The escalating abuse of cocaine in the United States over the past decade and its attendant social, economic and medical problems has stimulated intense interest in elucidating the neurochemical mechanisms responsible for its euphoric and reinforcing properties. Although studies in animals have implicated cocaine's interactions with the presynaptic ptic dopamine reuptake system as playing a major role in its reinforcing properties, there are a number of inconsistencies in the literature regarding the extent to which cocaine modifies the activity of post-synaptic dopaminergic receptors. This application describes studies with positron emission tomography (PET) to directly map and characterize cocaine binding sites in living human and baboon brain with carbon-11 labeled cocaine and to examine (directly in cocaine abusers) the effects of chronic cocaine use and withdrawal on presynaptic dopamine reuptake system (using [11C]cocaine) and the post-synaptic dopamine D2 receptor system using [18F]-N- methylspiroperidol). To better understand the neurochemical systems involved in cocaine binding, the pharmacological profile of cocaine binding in different brain regions will be determined in baboons by using labeled cocaine and selectively blocking the dopamine, norepinephrine and serotonin reuptake sites with highly specific drugs. Stereoselectivity of bindinl be examined by comparative PET studies of [11C]-(-)- cocaine and [11C]-(+)-cocaine, the active and inactive enantiomers of the drug respectively. The effects of cocaine abuse on both the binding of labeled cocaine and on the binding of [18F]-N- methylspiroperidol (to measure dopamine D2 receptor availability) will be assessed in cocaine abusers and the reversibility of cocaine induced changes in pre and post-synaptic dopaminergic systems will be measured over a three month drug-free period. Serial PET studies in which the subject (human or baboon) serves as his own control will be used to reduce problems associated with inter-subject variability. Specific hypotheses to be tested are (1) that [11C]cocaine will bind to the dopamine reuptake site, (2) that chronic cocaine use will lead to a decrease in dopamine D2 receptors and (3) that chronic cocaine use will lead to an increase in dopamine reuptake sites accompanied by an increase in cocaine binding sites and that with discontinuation of the drug the number of cocaine binding sites will return to normal. The direct examination of these dopaminergic systems in the living brain and the possibility of correlating clinical characteristics accompanying cocaine withdrawal with neurochemical changes as measured with PET holds the promise not only of understanding the neurochemical response to cocaine but of designing more effective therapeutic measures for cocaine addiction.
| Michaelides, Michael; Thanos, Panayotis K; Volkow, Nora D et al. (2012) Translational neuroimaging in drug addiction and obesity. ILAR J 53:59-68 |
| Wang, Gene-Jack; Geliebter, Allan; Volkow, Nora D et al. (2011) Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity (Silver Spring) 19:1601-8 |
| Volkow, Nora D; Fowler, Joanna S; Wang, Gene-Jack et al. (2010) Cognitive control of drug craving inhibits brain reward regions in cocaine abusers. Neuroimage 49:2536-43 |
| Wang, Gene-Jack; Volkow, Nora D; Thanos, Panayotis K et al. (2009) Imaging of brain dopamine pathways: implications for understanding obesity. J Addict Med 3:8-18 |
| Wang, Gene-Jack; Volkow, Nora D; Telang, Frank et al. (2009) Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation. Proc Natl Acad Sci U S A 106:1249-54 |
| Tomasi, Dardo; Wang, Gene-Jack; Wang, Ruiliang et al. (2009) Association of body mass and brain activation during gastric distention: implications for obesity. PLoS One 4:e6847 |
| Woicik, Patricia A; Moeller, Scott J; Alia-Klein, Nelly et al. (2009) The neuropsychology of cocaine addiction: recent cocaine use masks impairment. Neuropsychopharmacology 34:1112-22 |
| Volkow, Nora D; Wang, Gene-Jack; Telang, Frank et al. (2009) Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity (Silver Spring) 17:60-5 |
| Volkow, Nora D; Wang, Gene-Jack; Telang, Frank et al. (2008) Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues. Neuroimage 39:1266-73 |
| Volkow, Nora D; Fowler, Joanna S; Wang, Gene-Jack et al. (2007) Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol 64:1575-9 |
Showing the most recent 10 out of 75 publications
