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

Neuropsychopharmacology. 2020 Aug;45(9):1518-1526. doi: 10.1038/s41386-020-0680-5. Epub 2020 Apr 27.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology
  • Central Nervous System Stimulants* / pharmacology
  • Cocaine* / pharmacology
  • Dopamine
  • Dose-Response Relationship, Drug
  • Gap Junctions
  • Methylphenidate* / pharmacology
  • Modafinil
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Methylphenidate
  • Cocaine
  • Modafinil
  • Dopamine