One of the major symptoms of
narcolepsy is
cataplexy, a sudden loss of muscle tone. Despite the advances in understanding the neuropathology of
narcolepsy,
cataplexy is still treated symptomatically with
antidepressants. Here, we investigate in a murine
narcolepsy model the hypothesis that the
antidepressants specifically blocking
norepinephrine reuptake are more potent in treating narcoleptic episodes than the
antidepressants blocking of
serotonin reuptake. Furthermore, we tested the effects of α1 receptor stimulation and blockade, respectively, on narcoleptic episodes.
Orexin-deficient mice were treated with different doses of the
norepinephrine reuptake inhibitor
reboxetine, the
serotonin reuptake inhibitor escitalopram, the α1 receptor agonist
cirazoline or the α1 receptor antagonist
prazosin. The effect of these treatments on narcoleptic episodes was tested. Additionally, potential treatment effects on locomotor activity in an open-field were tested.
Reboxetine (doses ≥0.55mg/kg) as well as
escitalopram (doses ≥3.0mg/kg) dose-dependently reduced the number of narcoleptic episodes in
orexin-deficient mice. The ED50 for
reboxetine (0.012mg/kg) was significantly lower than for
escitalopram (0.44mg/kg).
Cirazoline and
prazosin did not affect narcoleptic episodes. Furthermore,
cirazoline but not the other compounds reduced locomotor activity of the mice. The present study strongly supports the hypothesis that a specific blockade of
norepinephrine reuptake is more potent in treating
cataplexy than a specific blockade of
serotonin reuptake. This argues for the development of more specific
norepinephrine reuptake inhibitors for the treatment of
narcolepsy.