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J Physiol Volume 560, Number 2, 587-592, October 15, 2004 DOI: 10.1113/jphysiol.2004.070573
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Developmental changes in CSF hypocretin-1 (orexin-A) levels in normal and genetically narcoleptic Doberman pinschers

Joshi John1,2, Ming-Fung Wu1,2, Nigel T Maidment1, Hoa A Lam1, Lisa N Boehmer1,2, Melanie Patton1,2 and Jerome M Siegel1,2,3

1 Department Psychiatry, University of California at Los Angeles, Los Angeles, CA 90095, USA
2 Neurobiology Research (151A3), Veterans Administration Greater Los Angeles Healthcare System, North Hills, CA 91343, USA
3 Brain Research Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA

Loss of hypocretin cells or mutation of hypocretin receptors causes narcolepsy. In canine genetic narcolepsy, produced by a mutation of the Hcrtr2 gene, symptoms develop postnatally with symptom onset at 4 weeks of age and maximal symptom severity by 10–32 weeks of age. Canine narcolepsy can readily be quantified. The large size of the dog cerebrospinal fluid (CSF) cerebellomedullary cistern allows the withdrawal of sufficient volumes of CSF for accurate assay of hypocretin levels, as early as postnatal day 4. We have taken advantage of these features to determine the relation of CSF hypocretin levels to symptom onset and compare hypocretin levels in narcoleptic and normal dogs. We find that by 4 days after birth, Hcrtr2 mutants have significantly higher levels of Hcrt than normal age- and breed-matched dogs. These levels were also significantly higher than those in adult narcoleptic and normal dogs. A reduction followed by an increase in Hcrt levels coincides with symptom onset and increase in the narcoleptics. The Hcrtr2 mutation alters the normal developmental course of hypocretin levels.

(Received 24 June 2004; accepted after revision 9 August 2004; first published online 12 August 2004)
Corresponding author J. M. Siegel: UCLA/VAGLAHS – Sepulveda, Neurobiology Research (151A3), 16111 Plummer Street, North Hills, CA 91343, USA. Email: jsiegel{at}ucla.edu






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