Date of Award
Doctor of Philosophy
Dr. Lisa E. Baker
Dr. Cynthia J. Pietras
Dr. Alan Poling
Dr. Russell E. Morgan
Modafinil, amphetamine, cocaine, drug discrimination, conditioned place preference, behavioral sensitization
Modafinil is an FDA-approved drug for the treatment of narcolepsy with efficacy in the treatment of chronic fatigue syndrome, obstructive sleep apnea, and shift-work sleep disorder. Modafinil’s wake-promoting and cognitiveenhancing effects are reportedly similar to those of traditional psychostimulants, but without the side effects typically associated with these substances. Modafinil has also been investigated as an agonist replacement therapy for psychostimulant dependence, although results of clinical trials are equivocal. Few studies have examined its behavioral effects in combination with psychostimulants and the neuropharmacological actions of modafinil are not well understood. The primary aim of this study was to assess modafinil’s effects in combination with the psychomotor stimulant, d-amphetamine, in four experiments utilizing preclinical behavioral assays of abuse liability. A secondary aim was to investigate modafinil’s neuropharmacological actions utilizing drug discrimination, an in vivo preclinical screening procedure with established predictive validity. The first experiment utilized a behavioral sensitization assay to determine if repeated d-amphetamine treatment followed by a washout period would produce cross sensitization to modafinil. Experiment 2 utilized a conditioned place preference (CPP) assay to determine if modafinil would establish a CPP or influence d-amphetamine-induced CPP. Experiment 3 utilized a drug discrimination assay to evaluate generalization with modafinil alone and with d-amphetamine in rats trained to discriminate d-amphetamine. Experiment 4 assessed several dopaminergic compounds for substitution or antagonism in rats trained to discriminate 256 mg/kg modafinil. Experiment 1 results indicated that repeated d-amphetamine treatment does not induce cross sensitization to modafinil. Experiment 2 results demonstrated that modafinil does not readily establish CPP or potentiate d-amphetamine-induced CPP. Modafinil produced dose-dependent d-amphetamine-lever responses and partial substitution for d-amphetamine in Experiment 3. Experiment 4 results represent the first demonstration that modafinil’s actions at the dopamine transporter are important in maintaining its discriminative stimulus effects. Considered together, these findings support previous reports of modafinil’s low abuse potential, but also indicate that it may have additive effects with psychomotor stimulants. In consideration of modafinil as a potential candidate for agonist replacement therapy, further preclinical investigations of modafinil in combination with other stimulants, such as drug self-administration, may be warranted.
Quisenberry, Amanda J., "Evaluation of Modafinil in Preclinical Behavioral Assays of Abuse Liability" (2013). Dissertations. 213.