Cortical activation during cocaine use and extinction in rhesus monkeys.
BACKGROUND
Acute re-exposure to cocaine or drug cues associated with cocaine use can elicit drug craving and relapse. Neuroimaging studies have begun to define neurobiological substrates underlying the acute effects of cocaine or cocaine cues in cocaine-dependent subjects.


OBJECTIVE
The present study was the first to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates.


METHODS
Positron emission tomography imaging with O15-labeled water was used to measure drug-induced changes in cerebral blood flow. The acute effects of cocaine administered noncontingently were characterized in four drug-naïve rhesus monkeys. The same subjects were trained to self-administer cocaine under a fixed ratio schedule during image acquisition. Subsequently, three subjects with an extensive history of cocaine use were trained to self-administer cocaine under a second-order schedule. The same subjects also underwent extinction sessions during which saline was substituted for cocaine under the second-order schedule.


RESULTS
Noncontingent administration of cocaine in drug-naïve subjects induced robust activation of prefrontal cortex localized primarily to the dorsolateral regions. In contrast, the pattern of brain activation induced by self-administered cocaine differed qualitatively and included anterior cingulate cortex. Moreover, drug-associated stimuli during extinction also induced robust activation of prefrontal cortex.


CONCLUSIONS
The effects of cocaine and associated cues extend beyond the limbic system to engage brain areas involved in cognitive processes. The identification of neural circuits underlying the direct pharmacological and conditioned stimulus effects of cocaine may be highly relevant toward efforts to develop treatments for cocaine addiction.
Howell
Leonard L
LL
Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, USA. lhowell@emory.edu
Votaw
John R
JR
Goodman
Mark M
MM
Lindsey
Kimberly P
KP
D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D001931:Brain Mapping / Q000379:methods; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000503:physiopathology* / Q000523:psychology; D003463:Cues; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects*; D005260:Female; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000098:blood supply / Q000187:drug effects; D012646:Self Administration; D013997:Time Factors
D000697:Central Nervous System Stimulants; D003042:Cocaine