Abstract: Craving has been implicated as a major contributor both to relapse and maintenance of addiction following absti- nence in cocaine abusers. Although a mechanistic understand- ing of the biological basis of cocaine craving could identify therapeutic approaches to reduce cocaine dependence, informa- tion on the involvement of specific neurochemical systems in this phenomenon is scarce. Ongoing and previous studies in human volunteers have shown that environmental stimuli re- lated to drug taking selectively increase cerebral glucose me- tabolism (Grant, 1995) and perfusion (Childress et all 1996) in cortical and limbic areas of brain and that activation in the dor- solateral prefrontal cortex and amygdala is correlated with self- reports of craving (London, 1996). We propose to elucidate the role of dopaminergic and serotonergic systems in spontaneous and cue-elicited cocaine craving, in an integrated approach uti- lizing positron emission tomOgraphy (PET) scanning and se- lective radioligands for dopamine(DA) and serotonin (5-HT) receptors and ransporters. Neurochemical markers, assayed by PET, will be related to self-reports of craving in cocaine abus- ers, and will be compared to measures in control subjects who have no significant history of illicit drag abuse. Our premise is that, not only is there considerable evidence in the literature for the role of dopamine and serotonin in craving, but that the acti- vated areas, previously seen in the amygdala and dorsal lateral prefrontal cortex can be examined further by examination of these neurotransmitter systems. We hypothesize that in our ex- perimental paradigm following withdrawal, extracellular dopamine and to a lesser extent serntonin will be decreased. It is then predicted that both intrasynaptic DA (InsDA) and intrasynaptic 5HT (Ins5HT) will increase following the phar- macologic challenge and that cue-elicited craving will correlate significantly with this increase. It is predicted that spontaneous craving however, will correlate negatively with D1 D2 and 5HT 2a receptors. Finally, it is predicted that both when cue- elicited craving is induced during PET imaging, increased InsDA and 5HT will be measurable and will correlate signifi- cantly with the craving score. Testing of these hypotheses will provide novel and fundamental answers to craving mecha- nisms.

Thesaurus Terms: brain visualization, cocaine, dopamine, drug addiction, motivation, psychopharmacology, serotonin cue, dopamine receptor, dopamine transporter, drug with- drawal, serotonin receptor, serotonin transporter behavioral / social science research tag, clinical research, human subject, positron emission tomography

~ROJECT TITLE

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 1998 Radiology 01-Sep-97 31-Aug-02 National Institute On Drug Abuse ZDA1

DOPAMINE TRANSPORTER IMAGING IN COCAINE ABUSE

Grant Number: 5R01DA09482-04 PI Name: Wong, Dean F.

Abstract: The long range goal of this project is to develop methods of quantifying the dopamine transporter (DAT) site in human brain to provide insight into the neuroscience of ad- dictive behavior in cocaine abuse. Positron emission tomog- raphy (PET) imaging studies will be employed to measure the DAT density and occupancy. The first goal will be to de- velop quantitative measurement of absolute density (B/max) in normal human brain as an improvement over existing mea- sures of B/max/K/D. Two methods will be studied, one with unlabeled mazindol and IV unlabeled WIN 35,428 given prior to the second of two high specific activity [1 l/C] WIN 35,428 PET scans. Using quantitative model calculations, B/ max will be obtained. Validation of these techniques in post- mortem baboon brains will be performed. Upon successful development of this procedure, we will apply these methods to obtain B/max in cocaine users immediately after cocaine withdrawal and one month later. The change in B/max will be compared with test-retest of B/max in normal volunteers studied at the same interval. This will allow examination of the brain response variability to long-term cocaine abuse and comparison to control B/max values. A parallel study will also be employed to examine the phamlacokinetics of poten- tial medications for cocaine abuse. The first step will be to test the hypothesis that time to peak drug level in brain is in- versely correlated with the behavioral response. Not only will this be tested with plasma levels but specifically with the onset of peak occupancy levels against subjective effects of IV cocaine. Testing of such hypotheses is a fundamental ele- ment in the understanding of drug abuse and dopamine. This will be done by monitoring the effects of IV cocaine given at different time intervals on the reduction in binding of cocaine given by programmed infusion. This will allow the relation- ship of DAT occupancy vs. drug dose injection rate. The next step is to measure the DAT occupancy for varying levels of two putative medications, oral GBR 12909 and IV unlabelled WIN 35,428. By measuring the dose response of DAT occu- pancy vs. drug dose, a number of steps towards medication development are achieved. These include determination of the drub doses at which percent occupancy is high and most optimal; examination of the subjective effects of these drugs when given orally or by slow infusion, thereby determining their suitability as therapeutic drugs. At the conclusion of this five year project, important neuroscience information concerning measurement of DAT in cocaine withdrawal will be obtained. A fundamental hypothesis of drug abuse and drug delivery will be tested. Furthermore, the DAT occu- pancy vs. dose relationships will be developed and applied to two putative treatment drugs, as a first step towards rational

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drug trials. The possible non-competitive nature of GBR 12909 will also be tested in vivo.

Thesaurus Terms: chemical binding, cocaine, dopamine transporter, drug addiction, drug receptor, drug withdrawal, neuroanatomy, neurochemistry dopamine antagonist, dopam- ine receptor, drug abuse chemotherapy, drug addiction an- tagonist, drug administration rate/duration, drug screening / evaluation, mathematical model, model design/development baboon, electrocardiography, human subject, positron emis- sion tomography, postmortem, psychometrics, urinalysis

Institution: Johns Hopkins University 3400 N Charles St Baltimore, MD 21218

Fiscal Year: 1998 Department: Radiology Project Start: 30-Sep-94 Project End: 31-Jan-00 ICD: National Institute on Drug

Abuse IRG: SRCD

Agency for Toxic Substances and Disease Registry

~ROJECT TITLE

EXPERIMENTAL INDUCTION OF CARPAL TUNNEL SYNDROME

Grant Number: 8R01AT00002-04 PI Name: Lang, Elvira V.

Abstract: Chronic nerve compression syndrome is a common clinical problem that has assumed epidemic proportions in the 1990s. Although an association between mechanical pressure on the median nerve and carpal tunnel syndrome (CTS) has been hypothesized, neither the relationship be- tween the severity and duration of such pressure and the re- sultant CTS, nor the underlying pathophysiology have been elucidated. To understand how mechanical pressure in the wrist leads to alterations in median nerve function and nerve morphology, we have developed an in vivo rabbit model in which graded, reversible compressive forces can be applied in the carpal canal and neurophysiologic and biologic conse- quences monitored. Static compressive loading will be ap- plied to the rabbit median nerve with pneumatic balloon cath- eters fixed at the transverse carpal ligament to create CTS. The duration of exposure required to cause carpal tunnel syn- drome as a function of the applied pressure will be deter- mined. The endpoint of CTS will be defined as an increase in motor latency that is consistently observed over a two-week time period by nerve conduction studies/electromyography (NCS/EMG). Changes in nerve vascularity and microcircula- tion will be studied by in vivo microscopic analysis prior to sacrifice. Histologic specimens will be prepared and graded for nerve morphology and inflammatory response. This in- formation will be used to develop an understanding of the chronology of events that occurs with CTS. Our goal is to es-

tablish a dose-response relationship between pressure within the carpal canal and CTS. We hypothesize that in the patho- mechanics of CTS, there is a significant relationship between pressure, duration of exposure to pressure, and various in- flammatory and vascular events that surround CTS. These data will have significant implications for human CTS. In the future, this model may serve to test the modulation of thresh- old pressure for developing CTS by various treatments in an effort to prevent CTS. Ultimately, we wish to realize a com- prehensive understanding of pathophysiology of CTS, its pre- vention, and when it occurs, its treatment. We will simulate clinical CTS reversal, as in carpal tunnel release, by deflating balloon catheters in animals in which CTS has already been induced. From this animal model of CTS reversal, we will generate a pathophysiology that relates duration and amount of pressure to resultant CTS reversal with NCS/EMG, micro- scopic evaluation of nerve vascularity, and tissue analysis.

Thesaurus Terms: carpal tunnel syndrome, disease/disor- der etiology, neurophysiology compression, inflammation, neural conduction, neuromuscular function, wrist disease model, electromyography, histology, laboratory rabbit

Institution:

Fiscal Year: Department: Project Start: Project End: ICD:

IRG:

Beth Israel Deaconess Medical Center

330 Brookline Ave Boston, MA 02215 1999

30-Sep-97 30-Apr-00 Agency For Toxic Substances

And Disease Registry HBPR

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