Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs.
A growing amount of evidence suggests that a deficiency in hypocretin/orexin neurotransmission is critically involved in animal and human forms of narcolepsy. Since hypocretin-containing neurons innervate and excite histaminergic tuberomammillary neurons, altered histaminergic neurotransmission may also be involved in narcolepsy. We found a significant decrease in histamine content in the cortex and thalamus, two structures important for histamine-mediated cortical arousal, in Hcrtr-2 mutated narcoleptic Dobermans. In contrast, dopamine and norepinephrine contents in these structures were elevated in narcoleptic animals, a finding consistent with our hypothesis of altered catecholaminergic transmission in these animals. Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy.
Nishino
S
S
Stanford University Center for Narcolepsy, 701B, First Floor, Palo Alto, CA 94304, USA. nishino@stanford.edu
Fujiki
N
N
Ripley
B
B
Sakurai
E
E
Kato
M
M
Watanabe
T
T
Mignot
E
E
Yanai
K
K
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004285:Dogs; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D006632:Histamine / Q000032:analysis / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D009290:Narcolepsy / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000235:genetics*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013788:Thalamus / Q000737:chemistry / Q000378:metabolism
C578626:HCRTR2 protein, human; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D006632:Histamine; D004298:Dopamine; D009638:Norepinephrine