HALOPERIDOL TREATMENT DIFFERENTIALLY REGULATES [H-3] DTG AND [H-3] (+)-3-PPP LABELED SIGMA-BINDING SITES

被引:6
作者
BAILEY, MA [1 ]
KARBON, EW [1 ]
机构
[1] SCIOS NOVA INC,BALTIMORE,MD 21224
关键词
HALOPERIDOL; DEXTROMETHORPHAN; SIGMA-BINDING SITES; PHENYTOIN; DTG (1,3-DI-O-TOLYLGUANIDINE); (+)-3-PPP((+)-3-(3-HYDROXYPHENYL)-N-(1-PROPYL)PIPERIDINE);
D O I
10.1016/0014-2999(93)90905-W
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The effect of repeated haloperidol administration on sigma binding sites in brain membranes was assessed using [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and [H-3]1,3-di-o-tolylguanidine (DTG). Administration of haloperidol (1 mg/kg, i.p.) to guinea pigs for 14 consecutive days followed by a 4 day drug-free period prior to sacrifice resulted in 75% and 6% decreases in the specific binding of [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [H-3]1,3-di-o-tolylguanidine, respectively, when measured using a single concentration (2 nM) of radioligand. Scatchard analysis revealed a reduction in both the maximum number of [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites and the affinity of these sites for the radioligand; the potency of 1,3-di-o-tolylguanidine to inhibit [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding was also reduced. In parallel studies, the potency of 1,3-di-o-tolylguanidine to inhibit [H-3]1,3-di-o-tolylguanidine binding was unaffected by haloperidol treatment, but the potency of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine against [H-3]1,3-di-o-tolylguanidine was reduced 3-fold. Phenytoin, which increased (10-fold) the potency of dextromethorphan to inhibit [H-3]1,3-di-o-tolylguanidine binding in control membranes, had no effect in membranes obtained from haloperidol-treated animals. The reduction in [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding was dependent upon the duration of the drug-free period and amounted to 73% and 25% in brain membranes prepared from animals sacrificed 14 days and 28 days, respectively, following cessation of drug treatment. Repeated administration of other antipsychotic and sigma agents including DTG, dextromethorphan, spiperone, chlorpromazine and clozapine had no effect on [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine or [H-3]1,3-di-o-tolylguanidine binding. These findings suggest that repeated haloperidol administration selectively regulates [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in guinea pig brain membranes. However, the observations that repeated drug treatment resulted in (1) reduced affinity of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine for [H-3]1,3-di-o-tolylguanidine binding sites, and (2) a loss of the ability of phenytoin to increase dextromethorphan's potency against [H-3]1,3-di-o-tolylguanidine, suggest that [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [H-3]1,3-di-o-tolylguanidine binding sites are distinct but functionally coupled.
引用
收藏
页码:243 / 250
页数:8
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