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Journal of Neuroscience, Vol 13, 266-275, Copyright © 1993 by Society for Neuroscience
Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals
PW Kalivas and P Duffy
Alcohol and Drug Abuse Program, Washington State University, Pullman 99164-6520.
Repeated administration of cocaine to rodents produces a progressive
augmentation in motor activity known as behavioral sensitization. By using
microdialysis in the ventral striatum, some studies have found that the
development of behavioral sensitization is associated with a similar
augmentation in dopamine release, while others have not. It was postulated
that differences in doses and withdrawal periods may account for the
discrepancies between studies. Rats were behaviorally sensitized to daily
peripheral injections using two cocaine treatment regimens (15 mg/kg, i.p.
x 5 d or 30 mg/kg, i.p. x 5 d). Using in vivo microdialysis in the ventral
striatum, the effect of acute cocaine (15 mg/kg, i.p.) on extracellular
dopamine content and motor behavior was examined at various times after
discontinuing daily treatments. Twenty- four hours after discontinuing the
low dose of daily cocaine, the increase in motor activity and extracellular
dopamine elicited by an acute cocaine challenge was significantly elevated.
In contrast, following the higher daily treatment regimen there was a
significant augmentation in motor activity, but the increase in
extracellular dopamine produced by cocaine was significantly reduced. When
rats were challenged 10-14 d after discontinuing either dosage regimen of
daily cocaine, the increase in both motor activity and extracellular
dopamine was augmented. In general, the increase in extracellular dopamine
by an acute cocaine challenge increased over time when rats were challenged
between 1 and 22 d after discontinuing daily cocaine. Basal concentrations
of extracellular dopamine were determined by measuring the in vivo flux of
dopamine across the dialysis membrane, and there was no significant
difference at 24 hr or 2 weeks following the last daily injection of saline
or cocaine. It is concluded that behavioral sensitization to cocaine is
generally associated with an augmentation in extracellular dopamine in the
ventral striatum, but that high doses of daily cocaine produce apparent
tolerance to the augmentation in extracellular dopamine during the early
withdrawal period.
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