Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding.
Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding.
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DOI：
10.1007/s00213-020-05625-6
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发表时间：
2020-11
影响因子：
3.4
通讯作者：
Salamone JD
中科院分区：
文献类型：
--
作者：
Rotolo RA;Kalaba P;Dragacevic V;Presby RE;Neri J;Robertson E;Yang JH;Correa M;Bakulev V;Volkova NN;Pifl C;Lubec G;Salamone JD
非典型的多巴胺(DA)转运阻滞剂，如莫达非尼及其类似物，可能对治疗抑郁症和其他疾病的动机症状有用。先前的研究表明，DA耗竭剂四苯肼可以可靠地诱导大鼠的动机缺陷，这在基于努力的选择任务中转向低努力偏向就是明证。这与人类研究表明，患有严重抑郁症的人倾向于低强度的活动是一致的。最近的研究表明，非典型的多巴胺转运抑制剂(S)-CE-123可逆转四苯肼所致的兴奋性缺失，增加递增比(PRAG)的杠杆压力，并增加伏隔核胞外DA的含量。在本研究中，最近合成的莫达非尼类似物(S，S)-CE-158在一系列的大鼠神经化学和行为研究中得到了评价。(S，S)-CE-158证明了逆转四苯肼的努力相关效应，并增加大鼠对高努力程序杠杆按压的选择能力，在进行程序/食物选择任务的测试中。与其他单胺转运体相比，(S，S)-CE-158表现出较高的选择性抑制多巴胺转运体，全身应用(S，S)-CE-158可使伏隔核胞外DA在行为活动过程中增加，这与(S)-CE-123和其他DAT抑制剂增强高努力反应的作用一致。这些研究提供了一种新的非典型DAT抑制剂的初步神经化学特征，并证明了该化合物在努力相关选择的模型中是活跃的。这项研究可能有助于开发新的化合物来治疗人类的动机障碍。
Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities. Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats. (S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine, and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared to other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding. These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans.
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影响因子：
6.6
作者：
Chung, Ka-Fai;Yu, Yee-Man;Yeung, Wing-Fai
通讯作者：
Yeung, Wing-Fai
DOI：
10.1111/ejn.13608
发表时间：
2017-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Hart EE;Gerson JO;Zoken Y;Garcia M;Izquierdo A
通讯作者：
Izquierdo A
影响因子：
3.6
作者：
Chong, Trevor T. -J.;Bonnelle, Valerie;Husain, Masud
通讯作者：
Husain, Masud
影响因子：
2.3
作者：
Frank, Stefanie Th.;Krumm, Bertram;Spanagel, Rainer
通讯作者：
Spanagel, Rainer
影响因子：
4.6
作者：
Jung, Jae-Chul;Lee, Yeonju;Oh, Seikwan
通讯作者：
Oh, Seikwan