Locomotor activity induced by MK-801 is enhanced in dopamine D3 receptor knockout mice but suppression by dopamine D3/D2 antagonists does not occur through the dopamine D3 receptor.

There are contradictory data regarding the role of the dopamine D(3) receptor in regulating N-methyl-d-aspartate (NMDA) receptor antagonist (e.g., dizocilpine) induced hyperactivity. The purpose of the present study was to examine the interaction of dopamine D(3) receptor preferring antagonists U99194A (5,6-dimethoxy-2(dipropylamino)indan) and S33804 ((3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide)) with dizocilpine (MK-801)-induced hyperactivity in wild type (WT) and dopamine D(3) receptor mutant (D(3)R KO) mice. D(3)R KO and WT mice were administered vehicle (saline, 1 ml/100g body weight, i.p.), or S33084 (1.0mg/kg.) and U99194A (0.1mg/kg or 0.01 mg/kg), and horizontal and vertical activity counts were recorded for 30 min. Mice were then treated with vehicle or MK-801 (0.12 mg/kg i.p.) and returned to the open field for an additional 55 min. D(3)R KO mice showed a significantly higher level of locomotor and rearing activity during the 1st 30 min after vehicle treatment compared to WT mice. MK-801-hyperactivity was significantly higher in D(3)R KO mice than WT mice. Dopamine D(3) receptor preferring antagonists suppressed the locomotor activity response to MK-801 to an equal extent in D(3)R KO and WT mice. The results confirm that MK-801-induced hyperactivity and novelty-induced behavioral activity and rearing are enhanced in D(3)R KO mice, but suppression by dopamine D(3) receptor preferring antagonists is not through dopamine D(3) receptor antagonism.

Behavioral effects of dopamine agonists and antagonists in MPTP-lesioned D3 receptor knockout mice.

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 stereotypies 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 D2 autoreceptor inhibition of DA release, and D2 receptor blockade by S33084 leads to release of that inhibition. This may be more apparent in MPTP-lesioned partially DA denervated mice.