Dopamine Agonists Modify the Development of Brain D1 and D2 Receptor Responsiveness

Dopamine (DA) agonist-induced behavioral supersensitivity in the adult rat has served as the standard model for certain of the motor and behavioral side effects associated with long-term exposure to DA agonists in humans. The mechanisms relating receptor events with behavior mediation, however, remain unclear. The striatum of rats progresses through a prolonged and varied postnatal developmental period. In order to examine the relative contribution of D1 and D2 receptor-mediated mechanisms to behavioral changes which follow chronic dopamine agonist exposure, developing rats were treated daily from birth with a D1 agonist, SKF 38393 hydrochloride (3.0 mg/kg $\times$ 32d, i.p.), or a D2 agonist, LY 171555 hydrochloride (3.0 mg/kg $\times$ 32d, i.p.), and/or 6-OHDA (134 $\mu$g, i.c.v., at 3 d after birth). Following a drug-free interval, behavioral responses to selective DA agonists were evaluated. The results indicate that (1) prolonged LY 171555 treatments in development produced a supersensitive animal model for yawning and eating behaviors. (2) Perioral movements of high frequency could be produced by a very low dose of the DA D2 antagonist spiroperidol in rats treated neonatally with 6-OHDA, thereby providing a useful animal model to study tardive dyskinesia. (3) The priming phenomenon described by Breese and co-workers which was thought to be produced by D1 agonists only has been found in this study to be produced by a D2 agonist as well. This model provides a means for studying specific stereotypic behaviors in animals. (4) (3H) SCH 23390 and (3H) spiroperidol binding to striatal tissue was not altered in rats treated in development with specific agonists or antagonists for the D1 and D2 receptors. A neonatal 6-OHDA lesion did not modify binding in any of the agonist- or antagonist-treated groups. In conclusion, DA D1 and D2 agonist treatments during postnatal development are effective means of producing new animal models that are potentially useful for studying clinical disorders in man