Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats
Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats
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DOI：
10.1124/jpet.113.208264
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Katz, Jonathan L.
中科院分区：
文献类型：
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作者：
Hiranita, Takato;Kohut, Stephen J.;Katz, Jonathan L.
非典型多巴胺摄取抑制剂具有低滥用潜力，可作为可卡因滥用治疗发展的先导。其中，3 α-[双（4 '-氟苯基）甲氧基]-托烷的苯扎托品（BZT）衍生物、N-丁基（JHW 007）、N-烯丙基（AHN 2 -005）和N-甲基（AHN 1 -055）类似物剂量依赖性地减少可卡因自我给药，而不影响食物维持反应。我们的研究通过评估它们对其他药物自我给药的影响来检查选择性。与可卡因一样，每种BZT类似物（1.0-10.0 mg/kg i.（第30页）剂量依赖性地降低了D-甲基苯丙胺（0.01-0.32 mg/kg/输注）的最大自我给药，但对海洛因（1.0-32.0 μ g/kg/输注）和氯胺酮（0.032-1.0 mg/kg/输注）自我给药无活性。此外，标准多巴胺间接激动剂[WIN 35，428（（2）-3 β-（4-氟苯基）-托烷-2-β-羧酸甲酯酒石酸盐），达非他明（0.1- 1.0mg/kg i. p.，各自）]的剂量依赖性左移的D-甲基苯丙胺、海洛因和氯胺酮的自我给药剂量效应曲线。非竞争性NMDA谷氨酸受体/通道拮抗剂[（+）-MK-801（0.01-0.1 mg/kg i. p.），美金刚（1.0-10.0 mg/kg i. p.）] D-甲基苯丙胺和氯胺酮（但不是海洛因）自我给药的剂量效应曲线也左移。μ-受体激动剂[dl-美沙酮和吗啡（1.0- 10.0mg/kg i. p.的情况下，每种）]剂量依赖性地降低了M-激动剂（海洛因、瑞芬太尼）的最大自我给药，但不降低D-甲基苯丙胺或氯胺酮的自我给药。μ-激动剂诱导的减少与BZT类似物对刺激剂自我给药的影响和食物预喂对食物强化维持的反应的影响相似。放射性配体结合和行为研究表明，多巴胺转运蛋白和sigma受体的抑制是阻断BZT类似物的刺激自我管理的关键。因此，目前的结果表明，BZT类似物对兴奋剂自我管理的影响是类似的μ-激动剂对μ-激动剂自我管理和食物预喂养对食物强化反应的影响，这涉及这些影响的行为机制，并进一步支持开发非典型多巴胺摄取抑制剂作为兴奋剂滥用的药物。
Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3 alpha-[bis(4'-fluorophenyl) methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i. p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 mu g/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((2)-3 beta-(4-fluorophenyl)- tropan-2-beta-carboxylic acid methyl ester tartrate), damphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDAglutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The mu-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i. p., each)] dose-dependently decreased maximal self-administration of m-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The mu-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and sigma receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of mu-agonists on mu-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse.