Developmental regulation of nicotinic acetylcholine receptor-mediated [3H]norepinephrine release from rat cerebellum.
Presynaptic modulation of synaptic transmission is the primary function of central nicotinic acetylcholine receptors (nAChRs) in developing and adult brain. nAChR activation regulates release of various neurotransmitters, including norepinephrine (NA). Given evidence that NA may serve a critical functional role in cerebellar development, we have undertaken studies to determine whether nAChRs modulate NA release in developing cerebellum. In vitro experiments using cerebellar slices examined the effects of nAChR stimulation on release of radiolabeled NA ([3H]NA). Our data indicate the presence of functional nAChRs on NA terminals in immature cerebellum and subsequent developmental regulation of receptor properties. During postnatal week one, the maximally effective dose of nicotine released 35.0 +/- 1.2% of cerebellar [3H]NA stores. There was a subsequent decline in maximal nicotine-stimulated NA release until postnatal day 30, when Emax values were statistically indistinguishable from adult. Although the efficacy of nicotine changed substantially throughout development, EC50 values did not differ significantly (EC50 = 4.4-12.0 micro m). Pharmacological analysis indicated that this developmental shift in maximum nicotine effect reflects a change in the properties of the nAChRs. These data support recent findings of a possible functional role of nAChRs in regulating cerebellar ontogeny, and provides further support for the role of NA as a neurotrophic factor during development.
O'Leary
K T
KT
Department of Anatomy and Neurobiology, College of Medicine, University of California, Irvine, CA 92697, USA. olearyk@uci.edu
Leslie
F M
FM
D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism* / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors; D014316:Tritium
D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011978:Receptors, Nicotinic; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; D014316:Tritium; C011386:nisoxetine; D009538:Nicotine; D009638:Norepinephrine