Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine use.
Using a model of recreational cocaine consumption, we have determined in four rhesus monkeys the impact of self-administered cocaine on mesolimbic and sensorimotor striatal dopaminergic neurotransmission. The effects of cocaine repeated within a self-administration session and across multiple sessions over a 6 month period were determined by the use of fixed-ratio self-administration and microdialysis procedures. The exposure to cocaine was modest, with at most two 0.5 mg/kg infusions permitted in each weekly session. Within a cocaine self-administration session, acute tolerance to the ability of cocaine to elevate extracellular striatal dopamine was observed. Over a period of 6 months of repeated self-administration, there was a significant increase in the impact of a fixed dose on extracellular dopamine, indicating that neurochemical sensitization to the effects of self-administered cocaine occurs in primates. A pronounced dopaminergic response to noncontingent cocaine was also observed, with no increases in extracellular dopamine in response to an unexpected saline substitution, indicating that the neurochemical response to self-administered cocaine is primarily caused by direct pharmacological effects of the drug rather than by conditioning to external environmental cues. These results highlight the contrast in time-dependent changes in neurochemical responsiveness to cocaine, depending on whether within-session or between-session comparisons are made. They also demonstrate that recreational levels of cocaine consumption can result in neurochemical sensitization, an enduring change in brain function that may contribute to addiction.
Bradberry
C W
CW
Departments of Psychiatry and Laboratory Medicine, West Haven Veterans Administration Hospital and Yale University School of Medicine, West Haven, Connecticut 06516, USA. charles.bradberry@yale.edu
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002908:Chronic Disease; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D004361:Drug Tolerance; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D017551:Microdialysis; D012044:Regression Analysis; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects*
D003042:Cocaine; D004298:Dopamine