CNS site of action and brainstem circuitry responsible for the intravenous effects of nicotine on gastric tone.
The purposes of our study were to determine (1) the effects of intravenous (i.v.) nicotine on gastric mechanical function of anesthetized rats, (2) the CNS site of action of nicotine to produce these effects, (3) the CNS nicotinic acetylcholine receptor (nAChR) subtype(s) responsible for mediating the i.v. effects of nicotine, and (4) the brainstem neurocircuitry engaged by i.v. nicotine for eliciting its gastric effects. This was accomplished by monitoring intragastric pressure (gastric tone) and contractility of the fundus and antrum while administering five doses of i.v. nicotine and microinjecting nicotine into specific brainstem nuclei. Additionally, c-Fos expression in the brainstem after i.v. nicotine and pharmacological agents were used as tools to identify the CNS site and circuitry and reveal the nAChR subtype(s) mediating the gastric effects of nicotine. Using these experimental approaches, we found the following. (1) When given intravenously in doses of 56.5, 113, 226, 452, and 904 nmol/kg, nicotine elicited only inhibitory effects on gastric mechanical function. The most sensitive area of the stomach to nicotine was the fundus, and this effect was mediated by the vagus nerve at doses of 56.5, 113, and 226 nmol/kg. (2) The CNS site of action and nAChR subtype responsible were glutamatergic vagal afferent nerve terminals in the medial subnucleus of the tractus solitarious (mNTS) and alpha4beta2, respectively. (3) The brainstem neurocircuitry that was involved appeared to consist of a mNTS noradrenergic pathway projecting to the dorsal motor nucleus of the vagus (DMV). This pathway seems to be activated via nitriergic interneurons engaged by vagally released glutamate in the mNTS and results in alpha2 adrenergic receptor-mediated inhibition of DMV neurons projecting to the fundus and controlling gastric tone.
Ferreira
Manuel
M
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.
Sahibzada
Niaz
N
Shi
Min
M
Panico
William
W
Niedringhaus
Mark
M
Wasserman
Adam
A
Kellar
Kenneth J
KJ
Verbalis
Joseph
J
Gillis
Richard A
RA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008365:Manometry; D008845:Microinjections; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011312:Pressure; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000145:classification / Q000378:metabolism; D013270:Stomach / Q000187:drug effects* / Q000294:innervation / Q000502:physiology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D018733:Nicotinic Antagonists; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D011978:Receptors, Nicotinic; D009538:Nicotine