Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy.
OBJECTIVE
To determine if the dopaminergic system modulates cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice.


METHODS
Hypocretin/orexin knockout (i.e., narcoleptic) and wild-type mice were administered amphetamine and specific dopamine receptor modulators to determine their effects on sleep, cataplexy and sleep attacks.


METHODS
Hypocretin knockout (n = 17) and wild-type mice (n = 21).


METHODS
Cataplexy, sleep attacks and sleep-wake behavior were identified using electroencephalogram, electromyogram and videography. These behaviors were monitored for 4 hours after an i.p. injection of saline, amphetamine and specific dopamine receptor modulators (D1- and D2-like receptor modulators).


RESULTS
Amphetamine (2 mg/kg), which increases brain dopamine levels, decreased sleep attacks and cataplexy by 61% and 67%, suggesting that dopamine transmission modulates such behaviors. Dopamine receptor modulation also had powerful effects on sleep attacks and cataplexy. Activation (SKF 38393; 20 mg/kg) and blockade (SCH 23390; 1 mg/kg) of D1-like receptors decreased and increased sleep attacks by 77% and 88%, without affecting cataplexy. Pharmacological activation of D2-like receptors (quinpirole; 0.5 mg/kg) increased cataplectic attacks by 172% and blockade of these receptors (eticlopride; 1 mg/kg) potently suppressed them by 97%. Manipulation of D2-like receptors did not affect sleep attacks.


CONCLUSIONS
We show that the dopaminergic system plays a role in regulating both cataplexy and sleep attacks in narcoleptic mice. We found that cataplexy is modulated by a D2-like receptor mechanism, whereas dopamine modulates sleep attacks by a D1-like receptor mechanism. These results support a role for the dopamine system in regulating sleep attacks and cataplexy in a murine model of narcolepsy.
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
Christian R
CR
Burgess
Gavin
G
Tse
Lauren
L
Gillis
John H
JH
Peever
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D002385:Cataplexy / Q000503:physiopathology*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009290:Narcolepsy / Q000503:physiopathology; D019257:Quinpirole / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects; D012457:Salicylamides / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects*; D014743:Videotape Recording
D001552:Benzazepines; D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; C534628:SCH 23390; D012457:Salicylamides; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000661:Amphetamine; C045989:eticlopride