Carmela M. Reichel, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The associations formed between the physiological effects of abused drugs and cues in the drug-taking environment are critical factors in the acquisition, maintenance, and relapse of drug-taking behavior. Because these conditioned associations exert some control over choice behaviors involving drug reward, behavioral intervention strategies may need to employ techniques to reduce the influence of conditioned drug reward over choice behaviors. For example, such programs may benefit by providing new learning opportunities to compete with conditioned drug reward. Access to novelty reward might provide an alternative learning history with the potential to compete with conditioned cocaine reward. By studying this competition, we hope to enhance the development of comprehensive drug abuse treatment programs. Therefore, one of the objectives of this proposal is to test whether a change in learning history can compete with conditioned drug reward for control over choice behavior. The experiments proposed in this application will help meet our goal by systematically investigating the extent to which novelty conditioned reward can compete with conditioned cocaine reward over a range of cocaine doses. We will also assess whether unpaired cocaine exposure is important for this competition. Additionally, we will determine whether novelty competition can be maintained over time. This competition will be investigated using a place conditioning procedure with cocaine and novelty. Initially, rats will be conditioned with cocaine to prefer one side of an unbiased place conditioning apparatus. In the subsequent phase, half of the rats will have repeated access to a novel object on their originally unpaired (no-drug) side. Both groups will then be tested on separate days for preference in a drug-free state and in the cocaine-drug state. Preliminary data indicates that access to novelty can shift a preference away from the cocaine-paired environment during drug-free testing and this shift remains even when rats are given an ensuing test in the cocaine-state. Thus, the conditioned rewarding effects of novelty changed choice behaviors motivated by drug reward. We expect that this competition will persist with higher doses of cocaine, when cocaine-paired cues are maintained, and at longer testing intervals. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Project Summary Meth-induced cognitive impairments observed in addicts after chronic drug use comprise a particularly serious problem in meth addiction and treatment. As such, there is a need for research efforts to develop animal models with translational relevance to the cognitive impairments observed in human meth addiction. Preclinical animal models reveal long-lasting impairments in recognition memory in rats. Specifically, high dose non-contingent meth injections can produce neurotoxicity and disrupt performance on memory tasks. Most object recognition studies have used short term, non-contingent drug delivery approaches to study the impact of meth on recognition memory. Intravenous meth self-administration offers a translational approach as a model of human meth addiction and the impact of chronic meth on cognitive function. The preliminary research shows that contingent long-access meth causes deficits in recognition memory, and that meth intake correlates with this memory deficit 24 hrs later. One purpose of this proposal is to determine whether these deficits in recognition memory involve a glutamatergic mechanism. In order to reverse meth-induced deficits in recognition memory, Specific Aim 1 will use a metabotropic glutamate receptor (mGluR) 2/3 agonist during acquisition of novel object recognition and Specific Aim 2 will use a mGluR5 positive allosteric modulator. Additionally, the experiments in this proposal will identify meth-induced changes in mGluR 2/3 and 5 expression in brain areas related to meth addiction (i.e., nucleus accumbens, dorsal striatum, and prefrontal cortex) and recognition memory (i.e., perirhinal cortex and hippocampus) following abstinence from long- access daily meth. Meth intake, object recognition scores, and receptor levels will be examined for correlations and predictive relationships. Identifying such relationships will provide new insights into meth- induced cognitive deficits, elucidate underlying neuronal mechanisms, and help identify possible therapeutic interventions in this animal model. PUBLIC HEALTH RELEVANCE: Project Narrative The overall purpose of these studies is to determine the relationships between motivated meth-taking behavior over time, meth-induced cognitive impairments, and the underlying neural mechanisms. The use of a translational animal model of meth addiction allows for the study of cognitive and motivational deficits that are manifested in meth addiction. Additionally, identification of neural mechanisms involved with this translational model may help identify promising new pharmacotherapeutic targets for meth-induced cognitive deficits.

DESCRIPTION (provided by applicant): Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug dependence. Environmental stimuli or contexts previously associated with drug use can initiate relapse to compulsive drug-seeking and drug-taking behaviors. Reinstatement of responding for drug-associated conditioned cues, both discrete and contextual, following chronic drug self-administration has been demonstrated in rats. Although the role of conditioned cues is well recognized as a factor in relapse, only recently has the fundamental neural circuitry of relapse to various drugs of abuse been explored in detail. Using an extinction/reinstatement model of relapse, the role of the basolateral amygdala complex has been shown to be critical in the acquisition, consolidation, and expression of drug-cue associations that drive relapse. Furthermore, the circuitry of conditioned-cued reinstatement engages a network of brain nuclei that include discrete subregions of the prefrontal cortex and nucleus accumbens. Although extinction/reinstatement paradigms allow investigators to isolate specific features of stimuli that elicit relapse, human addicts generally do not undergo explicit extinction training upon cessation of drug use. Recent studies from our laboratory suggest that activation of the neural circuitry underlying relapse to drug-seeking after abstinence from the drug and the drug-paired environment is uniquely different from that engaged following explicit extinction training. These findings have implicated a significant role of the dorsolateral caudate-putamen (dlCPu) in mediating relapse following abstinence. In this competing renewal application, studies are proposed to test the global hypothesis that neuroadaptive changes in the dlCPu underlie habitual drug-seeking following abstinence from chronic cocaine self-administration. Specifically, we hypothesize that the dlCPu is a key regulator of habit learning that drives compulsive drug-seeking during relapse after abstinence. These changes are hypothesized to involve a change in neuronal activity of the dlCPu as manifested by changes in specific dopamine and glutamate receptor-mediated cell signaling cascades and increased dopamine and glutamate release in the dlCPu during relapse. These experiments provide an integrated approach employing behavioral, molecular biological, and neurochemical techniques aimed at understanding the neuronal bases of long-term conditioned associations produced during and after chronic cocaine self-administration. Information gained from this project will provide direction for development of anti-relapse medications for the treatment of cocaine dependence, as well as other drugs of abuse.

DESCRIPTION (provided by applicant): Chronic methamphetamine (meth) self-administration in rats provides a translational animal model for the study of cognitive and motivational deficits of meth addiction in humans. This project consists of a multidisciplinary approach to study meth-induced cognitive and motivational dysfunctions, determine their critical neurobiological substrates in cortical glutamatergic circuitry, and reverse meth-induced changes with chronic pharmacotherapy. Specifically, we will first assess object recognition memory deficits in novel object and object-in-place recognition memory in rats with a history of chronic meth self-administration, withdrawal, and renewed drug-seeking. We hypothesize that chronic meth intake will negatively affect memory performance and that deficits will be related to altered glutamate receptors (AMPA, NMDA, mGluR2/3, and mGluR5) and glutamate receptor dependent neuron activity in the prefrontal and perirhinal cortices. We will also examine the ability of potential cognitive enhancers to reverse chronic meth-induced memory deficits by acting on glutamate receptors. We predict that chronic modafinil or an mGluR5 allosteric modulator (CDPPB) will reverse meth-induced cognitive deficits and reduce drug-seeking by acting on the aforementioned substrates. Finally, we will determine the impact of chronic meth SA on prefrontal cortex dependent attentional processing using a novel operant based attentional set-shifting task. These studies are significant in that they will provide novel insighs on chronic meth-induced changes in cognitive performance and neuroplasticity using a multifaceted assembly of behavioral, neurochemical, and neurophysiological techniques in a translationally relevant model of meth addiction. Ultimately, this project will advance our understanding of the neural substrates of cognitive deficits in meth addiction and the development of neurobiologically derived treatments for meth addiction.

DESCRIPTION (provided by applicant): An estimated 26 million people abuse methamphetamine (meth) worldwide. This high prevalence of abuse and the ensuing health and societal consequences necessitates a clear need to understand the long-term neural and vascular adaptations caused by chronic meth that contribute to addiction and relapse. Meth exposure interferes with the neuronal and vascular function required to establish connectivity and wiring of interconnected networks. An integral part of vascular-neural coupling, the blood brain barrier (BBB), is particularly sensitive to inflammatory mechanisms and BBB health reflects the general health of neurovascular crosstalk. Acute exposure to high doses of meth results in neuroinflammation and subsequent increases in BBB permeability. However, the long-term consequence of chronic meth-induced neuroinflammation on neurovascular health is an understudied area of meth addiction. Notably, these issues have not been addressed using a clinically relevant rodent model of meth addiction. Our central hypothesis is that chronic self-administered meth results in lasting neuroinflammation that compromises neural-vascular coupling of the BBB. To test this hypothesis, we will use cutting edge magnetic resonance based neuroimaging techniques to identify the progression of inflammation following prolonged meth self-administration. These inflammatory responses may be early indicators for meth-induced damage to neurovascular units and subsequent break down of the BBB. We will measure the time course of meth-induced changes in neuronal and vascular integrity during abstinence from meth by measuring white matter integrity and BBB transfer rate to map progressive tissue damage. These assessments are not possible by relying solely on histological outcomes. Therefore, the end point results will be correlated with histological outcomes on endothelial and inflammatory markers. The imaging experiment is designed to acquire information about spatial and temporal patterns of damage to neurovascular unit providing valuable information on the progression of meth-induced adaptations. Further, this study will provide novel information for diagnostic and treatment planning for meth addiction.

Project Summary/Abstract Many methamphetamine (meth) addicts suffer cognitive impairments that may perpetuate the addiction cycle. Although, meth impacts several cognitive domains (e.g., attention, impulsivity, memory), the relationship between impaired cognitive function, addiction, and relapse is not well understood. Repeated meth use results in maladaptive brain changes in areas involved in recognition memory and relapse including cortical and subcortical structures. For example, the perirhinal cortex (PRH) is the primary neural substrate involved in recognition memory and directs the flow of information in and out of the parahippocampal structure. The medial prefrontal cortex (mPFC) mediates inhibitory control over behaviors like risk-taking and drug over-consumption; and, the nucleus accumbens (NA) regulates reward-related behaviors. Meth induced impairments in these areas result in memory deficits, loss of inhibitory control, and biased reward processing of drug-associated cues that precipitate a relapse episode. In this proposal, we will study the relationship between motivated drug taking, meth induced cognitive dysfunction, and relapse using a long access (LA) meth self-administration (SA) regimen that reliably establishes recognition memory deficits and results in robust relapse to drug seeking. Given that the PRH is the primary substrate involved in recognition memory, combined with our previous reports of a meth-induced dysregulation of glutamate physiology in this area, we hypothesis that meth impairs recognition memory through PRH projection neurons loss of communication with the mPFC. We also suggest that the pathway encompassing prelimbic (PL) and infralimbic (IL) outputs of the mPFC that project to the NAcore and NAshell are dysregulated by meth resulting in the reinstated responding to conditioned drug cues. As such these separate pathways, PRH-mPFC and mPFC-NA, suggest that recognition memory deficits and relapse are distinct domains of the addiction pathology. However, the PRH-NAcore is a relatively unexplored circuit and the behavioral relevance of this connection has not been determined. We hypothesize that this connection may be the unifying pathway between meth-induced recognition memory dysfunction and relapse. Our Specific Aims will determine whether meth causes functional changes within the pathways involved in recognition memory and cued reinstatement. Specific Aim 1 will test the hypothesis that meth causes functional changes within the PRH-mPFC circuitry that result in recognition memory deficits. Specific Aim 2 will test the hypothesis that functional changes within the mPFC-NA circuitry mediate cued reinstatement of meth seeking using a rodent model of reinstatement. Specific Aim 3 will determine the functional and behavioral relevance of the PRH-NAcore pathway. We hypothesize that this pathway is involved in recognition memory and relapse to meth seeking. Upon completion of our aims we will have a more complete understanding of the pathways involved in recognition memory and cued drug-seeking to better inform treatment approaches for meth addiction.

PROJECT SUMMARY - Overall The personal, social and criminal consequences of opioid and cocaine abuse are enormous problems in North America. This is most tragically seen in rising morbidity due to heroin, prescription opioids and fentanyl overdose in the USA. Addiction to drugs typically cycles between three phases, active drug use, withdrawal from drug use and relapse to drug use. A point in the cycle of addiction where pharmacological intervention can be particularly beneficial is to interfere with the overwhelming motivation by addicts to relapse to drug use, even after extended periods of abstinence when acute withdrawal symptoms have dissipated. However, the enduring state of relapse vulnerability arises from interdependent brain adaptations produced during all three phases of addiction. Thus, in order to develop biological rationales for treating relapse, it is necessary to understand not only the neurobiology of relapse itself, but to determine which changes produced by drug administration and drug withdrawal contribute to the final enduring state of relapse vulnerability. The overarching goal of the Center for Opioid and Cocaine Addiction (COCA) is to create and maintain mechanisms of scientific synergy that will facilitate discovering the neuropathologies that underpin the enduring and uncontrollable drive to seek opioids and cocaine, and thereby advance biological rationales needed to efficiently generate pharmacotherapies that inhibit drug relapse. This goal will be achieved through a bidirectional translational strategy that involves 3 Cores and 4 research Projects. In addition to the Administrative and Pilot Cores, the Animal & Validation Core makes available transgenic rodents that have been trained to self-administer heroin or cocaine, and have been instrumented with intracranial cannulae, fiber optics or GRIN lens. This Core will also validate all viral reagents and transgenic animals shared by the COCA Cores and Projects. The 4 Projects range from determining the epigenetic substrates of long- lasting drug-induced alterations to understanding the molecular and brain circuit mechanisms of cue-induced drug seeking in rodents and humans. The Projects are designed to be highly integrated and form a bidirectional translation strategy for providing biological rationales for new therapeutic approaches to relapse prevention.

PROJECT SUMMARY ? Animal & Validation Core B The overarching goals and responsibilities of the Animal & Validation Core B are to provide transgenic rodents with uniform histories of contingent drug delivery to the Center on Opioid and Cocaine Addiction (COCA) projects and validate the reagents and transgenic animals that are used. As such, Core B is a critical component of COCA synergy between Core C, and Projects 1-3 in the COCA by providing research subjects. The rodents include age-matched male and female rats and mice that have undergone cocaine, heroin, or sucrose self-administration and that are distributed to the projects for subsequent use according to each projects aims. Animals supplied by Core B include transgenic mice and rats for determining cell-type and circuit specificity relevant to the neurobiology of addiction. The unified Core B provides an efficient rotation of laboratory animals that creates synergy between the projects. In addition to rodents, Core B promotes synergy through the production of custom AAV viral vectors, verification of viral vector efficacy and cell specific expression, and quantitative co-localization analysis. In providing the validation services and transgenic rodents, the Animal Core B will meet the following additional objectives: 1. Maintain a high quality of technical assistance through rigorous training protocols designed with strict adherence to all institutional guidelines regarding health and safety in order to guarantee consistency of handling and ensure we are generating the healthiest subjects for our experimental purposes. 2. Establish a centralized record keeping system updated on the COCA server that aids in the transparency and dissemination of data to allow for comparisons between behavioral data and the endpoint evaluations conducted by the projects. 3. Provide a database of confirmed reagents uploaded onto the public and private COCA servers in order to identify and unify solutions for common issues associated with validation of new reagents. 4. Serve as a training center for MUSC and non-MUSC personal interested in establishing contingent models of drug delivery in their laboratories for rats and mice. 5. Become a resource for personnel needing guidance on the use of viral vector plasmids, establishing cell-type specificity, validating transgenic animals, and using quantitative colocalization techniques.