title: Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats.
abstract: BACKGROUND
  N-Methyl-d-aspartate (NMDA) receptor antagonism and GABA(A) receptor activation are believed to be critical targets for general anesthetic action. However, as NMDA antagonism of intravenous anesthetic agents causes post-anesthetic emergence reactions such as hallucination and agitation, while the GABA(A)-mimetic intravenous anesthetic agents do not, these two classes of intravenous anesthetic agents produce differential clinical profiles.
  
  
  OBJECTIVE
  We have investigated the differential effects of the GABA(A) agonists propofol and midazolam and the NMDA antagonist ketamine on noradrenaline release from the medial prefrontal cortex of the rat using microdialysis, as noradrenergic neurons have a role to play in anesthesia and are known to be important in the control of sleep, attention and learning.
  
  
  METHODS
  Twenty-one male Wistar rats (200-270 g) were randomly allocated into three groups: ketamine 100 mg x kg(-1) (n = 6), propofol 60 mg x kg(-1) (n = 8) and midazolam 5 mg x kg(-1) (n = 7) IP. A unilateral guide cannula was implanted stereotaxically into the medial prefrontal cortex under pentobarbital anesthesia (50 mg x kg(-1) IP). Forty-eight hours later, a dialysis probe was inserted through the guide cannula, and perfused with an artificial cerebrospinal fluid solution containing 1 mM pargyline. Following an equilibration period, samples of dialysate were collected every 10 min. Noradrenaline content was measured by high-performance liquid chromatography using an electrochemical detector.
  
  
  RESULTS
  Anesthesia times, defined as the duration between the loss of righting reflex and recovery, were 24.7+/-5.6 (SEM), 20.5+/-1.9 and 25.2+/-1.5 min for propofol, midazolam and ketamine, respectively (no significant between-group differences). Both GABA(A )agonists, propofol and midazolam, significantly decreased noradrenaline release (75% and 71% of basal release, respectively). The NMDA antagonist ketamine markedly increased noradrenaline release (413% of basal).
  
  
  CONCLUSIONS
  These data suggest that different clinical profiles observed with these two classes of sedatives may result from changes in noradrenaline release from the medial prefrontal cortex.
authors.affiliation: Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036-8216, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kubota
authors.forename: K
authors.initials: K
authors.lastname: Hirota
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: N
authors.initials: N
authors.lastname: Anzawa
authors.forename: H
authors.initials: H
authors.lastname: Ohkawa
authors.forename: T
authors.initials: T
authors.lastname: Kushikata
authors.forename: A
authors.initials: A
authors.lastname: Matsuki
mesh_terms: D000818:Animals; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D008874:Midazolam; D009638:Norepinephrine; D015742:Propofol