Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy

Abstract

Study Objectives: To determine if the dopaminergic system modulates cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice. Design: 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. Patients or Participants: Hypocretin knockout (n = 17) and wild-type mice (n = 21). Interventions: 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). Measurements and Results: Amphetamine (2mg/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; 20mg/kg) and blockade (SCH 23390; 1mg/kg) of D1-like receptors decreased and increased sleep attacks by 77% and 88%, without affecting cataplexy. Pharmacological activation of D2-like receptors (quinpirole; 0.5mg/kg) increased cataplectic attacks by 172% and blockade of these receptors (eticlopride; 1mg/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.