The widespread abuse of cocaine and other stimulant drugs constitutes a major public health concern. In experimental situations, repeated stimulant administration produces progressive changes in behavioral responses, and these changes are believed to reflect processes that are involved in addiction and relapse in humans, as well as in the induction of stimulant psychosis with higher-dose patterns of stimulant intake. Extensive studies in rodents have greatly contributed to current perspectives regarding the relationships between neurochemical and behavioral actions of stimulants. These studies indicate that brain monoamines, particularly dopamine, are involved in mediating the behavioral effects of these drugs. However, little is known regarding the neurochemical effects of these drugs in humans or other primates. This lack of knowledge about the extent to which the neurochemical- behavioral relationships observed in rodents extend to primates is a serious deficiency in understanding the neurobiology of stimulant effects. It is proposed here to use in vivo microdialysis in awake monkeys to: 1) characterize the effects of acute cocaine administration on dopamine, norepinephrine, and serotonin dynamics in basal ganglia and neocortex and on concomitant behavioral and physiological measures; 2) characterize changes in transmitter, physiological, and behavioral response profiles with the repeated administration of cocaine; 3) assay the same measures during withdrawal and subsequent cocaine administration. MRI scans will be used to accurately implant guide cannulae for subsequent microdialysis sampling from motor cortex, caudate nucleus and nucleus accumbens. Animals will be chaired daily for 33 days, and behavioral, EEG and autonomic data will be collected each day. There will be a 5-day baseline period followed by 14 days of cocaine administration, 13 days of withdrawal, and a final day of cocaine challenge. On all days, animals will be treated similarly, except for receiving either i.v. cocaine (1.5 mg/kg) or saline. Dialysis samples will be collected on the first and last days of cocaine administration and on the challenge day, through dialysis probes inserted on the preceding day. The collection of neurochemical, behavioral, EEG, and autonomic measures in a controlled regimen will provide novel information concerning the effects of acute and chronic cocaine, as well as withdrawal and subsequent drug challenge, on these variables and their interrelationships.
