Stephen L. Dewey - US grants

Interactions between chemically different neurotransmitter systems provide the mechanisms responsible for maintaining homeostatic balance and for appropriate responses within the central nervous system (CNS) to changes in both the internal and external environment. The purpose of this proposal is to use positron emission tomography (PET) as a tool for further characterizing neurotransmitter interactions within the extrapyramidal motor system Specifically, we will examine interactions between the cholinergic, dopaminergic, GABAergic, and serotonergic systems in order to more completely understand the consequences of how a drug-induced perturbation in one of these neurotransmitter systems can manifest itself through any other neuroanatomically and/or functionally-linked system. Specific deficits in any one of these neurotransmitters have been implicated in abnormalities in motor coordination and psychiatric disorders. While PET studies have examined each one of these systems separately, studies designed to examine interactions between these neurotransmitters will provide a more complete understanding of the mechanisms responsible for these disorders. Previously we synthesized and measured the binding characteristics of a dopaminergic and cholinergic ligand and demonstrated that interactions between acetylcholine and dopamine can be measured with PET (Dewey, et al., 1991). The studies in this proposal will further our understanding of the role that GABA and serotonin play in these interactions. Pharmacologic intervention with drugs of known receptor specificity will be used in conjunction with the appropriate radiotracer to measure these effects. This unique strategy for studying neurotransmitter interactions in vivo has widespread clinical applications and may lead to a more complete understanding of many CNS disorders that have classically been attributed to a single neurotransmitter system (ie. schizophrenia, affective disorders, Parkinson's disease, Huntington's chorea, etc.). Furthermore, this approach takes full advantage of the unique capabilities of PET and the selective radiotracers 11C-benztropine (cholinergic), 11C-raclopride (dopamine D2), and 18F-altanserin (serotonergic, 5-HT2) for assessing dynamic neurotransmitter relationships and the consequences of their interactions-in the living brain. These studies will serve as the impetus for future investigations that will provide insight into the adaptive or responsive changes that occur in one neurotransmitter system following alterations in another. Finally, these studies can be used to assess the ability of a specific neurotransmitter system to adapt to drug-induced or pathological changes in the internal environment.

DESCRIPTION (provided by applicant): Adolescence is a stage of development that in humans is often associated with increased levels of risk-taking and reckless behaviors. Furthermore, brain development underlying motivation and decision making processes makes this age period particularly vulnerable with respect to impulse control and the development of addiction. Therefore, the objective of this competitive renewal is to develop an effective pharmacologic treatment regimen for cocaine and/or methamphetamine addiction using S-(+)-gamma-vinyl GABA (GVG) in adolescent animals, a notably vulnerable population. Currently, no effective pharmacologic treatments are available for these indications in any population regardless of age. Thus, in addition to identifying effective treatment regimens, studies in this application will establish whether these regimens need to be modified in adults as the consequence of an adolescent drug history. Using a strategy similar to the one currently funded for racemic GVG, these studies will be targeted in several new directions. First, using adolescent animals, studies will identify an effective treatment regimen using the new molecular entity, S-(+)-GVG, the pharmacologically active enantiomer of GVG. Next, studies will determine if this regimen is effective once these animals reach adulthood and whether it remains effective in adult animals with an adolescent drug history of cocaine or methamphetamine exposure. These studies will use micro-PET imaging with 11C-raclopride as an independent measure of cocaine or methamphetamine-induced reward (increases in brain dopamine) and 18-FDG to identify glucose metabolic changes in dopaminergic and non-dopaminergic brain regions. Preliminary results demonstrate that all the proposed experiments can be completed as detailed. Ultimately, these data will be targeted towards the development of S-(+)-GVG for the treatment of cocaine and/or methamphetamine addiction in adolescence. Finally, these studies will determine if drug exposure during adolescence alters the adult therapeutic response to S-(+)-GVG.

Description (provided by applicant): Inhalant abuse is a rapidly growing health problem particularly among children and adolescents. Yet we know surprisingly little about the neural mechanisms underlying abuse liability of inhalants particularly when compared to other drugs of abuse. Specifically, knowledge of the relationship between their regional brain pharmacokinetics and features classically associated with drugs of abuse is lacking The importance of this problem and the lack of information places a sense of urgency on understanding the interactions of these volatile substances with the brain and other organs in living systems. Here we propose a systematic study of the brain and body distribution and pharmacokinetics of volatile substances (VSs) of abuse using positron emission tomography (PET). Within this context there are two specific aims; (1) To develop efficient synthesis, purification and formulation methodology of carbon-11 and fluorine-18 labeled compounds representing five important classes of abused inhalants; (2) To characterize and compare across classes of compounds regional brain and whole body distribution, absolute uptake, and pharmacokinetics of radiolabeled inhalants using PET in anesthetized baboons and ex vivo methods and microPEl technology in rodents. We will test the hypothesis that the differences in profiles of behavioral effects among individual vapors seen in animals and in their abuse potential or nature of intoxicating and toxic effects in humans are related to the diversity in their chemical structures and regional pharmacokinetics. PET is an ideal scientific tool for investigating the brain and whole body uptake as well as regional CNS distribution and clearance of labeled compounds. Moreover, recent PET studies in our laboratory using carbon-11 labeled toluene (the most widely abused inhalant) support the value of this approach to advance our understanding of the processes responsible for both addictive and toxic effects of abused inhalants. More importantly, these studies will provide the strategy and tools to identify characteristics of inhalants that are associated with their abuse liability.

DESCRIPTION (provided by applicant): Striking phenotypic similarities have been noted between infants exposed to toluene in utero and infants diagnosed with fetal alcohol syndrome. However, data are lacking to relate the degree of maternal exposure to toluene and other inhalant drugs of abuse to their effects on the fetus. This is an important issue because a majority of persons who abuse inhalants are females in their prime childbearing years, and the National Pregnancy and Health Survey has indicated that 12,000 pregnant women each year abuse inhalants. There are no quantitative data on transplacental transfer of toluene or any other inhalants in humans, although rodent studies indicate that 10% of an inhaled dose of toluene reaches the fetus whereas this fraction is 2% -4% for chlorinated hydrocarbons or for more highly substituted aromatics such as xylene and styrene. The proposed work builds on our previous extensive neuroimaging studies of drugs of abuse using positron emission tomography (PET) and high-field magnetic resonance spectroscopic imaging, and our recent preliminary preclinical studies with the abused inhalant, toluene, labeled with the PET radioisotope carbon-11. The objective is to develop methodologies for quantifying exposure of fetal macaques after administration of the positron labeled inhalants [11C] toluene and [11C] butane to the macaque mother. This work with two inhalants with somewhat different physical properties and reported subjective effects will set the stage for hypothesis driven PET studies with these and other inhalants in pregnant non-human primates. Ultimately, the hope is to relate the mother's exposure to inhalants to the dose received by the fetus and to post-natal behavioral deficits.

[unreadable] DESCRIPTION (provided by applicant): This is a revised K02 application. Dr. Stephen L. Dewey is a neuroanatomist and a senior scientist. He has a distinguished record in neuroimaging, microdialysis and medications development for drug abuse. His early work focused on imaging neurotransmitter interactions. These pioneering studies produced a paradigm shift that represents one of the most effective applications of PET research today. As a result, Dr. Dewey identified gamma vinyl-GABA, (GVG, vigabatrin) for the treatment of drug abuse. Following the generation of an unprecedented published preclinical database, which produced 9 U.S. patents (1 additional pending), he designed and conducted 2 open labeled clinical trials in adult cocaine and methamphetamine abusers. These trials suggested clinical efficacy and demonstrated visual safety, while also serving as the foundation for 2 Investigative New Drug (IND) applications, recently accepted by the FDA, for Phase I and II clinical trials. Dr. Dewey has successfully graduated 3 doctoral students and is currently a thesis advisor for three additional doctoral candidates as well as being a mentor to several junior scientists. In 1994, Dr. Dewey initiated an outreach program to adolescents that reached more than 55,000 children last year alone (more than 300,000 since its inception), motivating his new research initiative in inhalant abuse. This K02 will release Dr. Dewey from teaching and provide 60% salary support, which will result in at least 75% protected time to focus on the new molecular entity, S- (+)-GVG, for the treatment of adult and adolescent methamphetamine or inhalant abuse. This application proposes 2 synergistic goals: (1) Research (60%); to identify optimal treatment regimens with the new molecular entity, S- (+)-GVG, for adult and adolescent methamphetamine or inhalant abuse using the identical strategies he successfully employed with GVG and (2); Mentoring and outreach (15%): to mentor junior investigators, post-doctoral fellows, and graduate and undergraduate students while continuing his extensive outreach program. This research benefits from collaborators at BNL, Stony Brook Univ, New York Univ, St. Johns Univ, and NIDA intramural. Thus, the objectives of this application are to identify optimal treatment regimens for methamphetamine or inhalant abuse while inspiring, teaching, and encouraging young scientists across disciplines to investigate the major public health consequences created by adolescent and adult drug abuse. [unreadable] [unreadable] [unreadable]