The norepinephrine reuptake inhibitor reboxetine is more potent in treating murine narcoleptic episodes than the serotonin reuptake inhibitor escitalopram.
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.
Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany.
Christian
C
Schmidt
Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany; Integrative Neuroscience Program, Otto-von-Guericke University Magdeburg, Germany.
Judith
J
Leibiger
Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany; Center of Behavioral Brain Sciences, Magdeburg, Germany. Electronic address: markus.fendt@med.ovgu.de.
Markus
M
Fendt
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009290:Narcolepsy / Q000188:drug therapy* / Q000235:genetics; D000068797:Orexins / Q000172:deficiency* / Q000235:genetics; D000077593:Reboxetine; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D015283:Citalopram; D009025:Morpholines; D000068797:Orexins; D000077593:Reboxetine; D017367:Selective Serotonin Reuptake Inhibitors
Antidepressants; Escitalopram; Narcolepsy; Narcoleptic episodes; Reboxetine