Department of Pharmacology & Toxicology, Virginia Commonwealth University, 410 N. 12th Street, Richmond, VA 23298, USA.
Eur J Pharmacol. 2010 Dec 1;648(1-3):127-32. doi: 10.1016/j.ejphar.2010.08.051. Epub 2010 Sep 16.
A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED(50) value of 3.13 (1.54-6.34) mg/kg, and reduced response rates with an ED(50) value of 20.39 (7.24-57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine-lever responding, while reducing response rates with lower potency than cocaine (ED(50)=30.94 (12.34-77.60) mg/kg). Pretreatment with D-84 (9.6-30.4 mg/kg) significantly (P<0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self-administration tests with D-84 (0.1-1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pretreatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine-abusing patients.
一种成功的替代药物治疗可卡因依赖的方法可能会减少可卡因的滥用，支持低滥用倾向，与可卡因的主观效应重叠，并具有较长的作用持续时间。多巴胺转运体（DAT）具有不同选择性的抑制剂已经接近这些特性。本研究的目的是描述一种非常选择性的 DAT 抑制剂（+）trans-4-（2-苯并基氧乙基）-1-（4-氟苄基）哌啶-3-醇（D-84）的行为效应，该抑制剂是 GBR-12935 的 3-羟基取代哌啶衍生物，用于其可卡因样辨别刺激效应、对可卡因自我给药的影响以及自身的自我给药。在可卡因辨别测试中，可卡因以 10mg/kg 的可卡因训练刺激引起 3.13（1.54-6.34）mg/kg 的 ED50 值，以 20.39（7.24-57.44）mg/kg 的 ED50 值降低反应率。D-84 不完全概括可卡因刺激，引起最大 76%的可卡因杠杆反应，同时降低比可卡因低的效力（ED50=30.94（12.34-77.60）mg/kg）。D-84（9.6-30.4mg/kg）预处理显著（P<0.05）降低了 17.1mg/kg D-84 时可卡因的摄入量，当时可卡因以 0.5mg/kg/输注的剂量自我给药，并且在 30.4mg/kg D-84 时可卡因以 0.1、0.5 和 1.0mg/kg/输注的剂量自我给药。在 D-84（0.1-1mg/kg/输注）的自我给药测试中，在 0.3mg/kg/输注的剂量时，输注次数显著超过载体水平。这些结果表明，D-84 预处理可以减少可卡因的摄入量，特别是在高剂量可卡因自我给药时。这一观察结果，加上其对可卡因辨别刺激不完全概括和报道的长效作用，提供了一种可能的替代治疗可卡因滥用患者的治疗方法。
