Comparison of the effect of substituted benzamides on midbrain dopamine neurones after treatment of rats for 21 days.

We have tested five different substituted benzamides (nemonapride, D,L-sulpiride, remoxipride, raclopride and zacopride) for their potential to decrease the number of spontaneously active dopamine neurones in the rat midbrain after treatment for 21 days. Nemonapride, D,L-sulpiride, and remoxipride significantly reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, indicating an antipsychotic potential, while raclopride and zacopride induced but minor effects. The number of active dopamine neurones in the substantia nigra pars compacta was reduced by nemonapride at higher doses which should indicate the propensity for developing extrapyramidal side-effects. In conclusion, several of the substituted benzamides showed an antipsychotic profile in this test model. In addition, some of the benzamides also showed a propensity for extrapyramidal side-effects and these results are in accordance with the profile reported from clinical trials. However, the results obtained with this model indicate that raclopride neither has antipsychotic potential nor induces extrapyramidal side-effects. The reason for this discrepancy is at present not known.