In vivo mechanism of action of the stimulant modafinil.
PI/Investigator: Paige Beck, undergraduate summer fellowship; E. Garcia-Rill, COBRE PI.
Institution: Center for Translational Neuroscience (COBRE), Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR
Background: Modafinil has been prescribed for the treatment of narcolepsy and excessive daytime sleepiness for a number of years. However, the mechanism of action of modafinil was unknown until recently. Investigators at the Center for Translational Neuroscience first reported the existence of electrical coupling in the reticular activating system (RAS). This represents an advance in understanding how cells fire together (coherence) in generating high frequency activity such as that observed in the EEG. Modafinil had been found to increase high frequency activity to promote waking, and has become the stimulant of choice for treatment of certain sleep disorders, especially because it does not activate the dopamine pathway and thus has low abuse potential. In vitro, modafinil was found to increase electrical coupling among cells, an effect that was blocked by gap junction blockers.
Advance: Studies in awake, freely-moving rats had shown that an auditory response recorded over the cortex, the P13 potential, represents an arousal response and output of the RAS. This waveform was increased by modafinil in a dose-dependent manner, and, significantly, was blocked by two different gap junction blockers. Gap junction blockers can have side effects, so that the use of different gap junction blockers with different side effects is essential to demonstrate a common effect on gap junctions.
Support: Summer fellowship and Core Facilities provided by COBRE award P20 GM104325.
Public Health Impact: These studies demonstrated, for the first time, the in vivo mechanism of action of a stimulant already on the market. They provide a demonstration of a novel mechanism of action based on electrical coupling, opening the door for the development of new anesthetics (gap junction blockers) and stimulants (gap junction amplifiers).
Citation and links: This publication earned an Editorial from the journal Sleep.
Beck, P., Odle, A., Wallace-Huitt, T., Skinner, R.D. and Garcia-Rill, E. Modafinil increases arousal determined by P13 potential amplitude; An effect blocked by gap junction antagonists. Sleep 31:1647-1654, 2008. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603487/