Gap Junctions Modulate The Effects Of Modafinil On Cocaine Self‐Administration Behavior In A Dopamine‐Independent Fashion In Rats

Abstract

Modafinil and methylphenidate are among the few clinically available medications that block the dopamine (DA) transporter (DAT), a mechanism shared by abused psychostimulants like cocaine. Modafinil is FDA approved for the treatment of narcolepsy and other sleep disorders, while methylphenidate is approved as a medication for neurological disorders (e.g., attention deficit hyperactivity disorder). Both drugs have been reported for their non‐medical use as “smart drugs”, raising concerns regarding their potential for abuse by populations that may also be exposed to illicit substances. In this preclinical study, we compared the potential for abuse of modafinil with that of methylphenidate and their interactions with the reinforcing effects of cocaine in rats trained to self‐administer cocaine (0.03–1 mg/kg i.v., Fixed‐Ratio 5) with 5 doses assessed within each session. Since changes in DA levels in the nucleus accumbens shell (NAS) have been related to reinforcing effects of drugs, we monitored extracellular DA concentrations using microdialysis procedures in rats. Methylphenidate (0.03–1.0 mg/kg) maintained intravenous self‐administration behavior at comparable levels to active doses of cocaine (0.03–1.0 mg/kg). Modafinil (0.1–10 mg/kg) failed to maintain self‐administration behavior at any dose tested. However, pre‐session treatments (i.p.) with both modafinil (10–32 mg/kg) or methylphenidate (1.0–10 mg/kg) potentiated cocaine self‐administration behavior. Administration of cocaine, at self‐administered doses, produced dose‐related stimulation of NAS DA levels. Methylphenidate (1.0–10 mg/kg, i.p.), but not modafinil, (10–32 mg/kg, i.p.), enhanced cocaine‐induced stimulation of DA levels. These microdialysis results suggest that the effects of methylphenidate on cocaine actions are DA‐dependent, while those of modafinil are not. Modafinil is known to facilitate electrotonic coupling between cells by actions on gap junctions. Thus, we assessed the effects of carbenoxolone pretreatments, a gap junction inhibitor, on the potentiation of cocaine self‐administration produced by modafinil or methylphenidate. Carbenoxolone (1 mg/kg i.p.) attenuated modafinil, but not methylphenidate, potentiation of cocaine self‐administration behavior, suggesting that the facilitation of electrotonic coupling plays a role in modafinil’s potentiation of cocaine’s effects. In conclusion, modafinil shares with cocaine and methylphenidate important actions at the DAT, but the present data suggest a unique pharmacological stimulant profile, lacking abuse potential and facilitating electrotonic coupling. These results, together with clinical studies, further suggest a potential therapeutic use of modafinil in patients with cocaine use disorder.Support or Funding InformationThis research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS