Role of striatal dopamine D2 receptors in the paw test, an animal model for the therapeutic efficacy and extrapyramidal side effects of neuroleptic drugs.

The effect of administration of the D2 antagonist sulpiride in three striatal areas (dorsal striatum, DS; nucleus accumbens, ACC; olfactory tubercle; OT) was studied in the so-called paw test. In the paw test two parameters are measured (the hindlimb retraction time (HRT) and the forelimb retraction time (FRT)) that model the therapeutic efficacy and the extrapyramidal side effects of neuroleptics, respectively. Sulpiride significantly enhanced the HRT in each of the three structures. Identical doses of sulpiride administered in the three structures produced similar effects. The FRT was enhanced after administration of sulpiride in the DS and in the ACC. The minimal effective dose was lower for the DS. Administration of sulpiride in the OT did not affect the FRT. The effects on the FRT were very slow in onset (strong effects 4 h or more following administration of sulpiride), especially in comparison to the rapid effect on FRT following systemic administration of classical neuroleptics. To analyze this slowness of effect, two additional experiments were performed: first, the inter-trial time was changed so that it was identical to that used in systemic studies; second, sulpiride was administered simultaneously in the DS and the ACC. Neither experiment produced an earlier effect on the FRT. The present data provide additional evidence for the theory that regional selectivity of drugs determines their propensity to induce extrapyramidal side effects. However, the data also suggest that the generally held view that the dorsal striatum is solely responsible for the extrapyramidal side effects of neuroleptic drugs is too simple.