D-2 DOPAMINE-RECEPTOR ANTISENSE OLIGODEOXYNUCLEOTIDE INHIBITS THE SYNTHESIS OF A FUNCTIONAL POOL OF D-2 DOPAMINE-RECEPTORS

In vivo administration of an antisense oligonucleotide targeted toward the D-2 dopamine (DA) receptor mRNA (D-2 AS) markedly inhibited D-2 receptor-mediated behaviors but produced only a relatively small reduction in the levels of D-2 DA receptors in mouse striatum. This apparent dissociation between DA receptor-mediated behaviors and the levels of D-2 DA receptors was addressed by inhibiting the total number of D-2 DA receptors by intraperitoneal administration of the selective, irreversibly acting D-2 DA receptor antagonist fluphenazine-N-mustard (FNM) and then determining the effects of D-2 AS, administered intracerebroventricularly, on the rate of synthesis of D-2 DA receptors and on the recovery of D-2 receptor-mediated behaviors. FNM inactivated similar to 90% of D-2 DA receptors within 4 hr of treatment, after which the receptors returned to normal levels by similar to 8 days. D-2 AS treatment significantly inhibited the rate of recovery of D-2 DA receptors in striatum of FNM-treated mice. FNM treatment also produced a number of behavioral alterations, including catalepsy, and the inhibition of stereotypic behavior induced by the D-2/D-3 DA receptor agonist quinpirole. Both of these behaviors returned to normal within 8 days after FNM treatment. D-2 AS treatment delayed the restoration of these FNM-induced behaviors. Thus, it reduced the rate of disappearance of the cataleptic behavior induced by FNM and significantly delayed the restoration of the stereotypic behavior induced by quinpirole. The changes induced by D-2 AS on D-2 receptor-mediated behaviors were reversed on cessation of D-2 AS treatment. A random oligomer given in the same amount and for the same length of time as that of the D-2 AS had no significant effects on either D-2 DA receptor synthesis or DA receptor-mediated behaviors. These studies demonstrate that in vivo administration of D-2 AS decreased the rate of recovery of D-2 DA receptors and inhibited the recovery of D-2 DA receptor-mediated behaviors after irreversible receptor inactivation and suggest that D-2 AS treatment inhibits the synthesis of a functional pool of D-2 DA receptors.