Increased dopaminergic
transmission mediates the wake-promoting effects of CNS stimulants
Nishino S, Mao J, Sampathkumaran R, Shelton J.
Stanford University School of Medicine,
Sleep Disorders Center,
Palo Alto, CA 94304, USA
Sleep Res Online 1998;1(1):49-61
ABSTRACT
Amphetamine-like stimulants are commonly used to treat
sleepiness in narcolepsy. These compounds have little effect on rapid
eye movement (REM) sleep-related symptoms such as cataplexy, and
antidepressants (monoamine uptake inhibitors) are usually required to treat
these symptoms. Although amphetamine-like stimulants and
antidepressants enhance monoaminergic transmission, these compounds are
non-selective for each monoamine, and the exact mechanisms mediating how
these compounds induce wakefulness and modulate REM sleep are not
known. In order to evaluate the relative importance of dopaminergic
and noradrenergic transmission in the mediation of these effects, five
dopamine (DA) uptake inhibitors (mazindol, GBR-12909, bupropion, nomifensine
and amineptine), two norepinephrine (NE) uptake inhibitors (nisoxetine and
desipramine), d-amphetamine, and modafinil, a non-amphetamine stimulant,
were tested in control and narcoleptic canines. All stimulants and
dopaminergic uptake inhibitors were found to dose-dependently increase
wakefulness in control and narcoleptic animals. The in vivo potencies of DA
uptake inhibitors and modafinil on wake significantly correlated with their
in vitro affinities to the DA and not the NE transporter. DA uptake
inhibitors also moderately reduced REM sleep, but this effect was most
likely secondary to slow wave sleep (SWS) suppression, since selective DA
uptake inhibitors reduced both REM sleep and SWS proportionally. In
contrast, selective NE uptake inhibitors had little effect on wakefulness,
but potently reduced REM sleep. These results suggest that presynaptic
activation of DA transmission is critical for the pharmacological control of
wakefulness, while that of the NE system is critical for REM sleep
regulation. Our results also suggest that presynaptic activation of DA
transmission is a key pharmacological property mediating the wake-promoting
effects of currently available CNS stimulants.
1. Modafinil for
sustaining the alertness of helicopter pilots
2. Modafinil augmentation
of antidepressant treatment
3. Modafinil the
unique properties of a new stimulant
4. Modafinil children
with attention-deficit/hyperactivity disorder
5. Modafinil dosage
and safety
6. Modafinil successful
treatment of hypersomnia & narcolepsy
7. Modafinil narcolepsy:
symptoms and management
8. Modafinil
amplification of cortical serotonin release
9. Modafinil
treatment of alcoholic organic brain syndrome
10. Modafinil
effect on melatonin, cortisol, and growth hormone
11. Modafinil
in obstructive sleep apnea-hypopnea syndrome
12. Modafinil
vs dextroamphetamine in treatment of adult ADHD
13. Modafinil
efficacy in narcolepsy
14. Modafinil
switching from narcolepsy drugs to modafinil
15. Modafinil
dopaminergic transmission mediates CNS stimulants
