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 (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.

Figure 1

Cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice. A and B: Raw EEG and EMG traces demonstrating the defining features of cataplexy and sleep attacks. C: Raw EEG and EMG traces showing masseter activity during cataplexy and a sleep attack. Note that muscle tone is absent during cataplexy, but cyclic during the sleep attack; this rhythmicity represents automatic chewing behavior, which is common in sleep attacks. D: Hypocretin knockout mice have significantly more REM sleep and a greater number of sleep-wake transitions than wild-type (WT) mice. *denotes P < 0.05 when compared to WT mice.

Figure 2

Amphetamine decreases sleep, sleep attacks and cataplexy. A: Amphetamine increased wakefulness and decreased both NREM and REM sleep in narcoleptic mice. B: Amphetamine increased wakefulness, decreased NREM sleep and abolished REM sleep in wild-type mice. C-E: Amphetamine decreased total time spent in sleep attacks (C) and attack frequency (D), but had no significant affect on sleep attack duration (E). F-H: Amphetamine reduced the frequency of cataplectic episodes (G), but had no measurable affect on the total time spent in cataplexy (F) or episode duration (H). *denotes P < 0.05 when compared to saline.

Figure 3

Inactivation of D1-like receptors increases sleep attacks. A: In narcoleptic mice, SCH 23390 (D1-like antagonist; 1mg/kg) increased NREM sleep and decreased wakefulness. B: In wild-type mice, SCH 23390 also increased NREM sleep and decreased wakefulness. C-E: SCH 23390 (1mg/kg) increased both the total time spent in sleep attacks (C) and sleep attack frequency (D), but had no affect on attack duration (E). F-H: SCH 23390 treatment had no affect on time spent in cataplexy (F) or on cataplexy frequency (G) or duration (H). *denotes P < 0.05 when compared to saline.

Figure 4

Activation of D1-like receptors decreases sleep attacks. A: In narcoleptic mice, SKF 38393 (D1-like agonist) decreased NREM sleep and increased wakefulness. B: In wild-type mice, SKF 38393 also decreased NREM sleep and increased wakefulness. C-E: SKF 38393 treatment decreased both the time spent in sleep attacks (C) and attack frequency (D), but had no affect on sleep attack duration (E). F-H: SKF 38393 had no affect on time spent in cataplexy (F) or on cataplexy frequency (G) or duration (H). *denotes P < 0.05 when compared to saline.

Figure 5

Activation of D2-like receptors increases cataplexy. A: Quinpirole (D2-like receptor agonist) had no affect on sleep-wake behavior in narcoleptic mice. B: Quinpirole also had no affect on sleep-wake behavior in wild-type mice. C-E: Quinpirole had no effect on the total time spent in sleep attacks (C) or on the frequency (D) or duration of attacks (E). F-H: Quinpirole did not significantly increase the total time spent in cataplexy (F), but at 0.5mg/kg it increased cataplexy frequency (G) without affecting duration (H). *denotes P < 0.05 when compared to saline.

Figure 6

Inactivation of D2-like receptors decreases cataplexy. A: In narcoleptic mice, 0.25mg/kg of eticlopride (D2-like antagonist) increased NREM sleep and decreased wakefulness, but at 1mg/kg it had no effect on sleep-wake behavior. B: Eticlopride had no effect on sleep-wake behavior in wild-type mice. C-E: Eticlopride had no effect on the total time spent in sleep attacks (C) or on the frequency (D) or duration of attacks (E). F-G: Eticlopride (1mg/kg) decreased both the total time spent in cataplexy (F) and its frequency (G) without affecting the duration of cataplectic episodes (H). *denotes P < 0.05 when compared to saline.