The locomotor-stimulant effects of cocaine, mediated through inhibition of the dopamine transporter (DAT), can be influenced by environmental factors. Previously, we found that following a short exposure to the testing environment, cocaine induces greater locomotor activation in inbred long-sleep (ILS) mice, compared to inbred short-sleep (ISS) mice. In the present study, all animals received prolonged habituation to the testing chambers prior to cocaine injection, and the results were compared with those from our previous study. When mice were tested with saline on day 1 and with either saline or cocaine (10-20 mg/kg) on day 2, we observed significant locomotor stimulation in ILS, but not ISS, mice at all tested doses of cocaine. Thus, prolonged habituation does not alter the differential responsiveness of these two strains of mice to cocaine. We found no strain differences in striatal cocaine levels. However, [3 H]WIN 35,428 binding studies showed a lower number of striatal DATs in ILS, compared to ISS, mice. In vivo analysis of striatal DAT activity revealed not only that ILS mice cleared exogenously applied DA more slowly than ISS mice, but also that cocaine (10 mg/kg) decreased DA clearance selectively in ILS mice. Thus, functional differences in striatal DATs between ILS and ISS mice likely contribute to the differential behavioral activation of cocaine in these two mouse strains.

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