Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 45; no. 9; pp. 1518 - 1526
• Main Authors: Mereu, Maddalena, Hiranita, Takato, Jordan, Chloe J., Chun, Lauren E., Lopez, Jessica P., Coggiano, Mark A., Quarterman, Juliana C., Bi, Guo-Hua, Keighron, Jacqueline D., Xi, Zheng-Xiong, Newman, Amy Hauck, Katz, Jonathan L., Tanda, Gianluigi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2020; Springer International Publishing
• Subjects: Animals; Benzhydryl Compounds - pharmacology; Central Nervous System Stimulants - pharmacology; Cocaine; Cocaine - pharmacology; Dopamine; Dose-Response Relationship, Drug; Drug abuse; Drug development; Drug self-administration; Gap Junctions; Intravenous administration; Mesolimbic system; Methylphenidate; Methylphenidate - pharmacology; Modafinil; Potentiation; Rats; Rats, Sprague-Dawley; Rodents
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-020-0680-5

Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as "smart drugs" by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.