Julia A. Chester - US grants

The broad, long-term goal of the proposed project is to investigate a role for the GABA neurotransmitter system in modulating the rewarding and aversive properties of ethanol. The proposed studies will utilize the place conditioning paradigm to examine the acquisition of conditioned place preference (CPP) and conditioned place aversion (CPA) in DBA/2J mice. The place conditioning procedure provides a useful model to study the learned association between environmental stimuli and a drug's rewarding and aversive effects, and allows for the investigation of specific neural pathways involved in the acquisition of place conditioning. Although the GABA system has been implicated in mediating many of ethanol's behavioral effects, it has not yet been investigated as a possible modulator of ethanol-induced CPP or CPA. The specific aims of this project are to test various doses of pharmacological antagonists selective for GABAA and GABAB receptor subtypes in the acquisition of ethanol-induced CPP and CPA. These studies will help elucidate the role of GABA in modulating the acquisition of conditioned responses to ethanol's neuropharmacological effects. Overall, the information gained from this project will contribute to an understanding of the neurochemical substrates underlying the motivational effects of ethanol. Studies such as these are important in order to develop appropriate clinical treatments for ethanol-seeking and addictive behavior in humans.

DESCRIPTION (provided by applicant): It has been hypothesized that the aversive motivational effects of alcohol withdrawal can contribute to alcohol drinking; however, it is not clear whether these aversive effects increase or decrease drinking. The broad, long-term objective of this R03 Small Grant proposal is to develop a sensitive and reliable place conditioning technique to measure the aversive motivational effects of alcohol withdrawal in mice. The goal of Specific Aim 1 is to identify conditioning parameters that will produce a conditioned place aversion to alcohol withdrawal in mice. This goal will be achieved by manipulating conditioning session duration, tine of conditioning during alcohol withdrawal, number of conditioning trials, and alcohol dose. The goal of Specific Aim 2 is to investigate the underlying mechanisms that contribute to the aversive effects of alcohol withdrawal and to manipulate the strength of conditioned place aversion to alcohol withdrawal. This goal will be achieved by examining the effect of a behavioral manipulation (convulsion induction) and a pharmacological manipulation (GABAA receptor antagonism) on the magnitude of conditioned place aversion to alcohol withdrawal. The development of a new place conditioning technique to measure aversive effects of alcohol withdrawal in mice will provide the basic methodology to be used in a subsequent R01 application that will examine genetic and neurobiological relationships between sensitivity to aversive motivational effects of alcohol withdrawal and alcohol drinking behavior in a genetic mouse model of alcoholism. This place conditioning technique will be a valuable tool for the alcohol research community to study the underlying mechanisms that contribute to differences in sensitivity to the aversive effects of alcohol withdrawal. Studies using this place conditioning technique are likely to provide important information that will lead to the development of novel behavioral and pharmacological treatments for alcoholism.

[unreadable] DESCRIPTION (provided by applicant): There is a remarkably high incidence of co-morbidity between post-traumatic stress disorder (PTSD) and alcohol use disorders in the human population. Some evidence suggests that the co-occurrence of PTSD and alcohol use disorders may arise from inherited genetic and biological factors that influence the risk for both diseases. However, the roles of these risk factors in the development of co-morbid disease have not been defined in humans. The broad, long-term objective of this R01 project is to use a genetic animal model of alcoholism to study genetic and biological factors that may influence risk for PTSD and co-morbid alcohol use disorders in humans. This goal will be achieved by examining the relationship between susceptibility toward learned fear/anxiety and innate propensity toward alcohol drinking behavior in mouse lines that have been selectively bred for high (HAP1 and HAP2) or low (LAP1 and LAP2) alcohol preference. Learned fear/anxiety will be measured using fear-potentiated startle (FPS) as an animal model of PTSD. The goal of Specific Aim 1 is to determine if learned fear/anxiety, as measured by FPS, is associated with a genetic propensity toward alcohol drinking and to examine the effects of alcohol on the acquisition and expression of FPS in HAP/LAP lines. The goal of Specific Aim 2 is to test whether acquisition of learned fear/anxiety increases subsequent alcohol drinking behavior and to examine how this phenomenon may depend on a genetic predisposition toward alcohol preference. The goal of Specific Aim 3 is to characterize hypothalamic-pituitary-adrenal (HPA) axis function in response to fear-conditioning in HAP/LAP lines by measuring corticosterone response profiles and to examine the effect of exogenous corticosterone administration on the acquisition of FPS. The results of this R01 project will provide exciting and novel preclinical data on the genetic and biological factors that may influence risk for developing co-morbid PTSD and alcohol use disorders. This work may aid in the development of behavioral and pharmacological treatment strategies to reduce co-morbid PTSD and alcohol use disorders in people who have an increased risk for these co-morbid diseases.In the human population, post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs frequently with alcohol use disorders, termed co-morbidity. The goal of this project is to use a genetic animal model of alcoholism to study genetic and biological factors that may influence risk for PTSD and co-morbid alcohol use disorders in humans. This work may aid in the development of behavioral and pharmacological treatment strategies to reduce the incidence of co-morbid PTSD and alcohol use disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Alcohol dependence, schizophrenia and anxiety disorders are comorbid disorders that occur at a remarkably high rate but there are presently very few treatments available for people with these comorbid mental diseases. Alcohol withdrawal may be one common factor in the pathogenesis of alcohol dependence and comorbid mental disorders. Alcohol withdrawal can damage the brain and produce cognitive and emotional impairments in alcohol-dependent individuals that are similar to that seen in people with schizophrenia and anxiety disorders. Evidence suggests that activating the 3',5'-cyclic adenosine monophosphate (cAMP) second messenger signaling pathway may reduce the behavioral effects of alcohol withdrawal. The broad, long-term objective of this exploratory R21 project is to explore the therapeutic potential of two promising drugs that raise intracellular cAMP levels, forskolin and rolipram, to reduce physical, cognitive, and emotional signs of alcohol withdrawal in mice. The goal of Specific Aim 1 is to explore the effects of forskolin and rolipram on the physical signs of alcohol withdrawal using handling-induced convulsions to assess withdrawal following chronic alcohol treatment. The goal of Specific Aim 2 is to explore the effects of forskolin and rolipram on cognitive signs of alcohol withdrawal using pre-pulse inhibition of the acoustic startle response to assess withdrawal following chronic alcohol treatment. The goal of Specific Aim 3 is to explore the effects of forskolin and rolipram on emotional signs of alcohol withdrawal (anxiety) using the fear-potentiated startle response to assess withdrawal following chronic alcohol treatment. We will also measure phosphorylated cAMP response element binding protein in three brain regions to provide a biological marker for cAMP activity under the proposed test conditions. The results of this exploratory R21 project may reveal that activation of the adenylate cyclase-cAMP signaling pathway reduces alcohol withdrawal effects and could improve cognitive and emotional function in people with alcohol dependence and comorbid mental diseases. PUBLIC HEALTH RELEVANCE: Alcohol dependence, schizophrenia and anxiety disorders are common comorbid disorders in that they are frequently found to occur together in the same individual. The goal of this project is to develop new models to assess alcohol dependence and comorbid conditions and identify two promising, novel therapeutic drugs to treat these conditions.

DESCRIPTION (provided by applicant): There is currently an urgent need to identify risk factors that increase vulnerability to develop co-morbid alcoholism and post-traumatic stress disorder (PTSD) in order to devise and implement appropriate prevention and treatment strategies for these disorders. The endocannabinoid system (ECS) modulates anxiety-related and alcohol drinking behaviors and has been identified as a promising target for pharmacotherapies to treat anxiety disorders and alcoholism. For this R21 project, a unique animal model that represents increased genetic risk to develop co-morbid alcoholism and PTSD in humans will be used to study the role of the ECS in influencing fear-related behavior in mice that differ in genetic propensity toward alcohol preference. In Specific Aim 1, male and female mice selectively bred for high (HAP) and low (LAP) alcohol preference will be used to determine whether brain region specific levels of the endocannabinoids, anandamide (AEA) and sn-2 arachidonylglycerol (2-AG), are associated with genetic propensity toward alcohol drinking and fear-related behavior. In Specific Aim 2, it will be determined whether drugs that target the ECS reduce fear-related behavior and whether these effects depend on genetic predisposition toward alcohol preference. The secondary goal of Specific Aim 2 is to determine whether EC brain levels are correlated with observed drug effects on the expression of fear-related behavior. The results of this project will provide exciting new preclinical data on the role of the ECS in modulating fear-related behavior in a unique animal model for co- morbid alcoholism and PTSD. Results from this project may facilitate rapid development of novel pharmacological strategies that target the ECS to treat individuals with co-morbid alcoholism and PTSD. The results may also help identify pharmacotherapy or pharmacoprevention approaches that are particularly effective in people who are at increased genetic risk for both alcoholism and PTSD. PUBLIC HEALTH RELEVANCE: The endocannabinoid system (ECS) modulates anxiety-related and alcohol drinking behaviors and has been identified as a promising target for pharmacotherapies to treat anxiety disorders and alcoholism. The goal of this project is to use a use a unique animal model that represents increased genetic risk to develop co-morbid alcoholism and PTSD in humans to explore the role of the ECS in regulating genetic differences in anxiety- related behavior. The project will also determine whether drugs that target the ECS may represent effective pharmacotherapies to treat individuals with co-morbid alcoholism and PTSD.