The goals of the current application are to either develop or apply methods to study the dopaminergic system with SPECT (single photon emission computed tomography) and microdialysis to assess the neurochemical alterations in the brain which are induced by chronic cocaine administration. During the previous funding cycle, we successfully implemented SPECT methods (first in monkeys and then in humans) to quantify dopamine D2 receptors and dopamine transporters; to combine i.v. amphetamine,challenge with D2 receptor imaging as an indirect measure of synaptic dopamine levels; and to combine microdialysis with SPECT imaging to provide direct measurements of extracellular dopamine levels. Two PET studies have recently demonstrated significant reductions in D2 receptors in non-detoxified male cocaine abusers as compared to healthy male controls using [18F]N-methylspiroperidol (Volkow et al., 1990 and 1993). These alterations in D2 receptors could have been confounded by abnormal cerebral blood flow in the cocaine addicts. We propose to compare levels of D2 receptors in active cocaine abusers and healthy controls using an equilibrium method which is not influenced by alterations of blood flow (Specific Aim #1). In addition, the D2 receptor imaging will be combined with on- going studies of the dopamine transporter to provide both pre- and postsynaptic measures of dopaminergic transmission in cocaine dependence. Since age and gender may have important effects on D2 receptors, equal numbers of males and females will be studied and cocaine addicts and controls will be individually matched for age. In addition, we will measure potential changes in D2 receptors during states of acute vs. sustained drug abstinence (Specific Aim #2). In the animal studies, we will use SPECT imaging of the D2 receptor before and after depletion of DA by AMPT (alpha-methyl-para-tyrosine) and reserpine to examine D2 receptor occupancy induced by basal levels of endogenous DA (Aim #3). In addition, we will examine the ability of the ability of both SPECT receptor imaging and microdialysis to measure sensitization induced by chronic amphetamine administration (Aim #4). The animal studies have been designed so that, if they generate positive results, we will have gathered critical data to extend these paradigms to study human subjects who abuse cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA004060-13
Application #
6103954
Study Section
Project Start
1998-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bradberry, Charles W (2011) Cortical and sub-cortical effects in primate models of cocaine use: implications for addiction and the increased risk of psychiatric illness. Neurotox Res 19:235-42
Greenwell, Thomas N; Martin-Schild, Sheryl; Inglis, Fiona M et al. (2007) Colocalization and shared distribution of endomorphins with substance P, calcitonin gene-related peptide, gamma-aminobutyric acid, and the mu opioid receptor. J Comp Neurol 503:319-33
Kosten, Thomas R; Scanley, Barbara Ellen; Tucker, Karen A et al. (2006) Cue-induced brain activity changes and relapse in cocaine-dependent patients. Neuropsychopharmacology 31:644-50
Abi-Saab, Danielle; Beauvais, John; Mehm, John et al. (2005) The effect of alcohol on the neuropsychological functioning of recently abstinent cocaine-dependent subjects. Am J Addict 14:166-78
Kosten, Thomas R; Tucker, Karen; Gottschalk, P Christopher et al. (2004) Platelet abnormalities associated with cerebral perfusion defects in cocaine dependence. Biol Psychiatry 55:91-7
Tucker, Karen A; Browndyke, Jeffrey N; Gottschalk, P Christopher et al. (2004) Gender-specific vulnerability for rCBF abnormalities among cocaine abusers. Neuroreport 15:797-801
Kosten, Thomas R; Kosten, Therese A (2004) New medication strategies for comorbid substance use and bipolar affective disorders. Biol Psychiatry 56:771-7
Tucker, Karen A; Potenza, Marc N; Beauvais, John E et al. (2004) Perfusion abnormalities and decision making in cocaine dependence. Biol Psychiatry 56:527-30
Browndyke, Jeffrey N; Tucker, Karen A; Woods, Steven P et al. (2004) Examining the effect of cerebral perfusion abnormality magnitude on cognitive performance in recently abstinent chronic cocaine abusers. J Neuroimaging 14:162-9
Kosten, Thomas R; Gottschalk, P Christopher; Tucker, Karen et al. (2003) Aspirin or amiloride for cerebral perfusion defects in cocaine dependence. Drug Alcohol Depend 71:187-94

Showing the most recent 10 out of 188 publications