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

多巴胺（DA）转运体（DAT）是莫达非尼（MOD）和其他滥用的精神兴奋剂如可卡因的主要药理学靶点。最近，我们进一步探索了MOD的神经化学和行为作用，以更好地表征其精神兴奋剂的特征。在小鼠中，我们评估了mod诱导的NAS或NAC DA水平的变化可能与强化行为相关。此外，还研究了训练小鼠区分可卡因（i.p.）和生理盐水的主观效应。我们发现MOD在刺激NAS和NAC DA水平方面的效力和疗效低于可卡因，但在与滥用精神兴奋剂的差异上，NAS和NAC之间没有统计学上显著的区域差异。与基于DA效应的预期相比，MOD在较低剂量和较早起效时间下表现出类似可卡因的主观效应。这些结果表明，尽管抑制DA再摄取可能是MODs治疗作用的主要机制，但非DA依赖性作用可能在其独特的药理学特征中发挥作用。

The dopamine (DA) transporter (DAT) is the main pharmacologic target of modafinil (MOD) and other abused psychostimulants like cocaine. Recently, we have further explored the neurochemical and behavioral actions of MOD to better characterize its psychostimulant profile. In mice, we assessed MOD-induced changes in NAS or NAC DA levels potentially related to reinforcing actions. Additionally, subjective effects were studied in mice trained to discriminate cocaine (i.p.) from saline. We found that MOD had a lower potency and efficacy than cocaine in stimulating NAS and NAC DA levels, but, at variance with abused psychostimulants there were no statistically significant regional differences between NAS and NAC. MOD showed cocaine-like subjective effects at lower doses and earlier onset times than expected based on its DA effects. Those results suggest that although inhibition of DA reuptake may be a primary mechanism underlying MODs therapeutic actions, non-DA-dependent actions may be playing a role in its unique pharmacological profile. In a recent study we compared the behavioral and neurochemical actions of MOD and methylphenidate, two clinically available medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. We showed that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil 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 addicts without alcohol abuse comorbidity), broader effective medications for psychostimulant use disorders are still an unmet medical need. To this end, newly synthesized analogs of Modafinil (MOD) have been tested in our preclinical models of drug abuse and addiction. We have compared the effects of the clinically available (R)-enantiomer of MOD with those of two novel bis(F) analogs of MOD, JBG1-048 and JBG1-049, on extracellular DA dynamics in the NAS measured in vivo by fast-scan cyclic voltammetry or by microdialysis in rats. All these drugs, when administered intravenously with cumulative drug doses, were able to block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight mechanistic underpinnings of R-MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders. In a recent study we established an in-vivo assay using electroencephalography (EEG) procedures in rats for the rapid identification of atypical DAT inhibitors with potential for medication development. The typical DAT blockers cocaine and methylphenidate dose-dependently decreased the power of the alpha, beta, and gamma bands. The atypical DAT blocker modafinil and its F-analog, JBG1-049, decreased the power of beta, but in contrast to cocaine, none of the other frequency bands, while another atypical DAT blocker, JHW007, did not significantly alter the EEG spectrum. Therefore, typical and atypical DUIs and drugs of other classes differentially affected EEG spectra, showing distinctive features in the magnitude and direction of their effects on EEG. Comparative analysis of the effects of test drugs on EEG indicates a potential atypical profile of JBG1-049 with similar potency and effectiveness to its parent compound modafinil. These data suggest that EEG can be used to rapidly screen compounds for potential activity at specific pharmacological targets and provide valuable information for guiding the early stages of drug development. Several MOD analogs have recently been tested as potential medications for methamphetamine (METH) and cocaine use disorder. Systemic injections of R-MOD and four novel, chemically unique MOD analogs, JJC8-016, JJC8-088, JJC8-089 and JJC8-091, were tested on intravenous (i.v.) METH self-administration in rats allowed short access (1 h; ShA) or long access (6 h; LgA) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA rats. JJC8-016, JJC8-089 and JJC8-091 decreased METH self-administration in both LgA and ShA rats. JJC8-088 did not have an effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorder. JJC8-091 and JJC8-088, were also 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 JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. While further development of JJC8-091 is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. In recent studies, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and 1 receptors. Within the series, RDS3-094 showed improved DAT affinity (Ki = 23 nM) over JJC8-091 (Ki = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While RDS3-094 increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of RDS3-094 as a potential treatment for psychostimulant use disorders. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders.