Jeffrey W. Grimm, M.S. Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The limiting factor in the treatment of drug addiction is the high rate of relapse seen in addicts, despite costly treatment interventions. Craving for the drug long after the initiation of abstinence is argued to be a primary contributor to this recidivism. Relapse is often preceded by subjective reports of intense craving for the drug. Such craving can be induced in an individual by the presentation of stimuli previously associated with their drug taking experiences. Cue-induced craving is modeled in procedures using rats wherein rats will press a lever for the presentation of a stimulus complex (a tone + light) previously associated with their drug taking. We have recently demonstrated (Nature, 412:141-2, 2001.) that responding for a stimulus previously associated with cocaine self-injections increases progressively over the course of withdrawal from self-administration (13-fold increase by day 60 of withdrawal). We have labeled the phenomenon an "incubation of craving". We have also recently observed the incubation of craving effect in rats responding for a stimulus previously associated with orally self-administered sucrose. The experiments outlined in this proposal will explore the neuroanatomical substrates of the incubation of craving effect in both cocaine- and sucrose-experienced animals. The basolateral amygdala and the nucleus accumbens will be examined in this regard using a procedure of reversible inactivation of each structure prior to testing at the different withdrawal time points. All experiments in this proposal are designed to allow full participation of undergraduate and master's level students in an area of research usually reserved for Ph.D. students and post-doctoral researchers. These experiments provide an initial examination of the incubation of craving effect and will influence the direction of a future RO1 proposal from my laboratory. Information gained from this project will provide direction for behavioral therapy and medications-based therapy for craving and relapse. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): High rates of relapse characterize drug and food addiction. Relapse is often preceded by subjective reports of intense craving and these cravings can be induced by drug or food-paired stimuli. Rats will press a lever for the presentation of a stimulus complex (a tone + light) previously associated with their food or drug taking, providing a model of cue-induced craving. We have demonstrated (Nature, 412:141-2, 2001) that responding for a stimulus previously associated with cocaine intake increases over the course of forced abstinence from self-administration (13-fold increase by 60 days of forced abstinence). We labeled the phenomenon an "incubation of craving" and have observed the effect in rats following sucrose self- administration. In recent studies, we have found that inactivation of the nucleus accumbens, a brain region involved in motivated behavior, attenuates the incubation of craving for either cocaine or sucrose. The experiments outlined in this proposal will further explore the role of the nucleus accumbens in the incubation of craving effect in sucrose-experienced animals. Dopamine and glutamate are known to functionally interact in the nucleus accumbens and have been linked to relapse behaviors. Core and shell subregion distinctions have also been made in this regard. Specifically, we propose to attempt to block the incubation of craving by challenging accumbal core and shell subregions with antagonists of dopamine and glutamate receptors at Day 1 or Day 30 of forced abstinence. All experiments in this proposal are designed to allow full participation of undergraduate and master's level students in an area of research usually reserved for Ph.D. students and post-doctoral researchers. These experiments will further our understanding of the incubation of craving effect and will influence the direction of future grant proposals from our laboratory. Information gained from this project may also provide direction for behavioral therapy and medications-based therapy for drug addiction and eating disorders. Relapse characterizes drug and food addictions. These are major public health problems. The studies in this proposal aim to identify neural substrates of relapse. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Relapse to drug and food seeking presents a significant public health concern as excessive preoccupation with drug or food seeking and taking contributes to numerous negative health outcomes. Using a rat model of reward seeking, this application aims to identify gene expression patterns in the brains of rats with a history of sucrose self-administration under short or long-term abstinence conditions known to produce low or high levels, respectively, of reward seeking ("incubation of craving"). In addition, some rats will experience abstinence in an enriched environment, a manipulation we have previously demonstrated to attenuate incubation of sucrose seeking. Gene expression will be visualized in the first Aim using Fos immunohistochemistry to map sucrose-cue activated regions. Aim 2 will utilize this mapping information to focus on discrete brain regions to isolate and quantitate dopamine D1 receptor signal cascade proteins, some in basal vs. phosphorylated states, as we have found that D1 receptor antagonism has time-dependent (incubation-dependent) effects on sucrose seeking. Beyond the goal of identifying neural substrates of addiction as a means to informing novel addiction therapies, the studies will be conducted as a means to expose undergraduate researchers to the scientific process. Engaging the students in this way will enhance their training experiences and the research environment at Western Washington University. PUBLIC HEALTH RELEVANCE: Relapse to drug or food seeking presents a significant public health concern as excessive preoccupation with, and consumption of, drugs and food contribute to numerous negative health outcomes. The proposed studies aim to identify differential gene expression in the brains of rats related to relapse behavior with or without the relapse-attenuating pre-treatment of extended enriched environment living conditions. The results of these studies may lead to a better understanding of the molecular biology of relapse behavior and thus facilitate development of novel relapse treatment approaches.

DESCRIPTION (provided by applicant): Relapse to drug and food seeking presents a significant public health concern. Drug and food-paired cues contribute to relapse. We previously observed that environmental enrichment (EE) has a profound ability to reduce sucrose cue-reactivity in a rat model of relapse. This proposal aims to provide a better understanding of how EE reduces sucrose cue-reactivity. In Aim 1 we will examine the effect of microinjection of a dopamine D1 receptor agonist into the nucleus accumbens core on sucrose cue-reactivity in rats that have experienced either acute or chronic EE. In Aim 2 we will measure levels of phosphorylation states of DARPP-32, a key mediator of dopamine signaling, in the nucleus accumbens core as well as in several other brain regions. Embedded in the design of both Aims is assessment of the effects of abstinence duration, as time-dependent increases in cue-reactivity (incubation of craving) may be a critical factor driving relapse. Beyond the goal of identifying neural substrates of addiction as a means to informing novel addiction therapies, the studies will be conducted as a means to expose undergraduate researchers to the scientific process. Engaging the students in this way will enhance their research experiences and the research environment at Western Washington University.

DESCRIPTION (provided by applicant): Relapse to drug and food seeking presents a significant public health concern. Drug and food-paired cues contribute to relapse. We previously observed that environmental enrichment (EE) has a profound ability to reduce sucrose cue-reactivity in a rat model of relapse. This proposal aims to provide a better understanding of how EE reduces sucrose cue-reactivity. In Aim 1 we will examine the effect of microinjection of a dopamine D1 receptor agonist into the nucleus accumbens core on sucrose cue-reactivity in rats that have experienced either acute or chronic EE. In Aim 2 we will measure levels of phosphorylation states of DARPP-32, a key mediator of dopamine signaling, in the nucleus accumbens core as well as in several other brain regions. Embedded in the design of both Aims is assessment of the effects of abstinence duration, as time-dependent increases in cue-reactivity (incubation of craving) may be a critical factor driving relapse. Beyond the goal of identifying neural substrates of addiction as a means to informing novel addiction therapies, the studies will be conducted as a means to expose undergraduate researchers to the scientific process. Engaging the students in this way will enhance their research experiences and the research environment at Western Washington University.

Project Summary/Abstract Craving and relapse are characteristic of drug and food addictions. A better understanding of what behavioral and neurobiological events underlie these behaviors could influence treatment approaches for addiction behaviors in general. We use an addiction model where rats self-administer (take) sucrose and then respond for a sucrose-paired cue (seek) when the sucrose is removed. We are interested in how the environment and passage of time since last having sucrose (abstinence) alters taking and seeking behaviors. We have found that environmental enrichment (EE) decreases taking and seeking, while abstinence increases both. The latter effect is known as ?incubation of craving? and it has been observed clinically for both drugs of abuse and food. Over the years of funding of this R15 we have conducted parametric evaluations of what environmental factors (e.g. social interaction, novelty) contribute to the EE effect. We have also tested the efficacy of behavioral (e.g. satiety) and pharmacological manipulations to reduce the incubation effect. Some of the pharmacological studies have targeted specific brain regions, and we have also evaluated changes in brain proteins following EE and/or abstinence. Recently, we found a large sex difference in sucrose taking and seeking. This R15 renewal proposal is to continue our successful line of research into the neurobiology of addiction, incorporating evaluation of sex differences. This proposal has 3 Aims. Aim 1 is to characterize sucrose taking in female and male rats, assessing primarily activational effects of sex hormones. Aim 2 compares males and females on sucrose taking and seeking following EE and/or abstinence from sucrose self-administration. Aim 3 also includes sex comparisons, and will examine the role of orbitofrontal cortex in the anti-seeking effect of EE. All of the work to be conducted will include undergraduate research assistants. This inclusion is a priority for the PI, and aligns with the objectives of the R15 mechanism. In addition, the work is of high quality and brings opportunities for undergraduates to gain experience in laboratory research at an institution where these opportunities are limited. Overall, these experiences will make it more feasible for students to pursue advanced training and careers in the biomedical and behavioral sciences.