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。

• 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
• 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

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）是可卡因等滥用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，莫达非尼几乎没有（如果有的话）滥用倾向。最近，我们探讨了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的特点。我们发现，MOD有一个较低的效力和功效比可卡因在刺激神经核壳（NAS）和核心（NAC）DA水平，但在方差与滥用精神兴奋剂有统计学显着的区域差异之间的神经核次区域。在药物辨别研究中，MOD在较低剂量下显示出可卡因样的主观效应，并且比基于其DA效应的预期起效时间更早。这些结果表明，非DA依赖性的行动可能发挥作用，其独特的药理作用。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。甘珀酸，间隙连接抑制剂，拮抗MOD，但不是哌甲酯增强可卡因自我管理。我们的研究结果表明，MOD与可卡因和哌甲酯有共同的机制，但具有独特的药理学特征，包括促进电紧张耦合和较低的滥用倾向，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。 虽然MOD可能被证明是治疗特定成瘾人群（例如，重度快克可卡因使用者，或可卡因和甲基苯丙胺成瘾者，但没有酒精滥用合并症）的有效药物，但精神兴奋剂使用障碍的更广泛有效药物仍然是未满足的医疗需求。为此，几种新合成的MOD类似物，例如JJC 8 -091和JJC 8 -088，已经在我们的临床前模型中作为甲基苯丙胺（METH）和可卡因使用障碍的潜在药物进行了测试。 JJC 8 -091和JJC 8 -088单独和与可卡因组合进行评估，以阐明与其不同行为特征的神经化学相关性。尽管JJC 8 -088具有显着的结构相似性，但JJC 8 -088更像可卡因，比JJC 8 -091更有效且更有力地增加NAS中细胞外DA浓度。相比之下，JJC 8 -091不是自我给药的，并且有效地阻断可卡因诱导的药物寻求的恢复。电生理实验证实，JJC 8 -091比JJC 8 -088更有效地抑制可卡因介导的DA神经传递增强。此外，当DAT-cre小鼠的VTA DA神经元受到光学刺激时，JJC 8 -088在刺激-反应曲线中产生了显著的位移，类似于可卡因，而JJC 8 -091将曲线向下移动，表明DA介导的大脑奖励减弱。计算模型预测，虽然JJC 8 -088喜欢或稳定DAT的外向构象，如可卡因，但JJC 8 -091使DAT稳定为更封闭的构象。 在最近的出版物中，我们表明，可卡因和可卡因样典型的精神兴奋剂引起的DA动力学的变化不同的非典型DAT阻断剂引起的，通过伏安法程序测量。当联合给药时，典型的DUI会增强可卡因对诱发的DA释放的刺激作用，而非典型的DUI会减弱这种作用。预处理与抑制剂的CaMKII，一种激酶，与DAT相互作用，调节突触蛋白磷酸化和动员储备池的DA囊泡，钝化的可卡因对诱发的DA释放的影响，提示作用CaMKII在调制可卡因对诱发的DA释放的影响，而不影响可卡因抑制DA再摄取。这种效应与可卡因稳定的特定DAT构象有关。此外，非典型的DUI，这更喜欢一个独特的DAT构象，钝可卡因的神经化学和行为的影响，表明一个独特的机制，其潜在的药物治疗精神兴奋剂使用障碍。 我们还扩展了我们的研究，以调查性别/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，可卡因减缓了雄性和雌性小鼠的DA清除率，但在雌性小鼠中诱发的NAS DA产生了更强烈的增加。R-莫达非尼产生轻度增加诱发NAS DA和减缓DA清除率的性别。莫达非尼类似物JJC 8 -088是一种典型的DAT抑制剂，在雌性和雄性小鼠中引起NAS DA增加。最后，JJC 8 -091，一种非典型的DAT抑制剂，产生有限的增加诱发NAS DA和减缓DA清除在两种性别。在这项工作中，我们开始梳理出性别差异如何可能改变DAT靶向的影响，并强调这如何可能有助于集中研究对精神兴奋剂使用障碍的有效治疗方案。 总的来说，这些数据揭示了DAT的潜在分子机制，可以利用这些机制来合理优化治疗精神兴奋剂使用障碍的线索。

项目成果

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

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

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