Stimulus generalization by fenfluramine in a quipazine-ketanserin drug discrimination is not dependent on indirect serotonin release.
The purpose of this study was to determine if animals trained to discriminate a serotonin2A (5-HT2A) receptor agonist from a 5-HT2A receptor antagonist would also be sensitive to alterations in serotonin neurotransmission brought about by 5-HT reuptake inhibitors and releasers. Previous work from our laboratory has shown that the quipazine-ketanserin discrimination is mediated solely by the 5-HT2A receptor, thus providing a behavioral continuum of 5-HT2A receptor function. Rats were trained to discriminate quipazine (0.35 mg/kg) from ketanserin (1.0 mg/kg) on a variable interval-30 schedule of reinforcement. Following acquisition, substitution tests were conducted with the training drug, quipazine, and agents that have been shown to alter the synaptic levels of 5-HT, including fenfluramine, norfenfluramine, 5-methoxy-6-methyl-2-aminoindan (MMAI) and fluoxetine. All compounds substituted, except fluoxetine. Antagonist tests with mianserin and MDL 100,907 indicated that fenfluramine's and MMAI's substitution for quipazine was mediated by the 5-HT2A receptor. Animals were pretreated with PCPA to determine whether 5-HT release or direct agonism mediated the discriminative stimulus effects of fenfluramine and MMAI. PCPA blocked the substitution of MMAI but not of fenfluramine for quipazine. Analysis of 3H-IP formation in cells showed that norfenfluramine dose-dependently stimulated phosphoinositide hydrolysis to levels similar to that of serotonin and quipazine. These results indicate that fenfluramine's substitution for quipazine in rats trained on a quipazine-ketanserin discrimination are due to direct agonism at the 5-HT2A receptor likely mediated by norfenfluramine, an active metabolite.
Smith
Randy L
RL
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
Gresch
Paul J
PJ
Barrett
Robert J
RJ
Sanders-Bush
Elaine
E
D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D011814:Quipazine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D005277:Fenfluramine; D012701:Serotonin; D011814:Quipazine; D007650:Ketanserin