Abstract
Blockade of dopamine (DA) reuptake via the dopamine transporter (DAT) is a primary mechanism identified as underlying the therapeutic actions of (±)-modafinil (modafinil) and its R-enantiomer, armodafinil. Herein, we explored the neurochemical and behavioral actions of modafinil to better characterize its psychostimulant profile. Swiss-Webster mice were implanted with microdialysis probes in the nucleus accumbens shell (NAS) or core (NAC) to evaluate changes in DA levels related to acute reinforcing actions of drugs of abuse. Additionally, subjective effects were studied in mice trained to discriminate 10 mg/kg cocaine (i.p.) from saline. Modafinil (17–300 mg/kg, i.p.) significantly increased NAS and NAC DA levels that at the highest doses reached ~300% at 1 h, and lasted > 6 h in duration. These elevated DA levels did not show statistically significant regional differences between the NAS and NAC. Modafinil produced cocaine-like subjective effects at 56–100 mg/kg when administered at 5 and 60 min before the start of the session, and enhanced cocaine effects when the two were administered in combination. Despite sharing subjective effects with cocaine, modafinil's psychostimulant profile was unique compared to that of cocaine and like compounds. Modafinil had lower potency and efficacy than cocaine in stimulating NAS DA. In addition, the cocaine-like subjective effects of modafinil were obtained at lower doses and earlier onset times than expected based on its dopaminergic effects. These studies suggest that although inhibition of DA reuptake may be a primary mechanism underlying modafinil's therapeutic actions, non DA-dependent actions may be playing a role in its psychostimulant profile.
| Original language | English |
|---|---|
| Pages (from-to) | 167-174 |
| Number of pages | 8 |
| Journal | European Journal of Neuroscience |
| Volume | 45 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2017 |
Bibliographical note
Funding Information:Animal experimentation described in this manuscript was approved by the local ACUC of the NIDA/IRP, Baltimore, MD. The animals in this study were maintained in an AAALAC International accredited facility in accordance with NIH Policy Manual 3040-2, Animal Care and Use in the Intramural Program (released 1 November 1999). Care of the subjects was in accordance with the guidelines of the National Institutes of Health and the National Institute on Drug Abuse Intramural Research Program Animal Care and Use Program, which is fully accredited by AAALAC International. This work was funded by the NIDA Intramural Research Program. We thank Dawn French-Evans for technical assistance. Abbreviations anova analysis of variance CSF cerebrospinal fluid DA dopamine DAT dopamine transporter EXT extinction FR fixed ratio i.p. intraperitoneally i.v. intravenously LEDs light-emitting diodes modafinil (?)modafinil NAC nucleus accumbens core NAS nucleus accumbens shell NS non-significant SEM standard error of the mean TO timeout
Publisher Copyright:
© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
Keywords
- ADHD
- cocaine abuse and addiction
- dopamine microdialysis
- methylphenidate
- modafinil
- nucleus accumbens shell
ASJC Scopus subject areas
- Neuroscience (all)