The effects of propofol in the area postrema of rats.
Propofol has an antiemetic effect that may be mediated by gamma-aminobutyric acid (GABA) influences on the serotonin system, the mechanism of which is not known. We used three techniques, immunohistochemistry, High Performance Liquid Chromatography, and electrophysiology, to define propofol's effects on the rat's brainstem. Paired male Wistar rats received propofol, 20 mg/kg/hr, or Intralipid for 6 h. The brains were then subjected to immunohistochemical analysis of serotonin. In a separate experiment after a propofol or Intralipid infusion, cerebrospinal fluid (CSF) was extracted from the fourth ventricle and analyzed for the amount of serotonin and 5-hydroxyindoleacetic acid. Electrophysiological neuronal recordings were made in the area postrema (AP) in response to propofol with and without a GABA or serotonin antagonist. Results showed that immunohistochemical staining for serotonin in the propofol rats was significantly increased (28 +/- 12%) in the dorsal raphe and decreased in the AP (17 +/- 6%) compared with control. There were no significant changes in the isoflurane-anesthetized animals. Both serotonin and 5-hydroxyindoleacetic acid in the CSF of the fourth ventricle at the level of the AP were significantly reduced by 63% and 36%, respectively. Both propofol and pentobarbital injections reduce AP neuronal activity, but only the propofol response was blocked by bicuculline, a GABA antagonist. We conclude that the reduced levels of serotonin in the AP and the CSF may explain the antiemetic property of propofol. Propofol may also directly act on AP neurons via a GABA(A) receptor to reduce their activity.


CONCLUSIONS
Propofol may produce its antiemetic effect by depleting the area postrema of serotonin as well as by a direct gamma-aminobutyric acid-mediated inhibition.
Departments of Anatomy and Cell Biology and Physiology, University of Western Ontario, London, Ontario. cechetto@julian.uwo.ca
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D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D004594:Electrophysiology; D020546:Fourth Ventricle / Q000187:drug effects* / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008839:Microelectrodes; D010424:Pentobarbital / Q000494:pharmacology; D020250:Postoperative Nausea and Vomiting / Q000503:physiopathology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000134:cerebrospinal fluid; D012702:Serotonin Antagonists / Q000494:pharmacology; D013238:Stereotaxic Techniques
D018686:Anesthetics, Intravenous; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D010424:Pentobarbital; D015742:Propofol