Microinjection of propofol into the perifornical area induces sedation with decreasing cortical acetylcholine release in rats.
BACKGROUND
Among many neurotransmitter systems in the central nervous system, the cholinergic system has been shown to contribute to propofol's sedative/anesthetic effects, because it has been shown that cholinesterase inhibitor reverses the level of propofol-induced unconsciousness in humans. It has been reported that intraperitoneal injection of propofol induced sedative/anesthetic actions and decreased the release of acetylcholine (Ach) from the rat cortex. However, the sites of action of propofol in the cholinergic pathway and its related pathways remain unresolved. We studied whether microinjection of propofol into the nuclei in the cholinergic pathway and its related pathways may induce sedation and decrease Ach from the cortex.


METHODS
Thirty-seven male Wistar rats weighing 270 to 320 g were used. Almost 5 days before the experiments, 23 rats anesthetized with pentobarbital (50 mg/kg) were outfitted with an electroencephalogram (EEG) socket, a microdialysis cannula in the cortex, and an intraperitoneal tube or a microinjection tube into the basal forebrain (BF), the perifornical area (Pef), or the striatum. The Ach effluxes in the somatosensory cortex were detected using in vivo intracerebral microdialysis in freely moving rats. Once basal levels of Ach were stabilized, samples were collected every 20 minutes and measured by high-performance liquid chromatography. In the intraperitoneal group, propofol was cumulatively administered (10, 30, and 100 mg/kg) into the peritoneal cavity. In the microinjection groups, propofol (40 ng in 0.2 microL) was administered into the BF, the Pef, or the striatum (control), and the cortical changes in Ach efflux and EEG were observed for 2 hours. In another 14 rats, the sedative/anesthetic score was obtained after intraperitoneal, Pef, or striatal injection of propofol. The placement of the tip of the microdialysis probe and the microinjection tube was confirmed by histological examination.


RESULTS
Intraperitoneal injection of propofol dose-dependently decreased the Ach efflux and induced light sedative to moderate anesthetic states. Loss of righting reflex was observed with significant increases in the relative alpha-power band at 100 mg/kg propofol. Microinjection of propofol into the BF significantly decreased the cortical Ach efflux to -40.2% + or - 19.9% at 40 to 60 minutes. However, there was no difference in the total Ach efflux for 2 hours between BF and control groups. In contrast, microinjection of propofol into the Pef immediately decreased the Ach efflux at 0 to 20 min and maximally to -59.3 + or - 20.4 at 100 to 120 minutes. The total Ach efflux in the Pef microinjection group was significantly less than that in the control group. The same dose of propofol injected into the Pef induced light to deep sedation. There was no significant change in the relative EEG power band between BF or Pef and control groups.


CONCLUSIONS
The nuclei in the Pef are, at least in part, responsible for the sedative action of propofol in rats.
Gamou
Sanae
S
Department of Anesthesiology, Teikyo University School of Medicine, 1-21-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Fukuda
Satoru
S
Ogura
Mai
M
Sakamoto
Hidetoshi
H
Morita
Shigeho
S
D000109:Acetylcholine / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage*; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D003243:Consciousness / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004569:Electroencephalography; D006993:Hypnotics and Sedatives / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D008845:Microinjections; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013003:Somatosensory Cortex / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D000109:Acetylcholine; D015742:Propofol