Selective down-regulation of D 1 dopamine mediated rotational behavior in supersensitive mice

Abstract

The effects of continuous exposure to selective D 1 and D 2 agonists on rotational behavior were examined in mice with unilateral 6-hydroxydopamineinduced lesions of the corpus striatum. Continuously exposing mice to the D 1 agonist SKF 38393 produced an initial rotational behavioral response which decreased dramatically within 4 hours. At the time these rotations ceased, the mice were totally unresponsive to an acute challenge injection of SKF 38393 but responded normally to an acute injection of the D 2 agonist quinpirole. Mice chronically implanted with guinpirole also showed marked rotational behavior, but in contrast to the results with SKF 38393, essentially no diminution of these rotations was seen during a one week period of exposure. The results suggest that there are different mechanisms involved in the long term regulation of D 1 and D 2 dopamine systems in supersensitive animals. There is substantial biochemical, anatomical and behavioral evidence that dopamine responses are mediated by at least two distinct subtypes of dopamine receptors, designated as D 1 and D 1 (Stoof and Kebabian, 1984). However, relatively little is known about how these receptor subtypes are regulated. Non-selective up-regulation of both D 1- and D 2-mediated dopamine responsiveness can be produced by destroying presynaptic dopamine nerve terminals in the corpus striatum using the neurotoxin 6-hydroxydopamine (Arnt and Hyttel, 1985). This up-regulated response to both D 1 and D 2 agonists can be reversed by continuously exposing mice to the nonselective dopamine agonist apomorphine (Winkler and Weiss, 1986). Selective up-regulation of d 1 receptors can be produced by chronic treatment with a selective D 1 dopamine antagonist (Porceddu, Ongini and Biggio, 1985). To explore the possibility that these subtypes of dopamine receptors can be selectively down-regulated, we have continuously exposed supersensitive animals to selective dopamine agonists and determined the effects of this treatment on a specific dopamine behavior.