Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder

Abstract

Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication for treatment of sleep disturbances, has been tested as a therapeutic for cocaine and methamphetamine use disorder. Positive results have been found in subjects dependent on psychostimulants without concurrent abuse of other substances. Novel structural analogs of MOD have been synthesized in the search for compounds with potentially broader therapeutic efficacy than the parent drug. In the present report we review their potential efficacy as treatments for psychostimulant abuse and dependence assessed in preclinical tests. Results from these preclinical proof of concept studies reveal that some modafinil analogs do not possess typical cocaine-like neurochemical and behavioral effects. Further, they might blunt the reinforcing effects of psychostimulants in animal models, suggesting their potential efficacy as pharmacotherapeutics for treatment of psychostimulant use disorders.

Figure 1:. Effects of R-MOD and MOD analogs on DA dynamics in mice accumbens shell.

Representative FSCV color plots, redrawn from [20], demonstrating the effects of R-MOD and MOD analogs, or their vehicle, on the elicited DA peak, DA_MAX and clearance rate of NAS DA from the electrode. The inset above each color plot represents the DA concentration vs time corresponding to the measurement on the color plot.

Figure 2:. Evaluation of the effects of JJC8–088 and JJC8–091 on self-administration or on cocaine self-administration behavior.

A: JJC8–091, but not JJC8–088, significantly lowered the number of cocaine self-administration (infusions) under the PR reinforcement schedule. B: JJC8088, but not JJC8–091, substitution sustained stable self-administration in rats that previously self-administered cocaine. C: Naive rats self-administered JJC8–088 intravenously similarly to cocaine. D: Naive rats did not self-administer JJC8–091 during the initial 10 days of self-administration training. When JJC8–091 was replaced by cocaine, animals rapidly acquired self-administration behavior for cocaine. **p < 0.01, compared to vehicle. Redrawn from [27].