Gaboxadol, a selective extrasynaptic GABA(A) agonist, does not generalise to other sleep-enhancing drugs: a rat drug discrimination study.
Gaboxadol is a selective extrasynaptic GABA(A) receptor agonist (SEGA) which enhances slow-wave sleep, and may act principally at extrasynaptic GABA(A)alpha4betadelta receptors. Drug discrimination is a very useful approach for exploring in vivo pharmacological similarities and differences between compounds and was therefore used to compare gaboxadol and zolpidem, an established hypnotic drug, against zopiclone, S-zopiclone, indiplon and tiagabine, all of which have been reported to enhance sleep. Gaboxadol generalised to itself, but not to zolpidem, zopiclone, S-zopiclone, R-zopiclone, indiplon or tiagabine. By contrast, zolpidem generalised to itself, zopiclone, S-zopiclone and indiplon, but not to R-zopiclone (the inactive enantiomer of zopiclone), gaboxadol or tiagabine. This suggests that zolpidem, zopiclone, S-zopiclone and indiplon share a discriminative stimulus, which may be mediated by their efficacy at GABA(A)alpha1betagamma receptors. Gaboxadol and tiagabine each have a different discriminative stimulus from all the other drugs tested.
McDonald
L M
LM
Neuroscience Research Centre, Merck, Sharp and Dohme, Terlings Park, Harlow, Essex CM21 2QR, UK. LouiseMcDonald1@gmail.com
Sheppard
W F
WF
Staveley
S M
SM
Sohal
B
B
Tattersall
F D
FD
Hutson
P H
PH
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004347:Drug Interactions; D018755:GABA Agonists / Q000494:pharmacology*; D005793:Generalization, Psychological / Q000187:drug effects*; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects*
D018755:GABA Agonists; D007555:Isoxazoles; C015542:gaboxadol