Effects of GBR 12909, a selective dopamine uptake inhibitor, on motor activity and operant behavior in the rat.

GBR 12909, an aryl 1,4-dialkylpiperazine derivative, is a potent and selective inhibitor of the presynaptic dopamine uptake complex. The behavioral effects of this compound were studied in rats using several different paradigms. GBR 12909 (1, 10, 20 mg/kg i.p.) elicited a dose-dependent, long-lasting behavioral activation characterized by locomotion, rearing, sniffing and stereotypies at the highest dose. A second experiment investigated the consequences of subchronic treatment (one injection every 2 days for 14 days) with a high dose (20 mg/kg) of GBR 12909. Evidence was obtained for sensitization to GBR 12909, indicated by progressively more intense stereotypy induced by the high dose of GBR 12909, and also by an enhanced locomotor response to subthreshold doses of the drug, which lasted up to 7 weeks following the end of subchronic treatment. In a test of fixed-interval responding for food reward, GBR 12909 strongly enhanced lever pressing and lowered quarter-life. Low rates of responding were affected more than high rates. GBR 12909 also potentiated responding for a conditioned reinforcer (a stimulus which had previously been paired with food), suggesting that the rewarding impact of the stimulus was increased. It is concluded that the behavioral profile of GBR 12909 is similar to other dopamine-enhancing psychostimulants, and the sensitization may involve long-term changes in the dopamine uptake site.