Mary E. Cain - US grants

DESCRIPTION (provided by applicant): Drug self-administration in rodents is a useful technique to examine the mechanisms and potential treatment of stimulant abuse. Previous research has shown that stimulant self-administration is greater in rats that are highly active in a novel environment (high responders) compared to rats that are relatively inactive (low responders). In addition, stimulant self-administration is greater in rats raised in an isolated environment compared to rats raised in an enriched environment. The experiments proposed in the present application will determine if rats that are prone to self-administer amphetamine, due to genetic or environmental factors, share a common neural profile of an overactive arousal system. The overall mechanistic framework for the proposed set of experiments is based on the role of the central nucleus of the amygdala (ACe) in regulating arousal due to its extensive cortical and subcortical projections. We hypothesize that the ACe is more active in high responder rats compared to low responder rats and in rats reared in an isolated condition compared to an enriched condition. The effects of ibotenic acid lesions of the ACe on subsequent amphetamine self-administration will be measured. In addition, the amount of c-Fos labeling will be measured in the ACe to determine if the ACe has greater activity in those rats prone to self-administer amphetamine. The findings from these experiments are intended to advance the understanding of vulnerability for stimulant abuse, and will potentially lead to better prevention and treatment interventions.

[unreadable] DESCRIPTION (provided by applicant): Numerous studies suggest that people who prefer novel or arousing stimulation (e.g. high sensation- seekers) use drugs more frequently than low sensation seekers. Thus, high sensation-seekers may be predisposed biologically to find both novel stimuli and drugs to be more rewarding than low sensation- seekers. The long-term goal of this research is to determine if individuals who prefer novel and arousing stimuli share a common neuroanatomical mechanism using an animal model. Rats that are highly active in a novel environment (high responders) are more sensitive to amphetamine-induced locomotor activity and self-administer more amphetamine compared to rats that are relatively inactive (low responders). Previous research has demonstrated that inactivation of the central nucleus of the amygdala (ACe) reduces amphetamine self-administration only in high responder rats. The overall mechanistic framework for the proposed set of experiments is based on the role of the ACe in regulating arousal due to its extensive cortical and subcortical projections. The hypothesis is that the ACe is more active in high responder rats compared to low responder rats. The effects of inactivation of the ACe on subsequent amphetamine- induced locomotor activity will be measured to determine if the ACe contributes to the increased sensitivity of high responder rats to amphetamine-induced locomotor activity. Further, the amount of conditioned activity in an amphetamine-associated environment will be measured to determine if the ACe contributes to conditioned activity and if high responder and low responder rats differ in conditioned activity. In addition, the amount of c-fos expression will be measured in the ACe to determine if the ACe has greater activity in high responder rats. The findings of these experiments are intended to advance the understanding of vulnerability for stimulant abuse, and will potentially lead to better prevention and treatment interventions. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Rodents reared in enriched conditions (EC) during childhood and adolescence have a variety of neurobiological and behavioral differences when compared to rodents reared in standard (SC) or isolated conditions (IC). These neurobiological differences impact numerous behaviors, including the response to a variety of drugs of abuse. It is well established that rearing in an EC reduces the motivation to respond for low doses of psychostimulants when compared to rats raised in an IC, however, the neurobiological mechanism for this effect remains unclear. Several studies have observed differences in dopaminergic function in the mesocorticolimbic pathway between EC and IC rats. Glutamatergic afferents to the mesocorticolimbic pathway mediate the response to psychostimulants and deficits in glutamate homeostasis are hypothesized to contribute to drug addiction. Differential rearing alters glutamatergic function and therefore the overarching hypothesis of the current application is that differential rearing alters glutamate homeostasis. It is predicted that enrichment augments glutamate homeostasis and this augmentation contributes to the ability of enrichment to protect against drug abuse. Conversely, isolation impairs glutamate homeostasis and this impairment contributes to the increased vulnerability to drug abuse. Specific Aim 1 will determine if differential rearing alters the function of receptors and transporters critical for glutamate homeostasis. The effect of agonists and antagonists to mGluR2/3, mGluR5, and GLT1on the self-administration of amphetamine in differentially reared rats will be examined. Specific Aim 2 will examine if differential rearing alters the expression of proteins that contribue to the maintenance of glutamate homeostasis. The expression of mGluR2/3, mGluR5, and GLT1 in the mesocorticolimbic dopamine pathway will be measured following acute and repeated amphetamine in differentially reared rats. Results supporting this hypothesis will suggest that environmental conditions alter glutamatergic function and that these changes affect drug use behavior. Use of the differential rearing model in the current application will enable future testing of the glutamate homeostasis theory in a model that displays an environmentally-induced continuum of reward sensitivity to validate, expand, and apply the glutamate homeostasis theory. These experiments will be conducted by undergraduate and graduate students. Completion of the proposed experiments will strengthen the research environment in the Kansas State University Psychology Department and will enable students to participate in all phases of a research program exploring the effects of differential rearing on glutamate homeostasis.

PROJECT SUMMARY A characteristic of alcoholism is an increased incentive motivation for ethanol. Incentive motivation is comprised of the motivation to respond for ethanol and the hedonic value of ethanol. Early drinking onset is correlated with an earlier onset of alcoholism, a stronger severity of alcohol dependence, and increased deficits in neuronal microstructure. While drinking rates in males and females are relatively similar during adolescence, exposure to ethanol during adolescence results in more damage to the neuronal microstructure in females while more males develop alcohol-use disorders in adulthood. In rodents, differential rearing environments during childhood and adolescence result in plasticity- dependent neuronal changes. These neuronal changes impact a variety of behaviors, including the response to ethanol. Rearing rats in an enriched condition decreases responding for ethanol in operant ethanol self-administration when compared to rats raised in an isolated or standard condition. The overarching goal of the proposed experiments is to determine if differential rearing-induced plasticity alters the integrity of the neuronal microstructure to affect both the hedonic value and the incentive salience for ethanol in adulthood. It is hypothesized that rearing male and female rats in an enriched environment will decrease hedonic responses to ethanol when compared to rearing male and female rats in an isolated or standard environment. The proposed experiments will also determine if differential rearing during intermittent adolescent ethanol exposure can alter the hedonic value and incentive salience for ethanol in adulthood. It is predicted that enrichment during adolescent ethanol exposure will protect against the increased risk for alcoholism in adulthood in both male and female rats. The proposed experiments will then examine how differential rearing during adolescent ethanol exposure alters the neuronal microstructure using diffusion tension imaging. It is predicted that rearing in an enriched environment will protect against the deleterious effects of ethanol exposure in adolescence when compared to rats reared in an isolated or social condition. We further predict that sex will alter the effects of adolescent ethanol exposure on neuronal microstructure integrity and therefore female isolated rats will have the most damage to the neuronal microstructure as a result of adolescent ethanol exposure. Completion of the project will determine that differential rearing alters incentive motivation for ethanol due to alterations of neuronal microstructure integrity. Development of this model will provide us the ability to test behavioral and neurobiological changes that result from adolescent ethanol exposure in a preclinical model system that results in divergent outcomes for both plasticity and ethanol sensitivity.