Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors
Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors
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DOI：
10.1124/jpet.108.145813
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发表时间：
2009-05-01
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;Soto, Paul L.;Katz, Jonathan L.
苯托品 (BZT) 类似物可抑制多巴胺的摄取，但在产生预测滥用倾向的行为效应方面不如可卡因有效。本研究比较了静脉注射 BZT 类似物与标准单胺摄取抑制剂的增强作用以及口服预处理对可卡因自我给药的影响。在固定比例五反应方案下，通过可卡因[0.032-1.0 mg/kg/注射(inj)]或食物强化来维持大鼠的反应。通过注射 0.32 mg/kg/注射可卡因或替代哌甲酯维持最大反应率，在较低和较高剂量下维持较低反应率。 N-甲基 BZT 类似物 AHN 1-055（3 α-[双（4'-氟苯基）甲氧基]-托烷）也保持响应（0.1 mg/kg/注射），但最大速率低于可卡因。 N-烯丙基、AHN 2-005（N-烯丙基-3 α-[双（4'-氟苯基）甲氧基]-托烷）和 N-丁基、JHW 007 [N-（正丁基）-3 α-[双（4'-氟苯基）甲氧基]-托烷]、BZT 类似物未将响应维持在媒介物水平以上，且用尼索西汀或西酞普兰。哌醋甲酯 (3.2-32 mg/kg) 的预压治疗剂量依赖性地使可卡因自我给药剂量效应曲线向左移动，而尼索西汀和西酞普兰的效果并不显着。中等剂量的 AHN 1-055 (32 mg/kg) 可增加低剂量可卡因维持的反应，并降低高剂量维持的反应。较高剂量的 AHN 1-055 完全抑制可卡因维持的反应。 AHN 2-005 和 JHW 007 均剂量依赖性（10-32 mg/kg）减少可卡因的自我给药，使其剂量效应曲线下移。服用哌醋甲酯和 BZT 类似物后，可卡因维持的反应会减少，而食物维持的反应则保持不变。在无法进行注射的部分中，哌醋甲酯和 AHN 1-055（而非 AHN 2-005 或 JHW 007）提高了缓解率。这些发现进一步支持了 BZT 类似物的低滥用可能性及其作为可卡因滥用药物的开发潜力。
Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032-1.0 mg/kg/ injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/ inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/ inj), although maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl, AHN 2-005 (N-allyl-3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane), and N-butyl, JHW 007 [N-(n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane], BZT analogs, and it was not maintained with nisoxetine or citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10-32 mg/kg) decreased cocaine self-administration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.