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 intracerebroventricular administration of the irreversible dopamine transporter inhibitor RTI-76, [3H]GBR12935 binding to the dopamine transporter (DAT) protein was inhibited in both the striatum and nucleus accumbens of the rat in a dose-dependent fashion (0.05-5.0 micromol). The rate of return of binding to control levels was used to calculate the half-life of DAT. Since changes in behavior 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 were examined. During the first day after i.c.v. administration, 1.25 micromol RTI-76 had no effect on locomotor activity, but 2.5 micromol RTI-76 significantly increased locomotor activity in rats, a time at which this dose inhibited 41 and 42% of [3H]GBR12935 binding in the striatum and in the nucleus accumbens, respectively. These results agree with earlier reports showing that significant blockade of the dopamine transporter protein in the striatum is required for increases in motor activity in rodents. However, 5.0 micromol RTI-76 did not increase locomotor activity, even though binding was inhibited to 38 and 37% of control levels in the striatum and nucleus accumbens, respectively. Furthermore, our present results suggest that locomotor activity does not continue to increase as the blockade of DAT increases. Notably, there were no increases in locomotor activity at the dose of RTI-76 (100 nmol) used to measure DAT half-life.