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.

Age-related differences in MK-801 induced behaviors in dopamine D3 receptor knock out mice.

It is not known if age plays an important role in the D(3) receptor regulation of N-methyl-D-aspartate (NMDA) receptor antagonist induced hyperactivity. Wild type (WT) and dopamine D(3) receptor mutant (D(3)R KO) mice were divided into young (under 7 months) and middle age (over 12 months) groups and tested for dizocilpine (MK-801)-induced hyperactivity and rearing. Mice were administered vehicle (saline, 1 ml/100g body weight, i.p.), or dopamine D(3) receptor preferring antagonists 3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl) benzamide) (S33084, 1.0mg/kg, i.p.) and 5,6-dimethoxy-2(dipropylamino)indan (U99194A, 5.0 mg/kg i.p.), and immediately placed into the open field apparatus. Horizontal and vertical activity counts were recorded for 30 min, followed by injection of vehicle or MK801 (0.15 or 0.30 mg/kg i.p.) and mice returned to the open field for an additional 55 min. Young D(3)R KO mice showed the highest level of locomotor and rearing activity during the 1st 30 min and 2nd 55 min session after vehicle treatment. At the lower dose of MK-801 horizontal activity was significantly higher in Young-D(3)R KO mice than in the other groups. At the higher dose of MK-801 horizontal activity was elevated to an equal extent in all groups. In response to S33084 and U99194A, MK-801 hyperactivity was reduced the most in the Middle Age-D(3)R KO and the least in the Young-D(3)R KO mice. Rearing showed pronounced age-related but not genotype effects. The results demonstrate that MK-801 induced-hyperactivity, novelty-induced behavioral activity and rearing are affected by age and D(3) receptor genotype.