Changes in basal and cocaine-evoked extracellular dopamine uptake and release in the rat nucleus accumbens during early abstinence from cocaine: quantitative determination under transient conditions.
Despite an abundance of studies on mechanisms of behavioral sensitization, considerable uncertainty exists as to whether alterations in dopamine neurotransmission underlie the exacerbated behavioral effects of cocaine observed during the early stages of abstinence. One of the factors contributing to the uncertainty and controversy may be the limitations in utilized measurement techniques (mostly conventional microdialysis). The techniques of quantitative microdialysis under transient conditions and rotating disk electrode voltammetry were used to characterize basal dopamine dynamics as well as time-related changes in extracellular dopamine concentrations and dopamine uptake that occur in response to an acute drug challenge in control animals and animals with previous history of cocaine. Basal extracellular dopamine concentrations were unaltered on abstinence day 3 from repeated cocaine administration (5 days, 20 mg/kg, i.p.). The extraction fraction of dopamine, an indirect measure of dopamine uptake, was significantly lower in cocaine-sensitized animals relative to controls. These two facts, taken together, suggest that basal dopamine release is depressed in cocaine-sensitized animals on abstinence day 3. At the same time, a cocaine challenge decreased the extraction fraction and increased the extracellular dopamine concentration in both experimental groups. The magnitude of the increase in extracellular dopamine concentration was greater in cocaine-sensitized animals, while the ability of cocaine to decrease the extraction fraction was unaltered, suggesting that the increase in extracellular dopamine concentration reflects an increase in drug-evoked dopamine release. Moreover, cocaine-pretreated rats demonstrated greater depolarization-induced dopamine release and the ability of dopamine D(2) receptor agonist, quinpirole, to inhibit release was decreased in these animals. These data demonstrate that a cocaine treatment regimen resulting in behavioral sensitization is associated with a reduction in basal dopamine release, an enhancement in both cocaine and K(+)-evoked dopamine release, and a subsensitivity of dopamine D(2) autoreceptors that regulate dopamine release in the nucleus accumbens.
Chefer
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Integrative Neuroscience Unit, Behavioral Neuroscience Laboratory, NIH/NIDA Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. vchefer@intra.nida.nih.gov
Shippenberg
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D000818:Animals; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D013287:Illicit Drugs / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013997:Time Factors
D018765:Dopamine Uptake Inhibitors; D013287:Illicit Drugs; D003042:Cocaine; D004298:Dopamine