Discriminative stimulus properties of (+/-)-fenfluramine: the role of 5-HT2 receptor subtypes.
The role of serotonin 5-HT2 receptors (5-HT2R) in the discriminative stimulus effects of fenfluramine was investigated. Male Sprague-Dawley rats were trained to discriminate (+/-)-fenfluramine (2 mg/kg ip) from saline using a 2-lever, water-reinforced paradigm. Drug-lever responding after fenfluramine was dose-dependent. The 5-HT(2C/1B)R agonist mCPP and the 5-HT(2C)R agonist MK 212 fully substituted, whereas the 5-HT(2A/2C)R agonist DOI partially substituted, for the training drug. The 5-HT(2B)R agonist BW 723C86 engendered saline-lever responding. The 5-HT(2C/2B)R antagonist SB 206553 completely antagonized the fenfluramine discrimination a well as the full substitutions of mCPP and MK 212 and the partial substitution of DOI. The selective 5-HT(2A)R antagonist M100907 partially suppressed the stimulus effects of fenfluramine, mCPP, and MK 212 and almost fully attenuated the partial substitution of DOI. RS 102221, a selective 5-HT(2C)R antagonist that does not cross the blood-brain barrier, did not alter the fenfluramine cue. Results demonstrate that the discriminative stimulus effects of fenfluramine are centrally mediated by 5-HT(2C)R and to some extent by 5-HT(2A)R.
McCreary
Andrew C
AC
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555, USA.
Filip
Malgorzata
M
Cunningham
Kathryn A
KA
D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D005277:Fenfluramine / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000502:physiology*; D012054:Reinforcement, Psychology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; C107821:8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione; D004338:Drug Combinations; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D011719:Pyrazines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D013449:Sulfonamides; D013876:Thiophenes; D005277:Fenfluramine; C014896:6-chloro-2-(1-piperazinyl)pyrazine; D007650:Ketanserin; C094868:SB 206553; C079049:volinanserin