Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats

Abstract

Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure-activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy. Here, we have tested the effects of the clinically available (R)-enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast-scan cyclic voltammetry and by microdialysis in Sprague-Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of MOD, JBG1-048 and JBG1-049. The results show that (R)-modafinil (R-MOD), JBG1-048, and JBG1-049, when administered intravenously with cumulative drug-doses, will 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 the 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.

Keywords: addiction; cocaine use disorder; dopamine microdialysis; fast-scan cyclic voltammetry; nucleus accumbens shell.

Figure 1:

Chemical structures and DAT binding affinities for R-MOD and the novel bis(F) analogs

Figure 2:

FSCV analysis of cumulative dosing experiments with R-MOD and each bis(F) analog. (A-D) Representative colorplots from individual animals showing the effects of the vehicle (10% DMSO, 15% Tween), and 17 mg/kg of R-MOD, JBG1–048, and JBG1–049. Inset into each colorplot is the CV corresponding to the peak oxidation wave indicating the presence of DA. Above each colorplot is the corresponding plot showing the change in DA concentration over time. The time and duration of stimulation is indicated by the red bar. (E) The time course of the cumulative dosing experiment for DA_Max showing a change in elicited DA with dose of DAT inhibitor after an initial baseline period and vehicle treatment. (F) Cumulative dose-response curves showing the effect of each compound on DA_Max with doses of 10–32 mg/kg (i.v.). The peak effect across doses and compounds was found to after 15 min, which was used to generate the dose-response curve. (G) Cumulative dose-response curves showing the effect of each compound on the rate of DA clearance from the electrode. The greatest effect of each dose was found to be after 15 min for each compound which was used to generate the dose-response curve.

Figure 3:

Time course of effects of intravenous administration of cumulative doses (10–32 mg/kg) of R-MOD, JBG1–048, JBG1–049, or their vehicle (2ml/kg) on DA levels in dialysates from the NAS. The first drug-dose was administered at time=0. Subsequent doses were then administered 30 min apart. The results suggest a slower onset of effects on DA levels for JBG1–049 compared to the other tested drugs. Also, R-MOD effects on DA levels appear to dissipate more rapidly compared to the JBG-compounds. Results are means, with vertical bars representing SEM, of the amount of DA in 10-min dialysate samples, expressed as percentage of basal values, uncorrected for probe recovery.

Figure 4:

Panel (A): Maximum increase in DA levels in dialysates from the NAS in rats obtained following intravenous administration of cumulative doses (10–32 mg/kg) of R-MOD, JBG1–048 and JBG1–049, or their vehicle (2ml/kg). The effects of R-MOD resemble those already reported for MOD and its enantiomers in mice (Loland et al., 2012), where the slope of the dose-response curve was shallow as compared to that for a widely abused psychostimulant like cocaine. Results are means, with vertical bars representing SEM, of the amount of DA in 10-min dialysate samples, expressed as percentage of basal values, uncorrected for probe recovery. Panel (B): Behavioral activity counts obtained during the first 30 minutes after each intravenous administration of cumulative doses (10–32 mg/kg) of R-MOD, JBG1–048 and JBG1–049, or their vehicle (2ml/kg). Our results show that the pattern of changes in behavioral effects related to these drugs appears similar to the pattern of changes in maximum increase in DA levels obtained with the same cumulative drug doses shown on panel A.