The positive reinforcing effects of cocaine have proven to be an important determinant of its abuse liability. Neurochemical studies have linked cocaine's reinforcing effects with the inhibition of dopamine uptake. An issue that has not been adequately addressed is the temporal change in D2 receptor expression following either acute or chronic cocaine exposure; these changes may play an important role in the reinforcing and addictive properties of cocaine. Additionally, an understanding of the temporal changes in D2 receptor density during drug acquisition and maintenance should provide valuable information toward developing effective strategies for treating cocaine abuse. The goal of the research described in this proposal is to study the longitudinal changes in D2 receptor density in a primate model of cocaine abuse using the in vivo imaging technique Positron Emission Tomography (PET). D2 studies are initially proposed because of the availability of an optimal ligand for making accurate estimates of D2 density with PET. Initially, cocaine-naive rhesus monkeys will be trained to respond under a food-reinforcement schedule and a series of PET studies will be conducted in order to obtain a stable baseline density of D2 receptors. The rhesus monkeys will then enter the self administration paradigm and a series of PET studies will be conducted from an acute exposure (15 mg/kg/i.v.) to 1 year following initial cocaine exposure. Each monkey will serve as his own control in order to avoid the problems of making between-subject comparisons. A set of control monkeys, trained only to respond under the food reinforcement schedule, will also be studied with PET in order to correct for the effects of lever-press responding and age on D2 receptor density. Since PET provides estimates of receptor density in the form of a binding potential, which is the ratio of BmaX/Kd, the PET results will also be validated using the in vitro technique of quantitative autoradiography. These studies will be conducted in order to determine if the changes in binding potential observed by PET are due solely to changes in BmaX or to a combined effect of BmaX and Kd resulting from changing levels of synaptic dopamine content that are unavoidable in vivo. Autoradiography studies will also be conducted in order to determine the effect of chronic cocaine exposure on dopamine D3 receptor expression. Results from the present studies should compliment and validate the current research being conducted with PET imaging of chronic cocaine abusers.
| Nader, Michael A; Morgan, Drake; Gage, H Donald et al. (2006) PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nat Neurosci 9:1050-6 |
| Mach, R H; Nader, M A; Ehrenkaufer, R L et al. (2000) Fluorine-18-labeled tropane analogs for PET imaging studies of the dopamine transporter. Synapse 37:109-17 |
| Nader, M A; Grant, K A; Gage, H D et al. (1999) PET imaging of dopamine D2 receptors with [18F]fluoroclebopride in monkeys: effects of isoflurane- and ketamine-induced anesthesia. Neuropsychopharmacology 21:589-96 |
