Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-100635.
Rats were trained to discriminate the specific 5-HT1A receptor agonist (+)-flesinoxan (R(+)-N(-)[2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4- benzodioxin-5-yl)-1-piperazinyl]ethyl]-4-fluorobenzoamide) (1.5 mg/kg p.o.) from water in a two-lever operant procedure. Generalization tests were conducted with the enantiomers and racemate of flesinoxan and the 5-HT1A receptor antagonists (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) and WAY-100635 ((N(-)[2(-)[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). (S)-UH301, WAY-100635 and fentanyl were investigated for their antagonistic properties. The (+)-flesinoxan stimulus generalized to (-)-flesinoxan and the racemate. The ED50 values for generalization corresponded well with the affinities of the enantiomers and the racemate for the 5-HT1A receptor. The flesinoxan cue could not be mimicked by (S)-UH301 or WAY-100635, but (S)-UH301 reduced response rates. Antagonism tests showed that both (S)-UH301 and WAY-100635 dose dependently antagonized the flesinoxan cue, with ID50 values of 0.52 and 0.03 mg/kg s.c., respectively. Fentanyl had no significant antagonistic properties. It is concluded that rats can learn to discriminate orally administered (+)-flesinoxan from water. The generalization of flesinoxan to the (-)-enantiomer and the antagonism of flesinoxan's cue by specific 5-HT1A receptor antagonists are further evidence for the involvement of flesinoxan's 5-HT1A receptor agonistic properties in its discriminative stimulus effects.
Gommans
J
J
Department of Psychopharmacology, Faculty of Pharmacy, Utrecht University, Netherlands.
Hijzen
T H
TH
Maes
R A
RA
Mos
J
J
Olivier
B
B
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology; D005793:Generalization, Psychological / Q000187:drug effects; D007279:Injections, Subcutaneous; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; C064282:UH 301; C056895:flesinoxan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005283:Fentanyl