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Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.

对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。

基本信息

批准号：
10928578
负责人：
Gianluigi Tanda
金额：
$ 204.65万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10928578
关键词：
Acute Affect Alcohol abuse Autoreceptors Behavior Behavioral Brain Brain Diseases Brain region Carbenoxolone Chemical Structure Chemosensitization Clinical Clinical Research Clinical Treatment Clinical Trials Cocaine Cocaine Users Cocaine use disorder Computer Models Coupling Crack Cocaine Data Dopamine Dopamine Receptor Dose Drug Design Drug Interactions Drug Prescriptions Electrochemistry Electrophysiology (science)Female Future Gap Junctions Gender Goals Human Investigation Measures Mediating Medical Membrane Metabolic Pathway Methamphetamine Methamphetamine use disorder Microdialysis Modafinil Molecular Molecular Conformation Mus Nerve Neurobiology Neurons Neurotransmitters Nucleus Accumbens Optics Pathologic Periodicity Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiological Population Pre-Clinical Model Procedures Publications Research Research Project Grants Rewards Ritalin Rodent Role Scanning Series Sex Differences Sleep Disorders Substance Use Disorder Synapses Synapsins Synaptic Receptors System Testing Therapeutic Vesicle Work abuse liability analog attenuation calmodulin-dependent protein kinase II cocaine self-administration comorbidity dopamine transporter dopaminergic neuron drug discrimination drug of abuse early onset effective therapy enantiomer experimental study extracellular inhibitor male neurochemistry neurotransmission novel pharmacologic postsynaptic pre-clinical preclinical study predictive modeling psychostimulant receptor regional difference response reuptake sex stimulant abuse stimulant use disorder substance use treatment virtual

项目摘要

The dopamine (DA) transporter (DAT) is the main pharmacologic target of abused psychostimulants like cocaine but also of prescribed medications like modafinil (MOD), which has shown little, if any, propensity for abuse in clinical or preclinical studies. Recently, we have explored the neurochemical and behavioral actions of MOD to better characterize its atypical psychostimulant profile. We found that MOD had a lower potency and efficacy than cocaine in stimulating nucleus accumbens shell (NAS) and core (NAC) DA levels, but, at variance with abused psychostimulants there were no statistically significant regional differences between accumbens subregions. In drug-discrimination studies MOD showed cocaine-like subjective effects at lower doses and earlier onset times than expected based on its DA effects. Those results suggest that non-DA-dependent actions may be playing a role in its unique pharmacological profile. In order to discover a potential non-dopaminergic mechanism for these MOD actions, we compared its behavioral and neurochemical effects with those of methylphenidate. Carbenoxolone, a gap junction inhibitor, antagonized MOD, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that MOD shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder. Though MOD might prove useful as a treatment for specific addicted populations (e.g. heavy crack-cocaine users, or cocaine and methamphetamine addicts without alcohol abuse comorbidity), broader effective medications for psychostimulant use disorders are still an unmet medical need. To this end, several newly synthesized analogs of MOD, for example JJC8-091 and JJC8-088, have been tested in our preclinical models as potential medications for methamphetamine (METH) and cocaine use disorder. JJC8-091 and JJC8-088, were assessed alone and in combination with cocaine to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the NAS efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that while JJC8-088 prefers or stabilizes an outward facing conformation of DAT, like cocaine, JJC8-091 stabilizes DAT towards a more occluded conformation. In a recent publication we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DAT blockers, as measured via voltammetry procedures. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKII, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release, suggesting a role for CaMKII in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder. We have also extended our studies to investigate the role of sex/gender in the neurochemical effects of typical and atypical DAT blockers. We found that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. R-modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog, JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for psychostimulant use disorder. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of psychostimulant use disorder.

多巴胺 (DA) 转运蛋白 (DAT) 是滥用的可卡因等精神兴奋剂的主要药理学靶点，也是莫达非尼 (MOD) 等处方药的主要药理学靶点，在临床或临床前研究中，莫达非尼 (MOD) 几乎没有显示出滥用倾向。最近，我们探索了 MOD 的神经化学和行为作用，以更好地表征其非典型精神兴奋剂特征。我们发现，MOD 在刺激伏隔核壳 (NAS) 和核心 (NAC) DA 水平方面的效力和功效低于可卡因，但与滥用的精神兴奋剂不同，伏隔核亚区域之间没有统计学上显着的区域差异。在药物歧视研究中，MOD 显示出与可卡因类似的主观效应，其剂量较低且起效时间比根据其 DA 效应预期的要早。这些结果表明，非 DA 依赖性作用可能在其独特的药理学特征中发挥了作用。为了发现这些 MOD 作用的潜在非多巴胺能机制，我们将其行为和神经化学作用与哌甲酯进行了比较。 Carbenoxolone 是一种间隙连接抑制剂，可以拮抗 MOD，但不能拮抗哌醋甲酯对可卡因自我给药的增强作用。我们的结果表明，MOD 与可卡因和哌醋甲酯具有相同的机制，但具有独特的药理学特征，包括促进电紧张耦合和降低滥用可能性，这可能会在未来可卡因使用障碍的治疗药物设计中得到利用。尽管 MOD 可能被证明可用于治疗特定的成瘾人群（例如重度强效可卡因使用者，或没有酒精滥用合并症的可卡因和甲基苯丙胺成瘾者），但针对精神兴奋剂使用障碍的更广泛有效的药物仍然是一个未得到满足的医疗需求。为此，几种新合成的 MOD 类似物，例如 JJC8-091 和 JJC8-088，已在我们的临床前模型中进行了测试，作为治疗甲基苯丙胺 (METH) 和可卡因使用障碍的潜在药物。 JJC8-091 和 JJC8-088 单独进行评估，并与可卡因联合评估，以阐明与其不同行为特征相关的神经化学物质。尽管具有显着的结构相似性，JJC8-088 更像可卡因，比 JJC8-091 更有效且更有效地增加 NAS 中的细胞外 DA 浓度。相比之下，JJC8-091 不是自我给药的，并且可以有效阻止可卡因诱导的药物寻求恢复。电生理学实验证实，JJC8-091 在抑制可卡因介导的 DA 神经传递增强方面比 JJC8-088 更有效。此外，当 DAT-cre 小鼠的 VTA DA 神经元受到光学刺激时，JJC8-088 的刺激反应曲线产生显着的左移，与可卡因类似，而 JJC8-091 则使曲线向下移动，表明 DA 介导的大脑奖赏减弱。计算模型预测，虽然 JJC8-088 更喜欢或稳定 DAT 的外向构象（如可卡因），但 JJC8-091 却将 DAT 稳定为更封闭的构象。在最近的一篇出版物中，我们通过伏安法测量表明，可卡因和类似可卡因的典型精神兴奋剂会引起 DA 动力学变化，这与非典型 DAT 阻滞剂所引起的变化不同。当联合使用时，典型的 DUI 会增强可卡因对诱发 DA 释放的刺激作用，而非典型的 DUI 则会减弱可卡因的刺激作用。 CaMKII（一种与 DAT 相互作用的激酶，调节突触蛋白磷酸化和 DA 囊泡储备库的动员）的抑制剂预处理，减弱了可卡因对诱发 DA 释放的影响，表明 CaMKII 在调节可卡因对诱发 DA 释放的影响而不影响可卡因对 DA 再摄取的抑制方面发挥作用。这种效应与可卡因稳定的特定 DAT 构象有关。此外，非典型酒后驾车更喜欢独特的 DAT 构象，会减弱可卡因的神经化学和行为效应，这表明其作为治疗精神兴奋剂使用障碍药物的潜力具有独特的机制。我们还扩展了我们的研究，以调查性别在典型和非典型 DAT 阻滞剂的神经化学作用中的作用。我们发现可卡因会减缓雄性和雌性小鼠的 DA 清除速度，但会在雌性小鼠中产生更强烈的诱发 NAS DA 增加。 R-莫达非尼使诱发的 NAS DA 轻度增加，并减慢了不同性别的 DA 清除率。莫达非尼类似物 JJC8-088 是一种典型的 DAT 抑制剂，可增加雌性和雄性小鼠的诱发 NAS DA 水平。最后，JJC8-091（一种非典型 DAT 抑制剂）对两性的 NAS DA 产生有限的增加，并减缓 DA 清除。在这项工作中，我们开始梳理性别差异如何改变 DAT 靶向的效果，并强调这如何有助于将研究重点放在精神兴奋剂使用障碍的有效治疗方案上。总的来说，这些数据揭示了 DAT 的潜在分子机制，可用于合理优化治疗精神兴奋剂使用障碍的线索。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.

DOI：
10.3390/molecules28135270
发表时间：
2023-07-07
期刊：
MOLECULES
影响因子：
4.6
作者：
Hersey, Melinda;Bartole, Mattingly K.;Jones, Claire S.;Newman, Amy Hauck;Tanda, Gianluigi
通讯作者：
Tanda, Gianluigi

A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids.

进一步评估 Toll 样受体 4 在阿片类药物增强和恢复作用中的作用。

DOI：
10.1097/fbp.0000000000000474
发表时间：
2020
期刊：
Behavioural pharmacology
影响因子：
1.6
作者：
Yue,Kai;Tanda,Gianluigi;Katz,JonathanL;Zanettini,Claudio
通讯作者：
Zanettini,Claudio

Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release.

DOI：
10.1038/s41398-023-02493-4
发表时间：
2023-06-13
期刊：
TRANSLATIONAL PSYCHIATRY
影响因子：
6.8
作者：
Keighron, Jacqueline D.;Bonaventura, Jordi;Li, Yang;Yang, Jae-Won;DeMarco, Emily M. M.;Hersey, Melinda;Cao, Jianjing;Sandtner, Walter;Michaelides, Michael;Sitte, Harald H. H.;Newman, Amy Hauck;Tanda, Gianluigi
通讯作者：
Tanda, Gianluigi

Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats.

DOI：
10.1016/j.neuropharm.2017.12.006
发表时间：
2018-03-15
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Tunstall BJ;Ho CP;Cao J;Vendruscolo JCM;Schmeichel BE;Slack RD;Tanda G;Gadiano AJ;Rais R;Slusher BS;Koob GF;Newman AH;Vendruscolo LF
通讯作者：
Vendruscolo LF