Effects of pertussis toxin on D2-dopamine receptor in rat striatum: evidence for coupling of Ni regulatory protein with D2-receptor.

It is well established that a pertussis toxin, islet activating protein (IAP), interacts directly with the Ni regulatory protein involved in the receptor-adenylate cyclase system. In this study we investigated the effect of the toxin on the dopaminergic function of the central nervous system in conjunction with the adenylate cyclase system. Direct bilateral microinjection of the toxin into rat striatum reduced the stereotyped behavior induced by apomorphine. This inhibitory effect was observed even 40 h after administration of the toxin, whereas the inhibition by haloperidol disappeared within 15 h. Toxin administration did not influence either the Bmax or affinity of specific binding of [3H]spiroperidol to the striatal membrane. However, it increased the IC50 value of apomorphine for the specific binding of [3H]spiroperidol. GTP (10(-4) M) had little effect on the apparent affinity of apomorphine to the [3H]spiroperidol binding sites in IAP-treated membrane, though an effect was clearly observed in untreated membrane. [3H]Spiroperidol binding sites were increased 34 +/- 8% (n = 4) on chronic treatment of haloperidol for 2 weeks. On the contrary, on long-term administration of IAP the ligand binding sites were decreased by 25 +/- 10% (n = 4). These results indicate that pertussis toxin can interact with the Ni protein coupled with striatal D2-dopamine receptor. Inhibition of the coupling between Ni protein and the D2-dopamine receptor attenuated the manifestation of rat stereotyped behavior. Furthermore, chronic administration of dopamine antagonist resulted in the up-regulation of the D2-dopamine receptor, while long-term inhibition of coupling between the D2-dopamine receptor and Ni regulatory protein reduced the amount of receptors.