Armodafinil-induced wakefulness in animals with ventrolateral preoptic lesions

Abstract

Armodafinil is the pharmacologically active R-enantiomer of modafinil, a widely prescribed wake-promoting agent used to treat several sleep-related disorders including excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Remarkably, however, the neuronal circuitry through which modafinil exerts its wake-promoting effects remains unresolved. In the present study, we sought to determine if the wake-promoting effects of armodafinil are mediated, at least in part, by inhibiting the sleep-promoting neurons of the ventrolateral preoptic (VLPO) nucleus. To do so, we measured changes in waking following intraperitoneal administration of armodafinil (200 mg/kg) or the psychostimulant methamphetamine (1 mg/kg) in rats with cell-body specific lesion of the VLPO. Rats with histologically confirmed lesions of the VLPO demonstrated a sustained increase in wakefulness at baseline, but the increase in wakefulness following administration of both armodafinil and methamphetamine was similar to that of intact animals. These data suggest that armodafinil increases wakefulness by mechanisms that extend beyond inhibition of VLPO neurons.

Keywords:

• EEG
• sleep
• orexin-saporin
• methamphetamine

Acknowledgments

This study was supported by grants from Cephalon Inc, and by National Institute of Health Grants NS073613, NS074205 and AG09975, and the G Harold and Leila Y Mathers Foundation. We are grateful to Quan Hue Ha for excellent technical assistance.

Disclosure

The authors report no conflicts of interest in this work.