Diana Martinez - US grants

DESCRIPTION: (Applicant's Abstract) Cocaine addiction is a chronic, relapsing disorder for which there is little effective pharmacologic treatment. The preclinical literature suggests that the mesolimbic dopamine system is critically involved in the reinforcing effects of cocaine and in vulnerability to relapse. However, to date relatively little is known about the neurochernical changes in mesolimbic dopamine function in humans and their putative role in mediating cocaine seeking behavior. Recent developments in brain imaging provide the unique opportunity to study these changes and their role in cocaine addiction. During the proposed career development award, the candidate will learn to develop neuroreceptor imaging techniques with PET and to implement these techniques in the study of neurochemical imbalances in chronic cocaine abuse. In addition, the career development period will include training in human behavioral pharmacology, in order to relate brain imaging findings with cocaine taking behavior in humans. Columbia University provides a unique environment to achieve this purpose. The specific aims include the study of pre- and post-synaptic parameters of dopamine transmission in mesolimbic regions (ventral striatum and amygdala) in chronic cocaine users and matched healthy controls. Alterations of dopamine transmission will then be related to laboratory measures of cocaine self-administration following a low dose of cocaine ("priming" dose). Based on preclinical literature, the hypotheses are that low mesolimbic D1 receptor density and high stimulant-induced dopamine release will be correlated with an increased likelihood of cocaine taking behavior in the laboratory. Thus, an unique aspect of this proposal is the combination of state-of-the-art PET technology and established laboratory methods for studying cocaine self-administration. The career development plan proposed in this application is designed both to address these scientific questions as well as to provide the principal investigator an unparalleled training in the neuroimaging and behavioral studies of substance abuse. Toward this aim, a comprehensive educational program including mentoring, didactics, and collaboration with experts in the field has been outlined in this application.

positron emission tomography; dopamine; brain imaging /visualization /scanning; alcoholism /alcohol abuse; molecular /cellular imaging; drug /alcohol abstinence; serotonin transporter; raclopride; dopamine transporter; amphetamines; neurochemistry; synapses; dopamine receptor; receptor binding; neurotransmitter transport; patient oriented research; magnetic resonance imaging; bioimaging /biomedical imaging; human subject; clinical research;

vaccines; cocaine; drug addiction antagonist; active immunization; pharmacokinetics; brain imaging /visualization /scanning; brain mapping; blood brain barrier; drug addiction; dopamine transporter; human therapy evaluation; clinical trials; drug receptors; patient oriented research; bioimaging /biomedical imaging; radiotracer; human subject; positron emission tomography; clinical research;

DESCRIPTION (provided by applicant): One of the most difficult aspects of treating cocaine dependence is the propensity for relapse to cocaine use after a period of abstinence. While previous research has focused on positive reinforcement and relapse, recent studies have begun to explore the neurobiology of negative reinforcement. Drug use in setting of stress provides negative reinforcement by relieving the stress. Preclinical studies show that kappa receptor activation mediates stress-induced, but not cocaine-induced, cocaine- seeking behavior, suggesting that that kappa receptor activation is selective for negative reinforcement. Previous postmortem studies in cocaine dependence have shown that the kappa receptor is unregulated in this disorder. However, studies investigating the behavioral significance of this change have been lacking due to the inability to image this receptor in vivo. In this application, we will use the newly developed kappa receptor selective PET radiotracer [11C]GR103545 to explore this alteration in neurochemistry in cocaine abuse. In addition, given that dynorphin is known to closely regulate striatal dopamine transmission we use the Monetary Incentive Delay Task, which produces reproducible activation of the striatum, and has been shown to correlate with striatal dopamine transmission. Thus, we will compare alterations neurochemistry and striatal function in cocaine abusers and matched controls for the first time. Additionally, within the cocaine abusing subjects, we will use a laboratory model of stress-induced cocaine seeking behavior in order to explore the correlation between the neurobiology and negative reinforcement. We will also include a group of cocaine abusers who undergo cocaine self-administration sessions following a priming dose of cocaine, in order to demonstrate the specificity of the kappa receptor system for stress-induced cocaine seeking behavior. A final specific aim of this application is to investigate in humans, a well- documented preclinical phenomenon in which binge dosing of cocaine significantly increases dynorphin levels. To investigate this, the cocaine abusing volunteers will participate in binge cocaine self-administrations sessions. Following the sessions, the imaging scans and the stress-induced cocaine self-administration sessions will be repeated, in order to investigate the effect of increased dynorphin in the brain. PUBLIC HEALTH RELEVANCE: The goals of the studies included in this application are to characterize the neurobiology of negative reinforcement in cocaine abuse by focusing on the kappa receptor/dynorphin system in the brain. Using both imaging and behavioral studies, this application seeks to further our understanding this important phenomena in relapse.

Previous clinical and pre-clinical studies have shown that the dysregulation in dopamine transmission plays a criticial role in substance abuse. The studies presented in this application include the candidate's work characterizing the alteration in dopamine transmission seen in addiction. These studies include research done in cocaine, alcohol, and heroin dependence, and show that each of these disorders is associated with a loss of D2/3 receptor binding and pre-synaptic dopamine transmission. Importantly, the work done in cocaine dependence shows that dopamine transmission is predictive of relapse. The next step is to explore the mechanisms that contribute to dopamine dysregulation in addition to studying other neurotransmitter systems that directly regulate dopamine transmission. These studies include imaging micriglial activation, in addition to the kappa and neurotensin receptors systems. The candidate developed her PET imaging career through the K23 award mechanism. Due to the support provided by that award, she was able to pursue a career in imaging studies in substance dependent populations. As an independent researcher, the candidate has continued this line of work. In addition, the candidate has pursued numerous collaborations in an effort to bring PET radioligand imaging into more types of clinical research. This application for a K02 awardwill allow the candiate's career to continue unbinterupted as she pursues new directions in PET imaging. RELEVANCE (See instructions): Previous work performed by the applicant for this award have shown that dopamine is involved in drug addiction. The next set of studies will examine the cause of the changes in brain dopamine and ways to correct this deficit.