Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs
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- PMID:11382896
- PMCID: PMC8846547
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Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs
J John et al. Sleep Res Online.2000.
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Abstract
Recent work has implicated the hypocretin (orexin) system in the genesis of narcolepsy. In the current study we demonstrate that systemically administered hypocretin-1 (Hcrt-1) produces an increase in activity level, longer waking periods, a decrease in REM sleep without change in nonREM sleep, reduced sleep fragmentation and a dose dependent reduction in cataplexy in canine narcoleptics. Repeated administration of single daily doses of Hcrt-1 led to consolidation of waking and sleep periods and to a complete loss of cataplexy for periods of three or more days after treatment in animals that were never asymptomatic under control conditions. Systemic administration of Hcrt-1 may be an effective treatment for narcolepsy.
Figures
a: Intravenous injection of Hcrt-1 produced a dose dependent change in cataplexy. b: FECT time also showed a dose dependent change. Doses of 1 and 2 /ug/kg did not affect cataplexy. Doses of 3 /ug/kg produced a significant decrease in the number of falls (a) and in the time it took to consume the food (eating time + cataplexy time) (b). In contrast, 4 /ug/kg doses significantly increased the number of falls (a) and the time required to consume the food (b) relative to baseline (dotted line). c–d: In the two dogs tested with repeated doses of Hcrt-1, a complete suppression of cataplexy resulted following the last dose. c: Three doses of Hcrt-1 produced a complete suppression of cataplexy for three consecutive days. d: In a more severely affected dog, the administration of five doses of Hcrt-1 produced a complete suppression of cataplexy during the FECT observed on three tests given over a six day period. c’ and d’ show the FECT time on the days of the tests in c and d respectively. Arrows indicate days in which the FECT was done with Hcrt-1 treatment, and doses are indicated in parentheses. On all the other days animals were tested after the administration of the same volume of saline. All values in a and b are mean ±SE; P=average of pretreatment days, +p<0.05, ++p<0.01, +++p<0.001 compared to saline control, /-test; *p<0.05, **p<0.0l, between doses, Newman-Keuls test,t indicates no cataplexy attacks observed during the FECT.
a:Polygraphic sleep-wake data for the 4 h periods after Hcrt-1 (3 /ug/kg) in comparison to the same periods after normal saline shows a significant decrease in REM sleep. b: Sleep-wake a\ctigraph data show a significant increase in sleep bout duration and a decrease in frequency during the dark period after Hcrt-1. c: Changes in wake bout duration and frequency (in 24-hour period). Pre=saline control before Hcrt-1; AW=active wake; QW=quite wake; nonREM=non-rapid eye movement sleep; REM=rapid eye movement sleep. All values are mean ±SE;tp<0.05 compared to saline control,t-test; *p<0.05, **p<0.01, compared to pre-treatment level, Newman-Keuls test.
a: A representative actigraph record (5 min bins) showing the activity level of a dog during the 2 h period following Hcrt-1 (3 /ug/kg) and normal saline administration. Hcrt-1 produced an increase in motor activity within 5 minutes of injection that persisted for 60 minutes. b: The increase of motor activity was statistically significant at 0–30 and 30–60 minutes after Hcrt-1 administration (n=6), as compared to saline control (n=6). In b values are mean ±SE, *p<0.05; **p<0.01, Newman-Keuls test.
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