Nicholas Goeders - US grants

Even though the chronic non-medical use of cocaine has currently reached epidemic proportions in this country, there is as yet no clear-cut consensus among health care professionals regarding optimal treatment strategies for cocaine abuse. The introduction of pharmacological interventions to increase the probability of successful cocaine abstinence has only recently been investigated since chronic cocaine use has not historically been assumed to produce prolonged physiological withdrawal symptoms upon discontinuation. However, since some individuals can remain casual recreational users of the drug, there may be factors in addition to cocaine's reinforcing properties that determine why other individuals progress to compulsive drug use. In fact, a subpopulation of chronic cocaine users may actually be self-medicating to regulate painful feelings and psychiatric symptoms via their drug use. A better understanding of potential environmental events that can alter drug-intake will increase knowledge of the etiology of drug addiction and may result in the more effective and efficient treatment of compulsive cocaine use and withdrawal. Changes in the amount or severity of environmental stress or anxiety may be one factor which predisposes some individuals to engage in compulsive drug use since both clinical and preclinical data have implicated an involvement of benzodiazepines in the behavioral and neurobiological effects of cocaine during both acute exposure and withdrawal from the chronic use of the drug. The experiments described in this proposal will therefore be used to systematically investigate the effects of controllable and uncontrollable electric footshock stress on the acquisition and maintenance of intravenous cocaine self-administration in rats. In addition, this behavioral model will be used as a baseline to evaluate whether various pharmacological interventions specifically alter drug-intake and/or the behavioral effects of withdrawal from cocaine or whether these drugs result in nonspecific effects on the ability of the animals to respond. The results of these investigations will increase knowledge of behavioral variables that potentially contribute to cocaine self-administration in rats and may therefore result in the development of novel pharmacotherapies in the treatment of cocaine withdrawal and abstinence in humans.

The chronic non-medical use of cocaine has currently reached epidemic proportions despite numerous drug-related health problems and sever penalties associated with the possession and sale of the drug. This increase in compulsive cocaine use has resulted in considerable interest in the clinical and neurobiological implications of this behavior. Unfortunately, however, a clear-cut consensus among health care professionals has not yet evolved regarding optimal treatment strategies for cocaine abuse. The increase in the number of people suffering from cocaine dependence who have requested medical assistance for withdrawal has resulted in a number of investigations attempting to develop more satisfactory treatment strategies. A better understanding of the complex neurobiological changes associated with chronic cocaine intoxication may assist in the search for improved methods of treatment in the clinic. In addition, the chronic use of cocaine and related stimulants can result in a paranoid psychosis in some individuals. These psychoses are difficult to distinguish from paranoid schizophrenia when these drugs are taken long enough at high enough doses. If the chronic use of cocaine results in alterations in the central nervous system that are analogous to the neuropathology associated with schizophrenia, then a better understanding of these changes may increase knowledge of the etiology of mental illness and may therefore lead to the more effective and efficient treatment and management not only of drug dependence, but also of schizophrenia and related disorders. Finally, while not all chronic users of cocaine manifest psychoses or other psychiatric dysfunctions, the continued use of this drug may result in neurobiological alterations which may affect performance in the work place. A better understanding of the behavioral and corresponding neurobiological effects of chronic exposure to cocaine may therefore assist in the identification of these drug-related problems in the work place and may indicate potential treatment strategies for these problems. The experiments proposed in this application will examine the neurobiological consequences of chronic cocaine intoxication using a multidisciplinary approach involving behavioral pharmacology, neurochemistry and neuroanatomy. The development of tolerance or sensitization to the effects of repeated cocaine injections on stereotypy and schedule-controlled behavior will be investigated by comparing the effects of pre-session or post-session injections with saline-treated controls. The involvement of receptor systems in the progressive development of this behavioral tolerance or sensitization will be determined by homogenate receptor binding and by light microscopic quantitative autoradiographic analyses of binding sites for various receptor systems in serial sections through the brain of each rat. Specific neurotoxin lesions and/or pharmacological interventions will be used to investigate the involvement of discrete brain regions and neurotransmitter systems in the behavioral pathology associated with chronic cocaine administration. These experiments will result in a better understanding of the behavioral, pharmacological, neurochemical and anatomical consequences of chronic cocaine intoxication.

This revised competing continuation application proposes to proceed with investigations of the effects of environmental-stress and the subsequent activation of the HPA axis on the initiation and maintenance of intravenous cocaine self-administration in rats. The primary hypothesis underlying these experiments is that the reinforcing and subjective effects of cocaine are mediated, at least in part, through interactions with common neurobiological effector systems also activated by stress. Data collected to date have demonstrated an important role for corticosterone in cocaine reinforcement, and preliminary data suggest that it is the actions of this hormone at glucocorticoid or Type II adrenocorticosteroid receptors that are responsible for this effect. The first experiments will investigate the effects of adrenocorticosteroids on responding under an alternating, multiple schedule of food reinforcement and cocaine self-administration to determine if the effects of adrenocorticosteroids on intravenous cocaine self-administration are the result of specific actions on cocaine reinforcement or nonspecific effects on the ability of the rats to respond. Follow-up experiments will also investigate the role for adrenocorticosteroids in the acquisition of intravenous cocaine self- administration in rats. Finally, experiments are proposed that will determine whether or not adreno-corticosteroids are also involved in the increased sensitivity to cocaine observed in rats exposed to stress. Another series of experiments will investigate the effects of adrenocorticosteroids in the reinstatement of intravenous cocaine self- administration to determine the effects of adrenocorticosteroids in this animal model of craving. Drugs which are effective in blocking the electric footshock and/or cocaine-induced reinstatement of cocaine-seeking behavior may also be effective in alleviating symptoms of cocaine craving in humans. Other experiments will investigate the effects of stress and adrenocorticosteroids in the discriminative stimulus effects of cocaine to determine whether or not the subjective and reinforcing effects of cocaine are mediated through similar mechanisms. These experiments will increase knowledge of how stress and the subsequent activation of the HPA axis influence cocaine reinforcement and may also suggest novel pharmacotherapies for the treatment of cocaine abuse and withdrawal in humans.

This is a new application for the formal establishment of a training effort for predoctoral students and postdoctoral fellows in the area of Stress and the Neurobiology of Drug and Alcohol Dependence. Support is requested for two postdoctoral fellows and two predoctoral students yearly, with a maximum of four students and four fellows at any given time. Predoctoral trainees will be graduates of a four-year program in chemistry, biology, psychology or a related discipline. These students will receive a doctoral degree in Pharmacology upon completion of the Training Program. Postdoctoral fellows will be recruited from among individuals who received their doctoral degrees in pharmacology, psychology or psychobiology. Although the department of Pharmacology & Therapeutics has a long and continuing tradition of collaboration, the creation of a NIDA-supported Training Program will greatly enhance our ability to successfully attract and train graduate students and postdoctoral fellows in drug abuse research. Students and fellows will have access to training in a wide variety of areas through the diverse, multi-disciplinary interests of the faculty serving as preceptors for this Training Program as well as through the highly collaborative nature of ongoing projects. This will enable them to acquire new techniques and information in areas of research other than those in which they are working directly. Predoctoral students will take a series of courses designed to provide them with a broad understanding of pharmacology with special emphasis on research in the general area of stress and the neurobiology of drug and alcohol dependence. This Program is structured to permit flexibility based on the particular needs and career plans of each individual student. The majority of each postdoctoral time is spent conducting research in the laboratory(s) of his/her preceptor(s) of his/her preceptor(s), with the inclusion of any didactic work individualized for each trainee. In addition, all trainees participate in a grant writing workshop designed to fine tune grant writing skills and to instruct the trainees in the critical evaluation of research proposals. The primary goal of this Training Program is to provide students and young scientists with comprehensive guidance in stress and drug abuse research.

DESCRIPTION (Adapted From The Applicant's Abstract): Substance abuse is a serious threat to society for which effective therapies are sought. Since no single effective treatment for substance abuse has been identified, current strategies seek to combine behavioral and pharmacological therapies. Successful pharmaceutical therapies include the agonist-based maintenance therapies: methadone (for heroin abuse) and nicotine patches (for tobacco abuse). Despite a profound understanding of the pharmacological actions of these drugs, the basis for their therapeutic effects remain unclear. In addition, no effective treatment has been found for cocaine abuse. Behavioral data from animal models may improve methods for developing these medications. Drugs that can decrease drug self-administration without having effects on other behaviors may be potential candidates. We recently developed a promising series of findings on the treatment of cocaine-maintained responding with the selective dopamine (DA) reuptake inhibitor GBR 12909. Acute administration abolished cocaine-maintained responding, while having no effect on food-maintained responding. Repeated administration sustained this effect, and a single injection of a long-acting decanoate formulation decreased cocaine-maintained responding for almost thirty days, while having little or no effect on food-maintained responding. While the behavioral effects of GBR 12909 and its decanoate appear very promising, their physiological effects may warrant further study. For example, cocaine has cardiovascular effects, and the potential of these drugs for interaction with this effect should be explored. Lastly, the effects of agonist-based treatments are likely to depend upon both specific pharmacological actions and behavioral factors. Our collaborators continue to modify the GBR series to improve its pharmacology and we also propose testing additional drugs as potential adjuvants to improve the effects of GBR analogs. The specific aims of this grant are to 1) further evaluate the effects of an ultra long-acting formulation of GBR 12909 alone and in combination with other drugs, 2) assess the behavioral effects of novel GBR 12909 analogs, with the aim of identifying improved decanoate candidates, and 3) assess the effects of GBR 12909 analogs and GBR 12909 decanoate alone, and in combination with cocaine, on cardiovascular functioning. These studies are designed to extend the agonist-based approach to the development of potential medications for the treatment of cocaine abuse and further our understanding of the behavioral pharmacology of the self-administration of cocaine.

DESCRIPTION (provided by applicant): Cocaine has been reported to have stimulant, reinforcing and addictive properties, among others. A consensus exists that mesocorticolimbic dopamine is involved in cocaine self-administration in rats and there are studies suggesting that corticosterone may be involved in cocaine reinforcement. Several studies have demonstrated that the context of cocaine delivery can alter the behavioral and neurochemical responses to the drug, emphasizing the importance of using appropriate behavioral models when assessing neural mechanisms of reinforcement. The hypothesis to be tested in this application is that drug-seeking behavior associated with cocaine self-administration triggers a sequence of events involving the interaction of dopaminergic systems in the brain with the hypothalamo-pituitary-adrenal (HPA) axis, which depends on the context of drug presentation, i.e., whether the drug is actively administered or infused passively. To test this hypothesis, it will be necessary to successfully combine the complex behavioral experiment (self-administration and yoked infusions) with the complex neurochemical procedure, in vivo microdialysis from different brain areas thought to be involved in the mediation of cocaine-seeking behavior. First, in vivo microdialysis coupled with high performance liquid chromatography (HPLC) will be used to determine the concentrations of dopamine and corticosterone in the microdialysates collected from the medial prefrontal cortex of rats in response to several doses of cocaine. In the second experiment, a limited dose response will be performed using in vivo microdialysis with the HPLC analysis of dopamine and radioimmunoassay of corticosterone in the microdialysis samples collected from the central nucleus of the amygdala. The results of this study will determine the role of mesolimbic and mesocortical dopaminergic projections in drug addiction, demonstrating whether or not the neurochemical response to self-administered cocaine is different from that observed after the passive infusions of cocaine. Using the combination of microdialysis with the yoked-triad model will allow us to distinguish the activating effect of cocaine on the HPA axis from the activation of the HPA axis related to drug-seeking behavior (i.e., self-administration vs. passively infused cocaine). Thus, the results of these experiments will demonstrate how control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the neural system. These results will also provide evidence of the role that is played by steroid hormones in shaping the functional activity of the brain.

The National Institute on Drug Abuse (NMA) recently launched an Institute-wide initiative to expand scientific reseal on the behavioral neurobiology of methamphetamine with the hopes of applying the results of this march to the prevention and treatment of methamphetamine abuse. This "Methamphetamine Initiative" is aimed at increasing scientific knowledge regarding methamphetamine and providing the public and health care practitioners with the latest available information about the drug's use, consequences, prevention, and treatment. This initiative was issued in response to the concern that the abuse of methamphetamine has become an extremely serious and growing problem. Although the drug was first used primarily in selected urban areas in the Southwestern part of the United States, high levels of methamphetamine abuse are now being observed in many areas of the Midwest, in both urban and rural settings, and by very diverse segments of the population. This is a revised application developed in response to this "Methamphetamine Initiative" and describes experiments designed to determine the potential role for stress and the subsequent activation of the hypothalamo-pituitary-adrenal (EPA) axis in the behavioral neurobiology of methamphetamine reinforcement. The primary hypothesis for this application is that the EPA axis influences the reinforcing efficacy of methamphetamine in a manner similar to tee. The influence of stress in methamphetamine reinforcement will be investigated during all three aspects of methamphetamine self-eon: namely the acquisition, maintenance and reinstatement of methamphetamine-seeing behavior. In this application, we highlight research we have conducted during the last 10 years or so demonstrating an important role for stress, CRF and corticosterone in cocaine self-administration using methodology we have developed and/or refined to investigate these Factors. This application describes experiments designed to investigate the influence of these factors in methamphetamine reinforcement using very similar procedures. Together, these experiments will increase knowledge of how stress and the subsequent activation of the EPA axis influence methamphetamine reinforcement and may also suggest novel pharmacotherapies for the treatment of methamphetamine abuse and withdrawal in humans.

Long Term Goal: To develop EMB-001 for the treatment of cocaine dependence. Background: Cocaine dependence and abuse afflict 1.6 million people in the U.S. and are associated with enormous costs to individuals and to the overall society. There are currently no medications approved for the treatment of cocaine dependence, and there is a compelling need for safe and effective therapeutics to treat this serious condition. The Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S) and Embera NeuroTherapeutics are developing EMB-001 for the treatment of cocaine addiction. EMB-001 is a combination drug product comprising two FDA-approved medications, the benzodiazepine oxazepam and the cortisol synthesis inhibitor metyrapone. The development of this new medication emerged from 20 years of NIH-funded research into the role of stress and the hypothalamo-pituitary-adrenal (HPA) axis in addiction. EMB-001 has already been demonstrated to be effective in multiple animal models of cocaine addiction and in a pilot clinical trial carried out using the commercially available single agent drugs in cocaine-dependent patients. This proposal is aimed at continuing the development of this promising therapeutic and advancing the combination drug product into clinical testing. The Specific Aims are as follows: Specific Aim 1: To complete the development and manufacture of EMB-001. Specific Aim 2: To complete the preclinical pharmacology and toxicology studies needed to support an IND submission. Specific Aim 3: To complete a Phase 1 clinical trial of EMB-001. At the completion of the funding period, we will be prepared to evaluate EMB-001 in Phase 2 safety and efficacy studies in cocaine-dependent subjects.