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. We are now investigating the potential of GAP-junctions to facilitate the effects of MOD on cocaines reinforcing actions. 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. The mu-opioid receptor agonists heroin and morphine dose-dependently decreased the power of gamma and increased power of the other bands. The effect of morphine on EEG power bands was antagonized by naltrexone. The NMDA receptor antagonist ketamine increased the power of all frequency bands. 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. We tested the effects of systemic injections of R-MOD and four novel, chemically unique MOD analogs, JJC8-016, JJC8-088, JJC8-089 and JJC8-091, 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 extensively and comparatively 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. 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, with JJC8-091 representing a compelling candidate for development. Another topic of interest has been suggested by reports that the neuropeptide oxytocin (OT), which plays a role in reward, stress, social affiliation, learning, and memory processes, might also be a potential treatment for substance use disorders. An interaction between OT and DA in the nucleus accumbens has been described, but its role in the neurochemistry related to psychostimulant use disorder is still unclear. We investigated the effect of OT, delivered intraperitoneally (i.p.), on the methylphenidate (MP) dose response function in rats. Food was used as a control condition. In a microdialysis study we measured the effect of OT on MP-stimulated striatal DA levels. Systemic OT pretreatment caused a downward shift in the MP dose response function while having no effect on motor activity. OT also caused a reduction in food self-administration, although a significantly higher dose of OT was required for this effect compared to that required for a reduction of MP self-administration. Systemic OT pretreatment caused a potentiation of MP-stimulated DA levels in the NAc shell but not in the core. Our findings suggest that OT might be tested in humans as a potential pharmacologic treatment for psychostimulant use disorders.
