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 D3 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 D3 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 D3 receptor mutant (D3R KO) mice. D3R KO and WT mice were administered vehicle (saline, 1 ml/100 g body weight, i.p.), or S33084 (1.0 mg/kg.) and U99194A (0.1 mg/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. D3R 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 D3R KO mice than WT mice. Dopamine D3 receptor preferring antagonists suppressed the locomotor activity response to MK-801 to an equal extent in D3R KO and WT mice. The results confirm that MK-801-induced hyperactivity and novelty-induced behavioral activity and rearing are enhanced in D3R KO mice, but suppression by dopamine D3 receptor preferring antagonists is not through dopamine D3 receptor antagonism.