Differential c-Fos immunoreactivity in arousal-promoting cell groups following systemic administration of caffeine in rats.
Despite the widespread use of caffeine, the neuronal mechanisms underlying its stimulatory effects are not completely understood. By using c-Fos immunohistochemistry as a marker of neuronal activation, we recently showed that stimulant doses of caffeine activate arousal-promoting hypothalamic orexin (hypocretin) neurons. In the present study, we investigated whether other key neurons of the arousal system are also activated by caffeine, via dual immunostaining for c-Fos and transmitter markers. Rats were administered three doses of caffeine or saline vehicle during the light phase. Caffeine at 10 and 30 mg/kg, i.p., increased motor activities, including locomotion, compared with after saline or a higher dose, 75 mg/kg. The three doses of caffeine induced distinct dose-related patterns of c-Fos immunoreactivity in several arousal-promoting areas, including orexin neurons and adjacent neurons containing neither orexin nor melanin-concentrating hormone; tuberomammillary histaminergic neurons; locus coeruleus noradrenergic neurons; noncholinergic basal forebrain neurons that do not contain parvalbumin; and nondopaminergic neurons in the ventral tegmental area. At any dose used, caffeine induced little or no c-Fos expression in cholinergic neurons of the basal forebrain and mesopontine tegmentum; dopaminergic neurons of the ventral tegmental area, central gray, and substantia nigra pars compacta; and serotonergic neurons in the dorsal raphe nucleus. Saline controls exhibited only few c-Fos-positive cells in most of the cell groups examined. These results indicate that motor-stimulatory doses of caffeine induce a remarkably restricted pattern of c-Fos expression in the arousal-promoting system and suggest that this specific neuronal activation may be involved in the behavioral arousal by caffeine.
Deurveilher
Samüel
S
Department of Anatomy and Neurobiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.
Lo
Henry
H
Murphy
Jeremy A
JA
Burns
Joan
J
Semba
Kazue
K
D000818:Animals; D001143:Arousal / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000008:administration & dosage*; D002452:Cell Count / Q000379:methods; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D000697:Central Nervous System Stimulants; D016760:Proto-Oncogene Proteins c-fos; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D002110:Caffeine; D014446:Tyrosine 3-Monooxygenase