Food consumption and activity levels increase in rats following intranasal Hypocretin-1.
Hypocretin-1 (HC, orexin-A) is a neuropeptide involved in regulating physiological functions of sleep, appetite and arousal, and it has been shown that intranasal (IN) administration can target HC to the brain. Recent clinical studies have shown that IN HC has functional effects in human clinical trials. In this study, we use rats to determine whether IN HC has an immediate effect on food consumption and locomotor activity, whether distribution in the brain after IN delivery is dose-dependent, and whether MAPK and PDK1 are affected after IN delivery. Food intake and wheel-running activity were quantified for 24h after IN delivery. Biodistribution was determined 30min after IN delivery of both a high and low dose of 125I-radiolabelled HC throughout the brain and other bodily tissues, while Western blots were used to quantify changes in cell signaling pathways (MAPK and PDK1) in the brain. Intranasal HC significantly increased food intake and wheel activity within 4h after delivery, but balanced out over the course of 24h. The distribution studies showed dose-dependent delivery in the CNS and peripheral tissues, while PDK1 was significantly increased in the brain 30min after IN delivery of HC. This study adds to the growing body of evidence that IN administration of HC is a promising strategy for treatment of HC related behaviors.
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
Shyeilla V
SV
Dhuria
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
Jared M
JM
Fine
Center for Immunochemistry, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, United States.
Deborah
D
Bingham
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
Aleta L
AL
Svitak
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
Rachel B
RB
Burns
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
Amanda M
AM
Baillargeon
Center for Immunochemistry, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, United States.
Scott S
SS
Panter
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
Abdul N
AN
Kazi
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States.
William H
WH
Frey
HealthPartners Institute for Education and Research, Center for Memory and Aging, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, United States. Electronic address: Leah.R.Hanson@HealthPartners.com.
Leah R
LR
Hanson
D000281:Administration, Intranasal; D000818:Animals; D001923:Brain Chemistry; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D000068797:Orexins / Q000008:administration & dosage* / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000737:chemistry
D000068797:Orexins; C000631429:PDK1 protein, human; C000631434:Pdk1 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1
Appetite; Hypocretin-1; Intranasal; MAPK; Orexin-A; PDK1