Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids.
Mice housed in social isolation exhibit a decreased response to gamma-aminobutyric acid-mimetic drugs [i.e., pentobarbital (PTB)] associated with a down-regulation of telencephalic allopregnanolone (Allo) levels. In these mice, the PTB-induced loss of righting reflex is greatly reduced. Fluoxetine (FLX) and norfluoxetine (NFLX) stereospecifically reverse the effect of social isolation on the PTB-induced loss of righting reflex and on the decrease of telencephalic Allo content. The S-isomers of FLX and NFLX are 2- and 7-fold more potent, respectively, than their respective R-isomers. The EC(50)s of FLX and NFLX required to normalize brain Allo content and PTB action are 10-50 times lower than the IC(50)s required for selective serotonin reuptake inhibitor activity. We conclude that normalization of PTB action elicited by the S-isomers of FLX and NFLX is related to the reversal of the down-regulation of brain Allo content and is independent of selective serotonin reuptake inhibitor activity.
Pinna
Graziano
G
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
Costa
Erminio
E
Guidotti
Alessandro
A
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010424:Pentobarbital / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013237:Stereoisomerism
D005473:Fluoxetine; D006993:Hypnotics and Sedatives; D010424:Pentobarbital; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine