Structurally Similar and Behaviorally Unique Modafinil Analogs as Potential Pharmacotherapeutics for Psychostimulant Use Disorder

Abstract

Modafinil has been used off‐label to treat psychostimulant use disorders (PSUD). However, its effectiveness in clinical trials seems limited to a subpopulation of subjects without concurrent alcohol or poly‐drug use. Since the main pharmacological target of cocaine is the dopamine transporter (DAT), recent efforts to develop more globally effective pharmacotherapies for PSUD have focused on two new DAT inhibitors and structural analogs of modafinil, JJC8‐088 and JJC8‐091, as promising lead compounds.In this study, the behavioral effects of these compounds were tested in rat models of cocaine self‐administration and reinstatement to drug seeking. Neurochemical correlates to those behaviors were assessed in microdialysis and fast‐scan cyclic voltammetry (FSCV) procedures aimed to measure extracellular dopamine levels and potential changes in dopamine dynamics in the nucleus accumbens shell (NAS).Our results show that JJC8‐088 (3, 10, 30 mg/kg, i.p.) dose‐dependently decreased the number of cocaine infusions under a fixed ratio schedule of self‐administration, while JJC8‐091 (10, 30, 56 mg/kg) failed to significantly alter cocaine self‐administration. In contrast, JJC8‐088 failed, while JJC8‐091 effectively decreased the break‐point for cocaine self‐administration under a progressive ratio schedule of behavior. JJC8‐088 maintained self‐administration behavior in both drug‐naïve and cocaine trained rats, while JJC8‐091 did not. Moreover, only priming injections of JJC8‐088 dose‐dependently reinstated drug‐seeking behavior in rats following previous cocaine extinction. Importantly, in the same rats, JJC8‐091 pretreatment blocked cocaine‐induced reinstatement of drug seeking behavior.The neurochemical assessment of JJC8‐088 and JJC8‐091 effects showed that both drugs dose‐dependently increased extracellular DA concentrations in dialysates from the NAS. However, JJC8‐088 was more potent and more efficacious in increasing DA levels compared to JJC8‐091. Indeed, the maximal changes in DA levels elicited by JJC8‐088 resemble those obtained with cocaine, in contrast to JJC8‐091.The FSCV studies showed that both JJC8‐088 and JJC8‐091 dose dependently reduced the rate of DA clearance, with JJC8‐088 producing effects greater in magnitude at lower doses than JJC8‐091. Finally, like cocaine, cumulative doses of JJC8‐088 produced a dose‐dependent increase in DAMax, while JJC8‐091 was ineffective at all doses tested.Collectively, these data show that despite sharing significant structural similarity, JJC8‐088 was cocaine‐like, while JJC8‐091 was not. Indeed, in contrast with JJC8‐088, JJC8‐091 did not elicit significant reinforcing actions and reduced or blunted the reinforcing effects of cocaine. Taken together, our data support further development of JJC8‐091, as a potential pharmacotherapy for the treatment of PSUD.Support or Funding InformationSupport for this research was provided by the Medication Development Program, National Institute on Drug Abuse ‐ Intramural Research Program, NIH/DHHSThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.