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The Journal of Neuroscience, April 1, 2003, 23(7):3076

Enhanced Responsiveness to Novelty and Cocaine Is Associated with Decreased Basal Dopamine Uptake and Release in the Nucleus Accumbens: Quantitative Microdialysis in Rats under Transient Conditions

Vladimir I. Chefer, Irina Zakharova, and Toni S. Shippenberg

Integrative Neuroscience Section, Behavioral Neuroscience Branch, National Institutes of Health/National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224

Male rats were screened for their response to a novel environment and designated as high responders (HRs) or low responders (LRs). They then received daily injections of saline or cocaine (20 mg/kg, i.p.). Basal and cocaine-evoked extracellular dopamine (DA_ext) levels as well as basal DA uptake rate and cocaine-evoked inhibition of uptake in the nucleus accumbens were determined on abstinence day 3 using quantitative microdialysis under transient conditions. The kinetics of uptake, dopamine transporter (DAT) expression, and [³H]()-2--carbomethoxy-3--(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate ([³H]WIN35428) binding were also examined. The locomotor activating effects of cocaine and the magnitude of behavioral sensitization were greater in HRs. Saline-treated HRs had lower basal uptake than LRs. DA uptake after cocaine challenge was also lower in these animals. Although basal DA_ext did not differ, cocaine-evoked DA_ext was greater in HRs. The K_m and V_max of DA uptake were higher in naive HRs than LRs, as were the K_d and B_max of [³H]WIN35428 binding. DAT protein expression did not differ. Previous cocaine exposure decreased basal DA uptake. It increased cocaine-evoked DA_ext and decreased the cocaine-induced inhibition of uptake, especially in HRs, indicating greater DA release during cocaine challenge in this phenotype. We hypothesize that lower basal uptake in HRs results from a decrease in DAT binding affinity that is compensated for, in part, by an increased number of plasma membrane binding sites. Basal uptake, but not DA_ext, was lower in HRs, indicating lower basal DA release in HRs. The finding that cocaine-evoked DA_ext is higher in naive and cocaine-exposed HRs suggests that the greater responsiveness of DA neurons in HRs may underlie the enhanced behavioral responses that characterize this phenotype.

Key words: individual differences in response to novelty; dopamine; dopamine uptake and release; nucleus accumbens; cocaine; transient no net flux microdialysis

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2373076-09$05.00/0

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