Haloperidol-induced catalepsy is absent in dopamine D2 but maintained in dopamine D3 receptor knock-out mice

被引:56
|
作者
Boulay, D
Depoortere, R
Oblin, A
Sanger, DJ
Schoemaker, H
Perrault, G
机构
[1] Sanofi Synthelabo, Dept Psychopharmacol, F-92220 Bagneux, France
[2] Sanofi Synthelabo, Dept Neurochem, F-92220 Bagneux, France
关键词
catalepsy; dopamine D-2 receptor; dopamine D-3 receptor; haloperidol; knock-out mice; SCH; 23390;
D O I
10.1016/S0014-2999(99)00916-4
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
We have previously found that mice homozygous for the deletion of the dopamine D-2 receptor gene (D-2(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test'', in the present study. we sought to analyse the reactivity of D-2 receptor mutant mice to the cataleptogenic effects of dopamine D-2-like or D-1-like receptor antagonists. in parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D-3 receptor mutant mice. D-2(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D-2-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D-2(-/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D-2 receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [H-3]spiperone for D-2(+)/(+), D-2(+/-) and D-2(-/-) mice, respectively). However, D-2(-/-) and D-2(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D-1-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride (SCH 23390. 0.03-0.6 mg/kg s.c.). Striatal dopamine D, receptor expression (as measured using [H-3]SCH 23390 binding) was not significantly affected by the genotype. Tne ability of SCH 23390 to induce catalepsy in D-2(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D-2 receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D-2 and dopamine D-1 receptor expression was essentially identical in D-3(+/+), D-3(+/-) and D-3(-/-) mice, dopamine D-3 receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D-3 receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D-3 receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D-2 and dopamine D-1 receptors in this model. These results suggest that the dopamine D-3 receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D-3 receptor subtype appears to exert no observable control over the catalepsy produced by dopamine.
引用
收藏
页码:63 / 73
页数:11
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