Abstract

To test the modulatory role of D-3 receptors in normal and dopamine-depleted mice, D-3 receptor KO mice and wild-type (WT) littermates were administered saline, L-dopa/carbidopa (20/2 mg/kg ip), a preferential D-3>D-2 agonist S32504, a D1+D-2/D-3 agonist apomorphine, a selective D-3 antagonist S33084, or apomorphine with S33084 prior to and after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We monitored lines crossed in a 55-min session, average number of rears, and average number of grooming bouts. MPTP treatment produced equivalent 70% losses of dopamine fibers in the caudate putamen (CPu) and nucleus accumbens (NAC) of WT and D-3 KO mice as compared to their control (vehicle injected) counterparts. D-3 receptors were absent in KO mice, and the number of D-3 receptors was unaffected by MPTP-induced loss of DA terminals in WT mice. The results support a lack of involvement of the D-3 receptor for D1:D2 receptor-mediated behavioral activity (synergy). First, S32504 inhibited all behaviors and to a similar degree in D-3 KO and WT mice. Second, S33084 at the higher concentration increased number of lines crossed in response to high dose apomorphine in both D-3 KO and WT mice. Third, in nonlesioned mice, apomorphine-induced gnawing stercotypies were inhibited by S33084 in both D-3 KO and WT mice. Interestingly, the inhibition of apomorphine-induced gnawing was not apparent in MPTP-lesioned mice, and this stereotypy was elevated in D-3 KO-MPTP-lesioned mice. Thus, the suppressive effects of S32504 could be via D-2 autoreceptor inhibition of DA release, and D-2 receptor blockade by S33084 leads to release of that inhibition. This may be more apparent in MPTP-lesioned partially DA denervated mice. (C) 2003 Elsevier Inc. All rights reserved.