This proposal is designed to examine the consequences of chronic cocaine self-administration on measurements of neurochemical brain function in rhesus monkeys. Measurements will be made in-vivo using magnetic-resonance directed microdialysis methodology in place in the investigators' laboratory, and also postmortem tissue assays. Preliminary results indicate cocaine self-administration increases extracellular dopamine, serotonin, and glutamate, with effects on extracellular glutamate especially pronounced. Microdialysis measurements will be made in the dorsolateral striatum, ventromedial striatum, the striatal shell, and in the orbitofrontal cortex using chaired rhesus monkeys trained to self-administer food and cocaine.
The specific aims are: 1) To compare the effects of self-administered cocaine before and after 16 weeks of chronic self-administration on the extracellular levels of dopamine, serotonin, and glutamate in the anatomical sites listed above. A comparison group will self-administer food. A third group of animals will be used for general microdialysis characterization studies before and after 16 weeks of chronic food self-administration in order to determine if a within-groups comparison before and after chronic cocaine self-administration is valid in addition to a between groups comparison. This group will also provide a control for the experiences of surgery, probe implantations, and extensive working for a non-cocaine (food) reward in the post-mortem studies and will provide a general characterization of the microdialysis methodology in primates. 2) Determine if cues predicting cocaine availability will trigger neurochemical signals before and after a period of prolonged cocaine self-administration. During the procedures in specific aim 1, we will determine the impact of cue exposure signaling impending cocaine or food availability on extracellular neurotransmitter levels. This addresses the clinically relevant topic of craving, which can be triggered in humans by environmental cues, and its neurochemical basis. 3) To compliment the presynaptic measurements of neurotransmitter function provided by microdialysis, post-mortem tissue assays will be done to examine neurotransmitter receptors, transporters, tyrosine hydroxylase, AP-1 binding of nuclear protein extracts and Fos-related antigens which are known to bind to AP-1 sites and act as gene transcription regulatory elements. It is hoped that these studies will provide information uniquely relevant to cocaine addiction because of clear differences between the actions of cocaine in rodents versus the phylogenetically closer primates.
