RTI-76, an irreversible inhibitor of dopamine transporter binding, increases locomotor activity in the rat at high doses

An earlier study in our laboratory showed that 24 h after intracerebroventr icular administration of the irreversible dopamine transporter inhibitor RT I-76, [H-3]GBR12935 binding to the dopamine transporter (DAT) protein was i nhibited in both the striatum and nucleus accumbens of the rat in a dose-de pendent fashion (0.05-5.0 mu mol). The rate of return of binding to control levels was used to calculate the half-life of DAT. Since changes in behavi or could conceivably influence the half-life, the effects of various doses of RTI-76 on locomotor activity 1 and 3 days after RTI-76 administration we re examined. During the first day after i.c.v. administration, 1.25 mu mol RTI-76 had no effect on locomotor activity, but 2.5 mu mol RTI-76 significa ntly increased locomotor activity in rats, a lime at which this dose inhibi ted 41 and 42% of [H-3]GBR12935 binding in the striatum and in the nucleus accumbens, respectively. These results agree with earlier reports showing t hat significant blockade of the dopamine transporter protein in the striatu m is required for increases in motor activity in rodents. However, 5.0 mu m ol RTI-76 did not increase locomotor activity, even though binding was inhi bited to 38 and 37% of control levels in the striatum and nucleus accumbens , respectively. Furthermore, our present results suggest that locomotor act ivity does not continue to increase as the blockade of DAT increases. Notab ly, there were no increases in locomotor activity at the dose of RTI-76 (10 0 nmol) used to measure DAT half-life. (C) 2001 Published by Elsevier Scien ce B.V.