Involvement of dotarizine in nigrostriatal dopamine system of adult and aged rats : biochemical and immunohistochemical analysis

To assess the possibility that a newly produced diphenylpiperazine derivative calcium channel blocker, dotarizine, may induce extrapyramidal motor signs related to the nigrostriatal dopamine system in a fashion similar to flunarizine and cinnarizine, we examined its effect on striatal dopamine receptors and nigrostriatal dopamine movement in adult and aged rats. Using a radiolabeled receptor assay, we found that dotarizine slightly affects the binding of ligand to D-2, but not D-1 dopamine receptors. The dotarizine displacement curve for the binding of [3H]spiperone to D-2 receptors was not altered by the addition of 5'-guanylylimidodiphosphate, indicating that dotarizine acts as a D-2 receptor antagonist. There was no significant difference in the dotarizine binding to D-2 receptors between adult and aged animals. On the other hand, when the dopamine content of the substantia nigra and striatum was determined by HPLC, dotarizine had no effect in either age group. Immunohistochemical determination of dopamine yielded essentially the same result. In addition, no adult nor aged animals showed any extrapyramidal motor signs, even when a near-lethal doses of drug has used. These results suggest that the level of dotarizine-induced, nigrostriatal dopamine-linked extrapyramidal side effect may be very low or even zero. Nevertheless, careful monitoring be continued during clinical therapy with dotarizine.