The effect of chronic postnatal treatment of rats with selective D1- and/or D2-receptor antagonists on the development of D1- and D2-receptors in the striatum was studied. When neonatal rats were treated postnatally from the day of birth for 32 successive days with the D1-receptor antagonist, SCH-23390 (0.30 mg/kg i.p.), the development of striatal dopamine D1-receptors was markedly impaired, and the development of striatal D2-receptors was slightly impaired. Alternatively, chronic treatment with the D2-receptor antagonist, spiroperidol (1.0 mg/kg i.p.), resulted in a markedly impaired development of striatal dopamine D2-receptors, and a slightly impaired development of striatal D1-receptors. Scatchard analysis revealed that chronic SCH-23390 treatment during development resulted in a 78% decrease in the Bmax for in vitro binding of [3H]SCH-23390 to striatal homogenates, while the Kd was unaltered. Similarly, chronic postnatal treatment with spiroperidol was associated with a 74% reduction in the Bmax, while the Kd for in vitro binding of [3H]spiroperidol to striatal homogenates was unchanged. These findings demonstrate that chronic selective dopamine receptor antagonism affects development of both striatal D1- and D2-receptor types. The critical period during which striatal dopamine receptor ontogeny can be altered is not restricted to prenatal periods, since suitable postnatal challenge will alter striatal dopamine-receptor development.

Long-term postnatal treatment of rats with the dopamine D2 receptor antagonist, spiroperidol, results in the impaired development of striatal D2 receptors. Because the tripeptide prolyl-leucyl-glycinamide (MIF-1) attenuates haloperidol-induced up-regulation of striatal dopamine D2 receptors in adult rats, we studied the effect of MIF-1 on the spiroperidol-induced alteration of striatal D2 ontogeny. Postnatal treatment of rats with spiroperidol (1.0 mg/kg/day, IP, ×32 days from birth) resulted in a 74% decrease in the Bmax for [3H]spiroperidol binding with no change in the Kd at 5 weeks. When rats were studied at 8 weeks, in the absence of additional treatment, total specific [3H]spiroperidol binding was reduced by 59%. While MIF-1 alone (1.0 mg/kg/day, IP, ×32 days from birth) had no effect on [3H]spiroperidol binding, MIF-1 completely attenuated the ontogenic impairment of striatal D2 receptors that was produced by spiroperidol treatment. At 5 weeks the Bmax for [3H]spiroperidol binding was at the saline control level in the group of rats cotreated with spiroperidol and MIF-1. At 8 weeks, with no additional treatments, the specific binding of [3H]spiroperidol to striatum was also at control levels in the group cotreated with spiroperidol and MIF-1. These findings demonstrate that MIF-1 attenuates spiroperidol-induced impairment of development of striatal dopamine D2 receptors in rats.

Previous reports have indicated that prenatal, but not postnatal, haloperidol impairs the ontogenic development of striatal dopamine D-2 receptors. In the present study a specific D-2 receptor antagonist, spiroperidol (1.0 mg/kg i.p.) and/or a specific D-1 receptor antagonist, SCH 23390 (0.30 mg/kg i.p.), was administered to rats for 32 successive days from birth. Postnatal spiroperidol and SCH 23390 treaments markedly impaired the development of striatal dopamine D-2 and D-1 receptors, respectively, at 12 weeks after birth. Spiroperidol did not affect D-1 receptor development and did not modify the effect of SCH 23390 treatment. Also, SCH 23390 did not affect D-2 receptor development and did not modify the effect of spiroperidol treatment. When rats with impaired development of striatal D-2 receptors were challenged at 12 weeks with spiroperidol (1.0 mg/kg per day i.p. × 17 days) D-2 receptors did not up-regulate. However, when rats with impaired development of striatal D-1 receptors were challenged at 12 weeks with SCH 23390 (0.30 mg/kg per day i.p. × 17 days) D-1 receptors did up-regulate. These findings demonstrate that postnatal treatment with D-1 and D-2 receptor antagonists can permanently impair the development of striatal D-1 and D-2 receptors. Moreover, the ability of developmentally impaired striatal D-1 receptors to up-regulate in adulthood appears to be greater than that for the developmentally impaired striatal D-2 receptors.