Effects of tiaspirone (BMY-13859) and a chemical congener (BMY-13980) on A9 and A10 dopamine neurons in the rat.

Two new potential antipsychotic drugs, BMY-13980 and BMY-13859 were compared for the ability to influence the electrophysiological activity of dopaminergic neurons in the substantia nigra zona compacta (A9 DA cells) and ventral tegmental area (A10 DA cells) in the brain of the rat. Both drugs reversed the rate-suppressant effects of the DA agonist apomorphine on DA cells in A10 to a greater extent than DA cells in A9; BMY-13980 was particularly selective in this regard. These results indicate that both drugs may exert DA antagonist effects which are suggestive of antipsychotic potential. In other experiments, the effects of chronic (28 days) treatment with BMY-13980 and BMY-13859 on the neuronal activity of DA were evaluated. Both compounds caused a significant decrease in the number of spontaneously active DA neurons in A10 recorded per electrode track, an effect previously demonstrated to be associated with antipsychotic efficacy. The drug BMY-13859, but not BMY-13980, also significantly decreased the number of spontaneously active DA cells/track in A9, an effect which may predict the liability of potential antipsychotic drugs for causing extrapyramidal motor dysfunction, including tardive dyskinesia. Thus, these experiments indicate that both BMY-13980 and BMY-13859 exert effects which may predict potential antipsychotic efficacy in clinical trials and that BMY-13980 may be less likely to cause extrapyramidal side effects.