Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine.
Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine.
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DOI：
10.1016/j.biopsych.2014.03.031
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发表时间：
2014-11-15
影响因子：
10.6
通讯作者：
Tanda G
中科院分区：
文献类型：
--
作者：
Kohut SJ;Hiranita T;Hong SK;Ebbs AL;Tronci V;Green J;Garcés-Ramírez L;Chun LE;Mereu M;Newman AH;Katz JL;Tanda G
与可卡因滥用相关的主观效应主要是通过阻断多巴胺（DA）转运体（DAT）介导的。本研究评估了DAT的不同构象平衡调节结构不同的DA摄取抑制剂（DUI）诱导的细胞外DA差异及其可卡因样主观效应的假设。采用可卡因鉴别和da微透析方法，研究了可卡因样主观效应与标准duis（可卡因、哌甲酯、WIN35,428）和非典型duis（苯托品类似物：AHN1-055、AHN2-005、JHW-007）对大鼠中脑代际da水平的刺激之间的关系。所有药物刺激的da水平表现出不同的时间过程和最大效应。标准duis优先结合向外的dat构象，完全取代可卡因，在DA水平超过基础值100-125%时，无论剂量或预处理时间如何，都能持续产生这些主观效应。非典型duis，其DAT结合受DAT构象的影响最小，产生不一致的可卡因样主观效应。如果有充分的效果，则仅在少量剂量和预处理时间下获得，并且da水平比基础值高600-700%。重要的是，在标准酒驾中获得的可卡因样主观效应与刺激da水平之间的线性、时间无关的关系，在非典型酒驾中没有得到。这些结果表明，非典型duis的可卡因主观效应降低，可能是由分子方法确定的结合方式不同诱导的，其背后存在一个与时间相关的脱敏过程。由于DAT是治疗神经精神疾病（如多动症）的几种药物的靶标，这些结果有助于确定安全有效的药物，这些药物具有最小的可卡因样主观效应，从而导致滥用风险。
Subjective effects related to cocaine abuse are primarily mediated by blockade of the dopamine (DA) transporter (DAT). The present study assessed the hypothesis that different conformational equilibria of the DAT regulate differences in extracellular DA induced by structurally diverse DA uptake inhibitors (DUI) and their cocaine-like subjective effects. The relationship between cocaine-like subjective effects and stimulation of mesolimbic-DA levels by standard-DUIs (cocaine, methylphenidate, WIN35,428), and atypical-DUIs (benztropine analogs: AHN1-055, AHN2-005, JHW-007) was investigated using cocaine-discrimination and DA-microdialysis procedures in rats. All drugs stimulated DA-levels showing different time-courses and maximal effects. Standard-DUIs, which preferentially bind to the outward-facing DAT-conformation, fully substituted for cocaine, consistently producing those subjective effects at DA levels of 100-125% over basal values, regardless of dose or pretreatment time. The atypical-DUIs, with DAT binding minimally affected by DAT conformation, produced inconsistent cocaine-like subjective effects. Full effects were obtained, if at all, only at a few doses and pretreatment times, and at DA-levels 600-700% greater than basal values. Importantly, the linear, time-independent, relationship between cocaine-like subjective effects and stimulation of DA-levels, obtained with standard DUIs was not obtained with the atypical-DUIs. These results suggest a time-related desensitization process underlying the reduced cocaine subjective effects of atypical-DUIs that may be differentially induced by the binding modalities identified using molecular approaches. Since the DAT is the target of several drugs for treating neuropsychiatric disorders, such as ADHD, these results help to identify safe and effective medications with minimal cocaine-like subjective effects that contribute to abuse liability.