohol consumption as this is critical to both our understanding of the susceptibility. Based on INIA investigators' needs the following Specific Aims have been formulated: Specific Aim 1. To provide established and refined neuroadaptive models to INIA investigators and Specific Aim 2. To combine neuroadaptive models with genetic models for INIA investigators.



Target Validation Core Rats Project Title,

Therese Kosten
, Ph.D.
Baylor College of Medicine

2U01 AA013476   27 September 2001 - 31 August 2016

This application proposes a core integral to the INIA-West Consortium tasked to identify target medications to treat alcoholism. Agents will be identified based on information obtained from projects within INIA-West. The agents will be examined to determine if they alter behaviors reflective of the various aspects of alcoholism including binge-intoxication, negative affect, and preoccupation-anticipation in a systematic manner using established behavioral methods with rats. Agents will be tested in a systematic manner. An agent’s ability to alter behaviors indicative of binge-intoxication is examined using maintenance of operant self-administration of alcohol under progressive ratio schedules and promising results followed by place conditioning and 2-bottle preference procedures. Alleviation of negative affect is assessed by measuring withdrawal signs, and anxiety- and depressive-like behaviors with elevated plus maze and forced swim tests. Preoccupation-anticipation (“craving”) is assessed with drug/cue-induced reinstatement of extinguished operant responding, conditioned approach, and sign-tracking. This set of “craving” studies is a focal point of the grant given the importance of relapse prevention in alcoholism treatment and a reason rats are used as these procedures are more difficult to establish with mice. Further, because excessive alcohol can cause cognitive deficits that would likely interfere with psychological treatments (which are often combined with pharmacological treatments), we will also assess whether target agents alter cognitive function using standard learning and memory tasks (e.g., fear conditioning, object recognition). Studies will be conducted in rats that have been chronically exposed to alcohol vapors. Finally, in collaboration with other projects and cores and using molecular genetic and neuropharmacological approaches, we will confirm the neurobiological effects of the target agents to alter chronic alcohol effects.

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