Sleep suppressant action of fenfluramine in rats. II. Evidence against the involvement of presynaptic serotonergic mechanism.
The present study investigated the involvement of presynaptic serotonergic mechanisms in the sleep suppressant action of fenfluramine, an indirect serotonin (5-HT) receptor agonist. Rats implanted with cerebrocortical and dorsal neck muscle electrodes were pretreated with either fluoxetine, an inhibitor of 5-HT uptake, or p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis. Animals were continuously monitored by the EEG for 12 hr after an i.p. injection of 5 mg/kg of dl-fenfluramine hydrochloride. Pretreatment with fluoxetine failed to antagonize the fenfluramine-induced suppression of slow-wave sleep and rapid-eye-movement sleep. However, chemical analyses showed that fluoxetine pretreatment completely prevented the depletion of brain 5-HT produced by fenfluramine, suggesting that fenfluramine did not gain entry into serotonergic neurons. Depletion of brain 5-HT by PCPA also failed to antagonize the sleep suppression caused by fenfluramine as well as that observed after administration of quipazine, a direct 5-HT receptor stimulant. Because administration of fenfluramine to PCPA-pretreated rats produced no additional depletion of 5-HT, it appears that 5-HT was no longer available for release by fenfluramine in these animals. Furthermore, neither pretreatment with fluoxetine nor PCPA antagonized the head-shaking induced by fenfluramine, a behavior associated with activation of central 5-HT receptors. These data indicate that the suppression of sleep produced by fenfluramine is not mediated through release of 5-HT as brain 5-HT concentrations were not related to the behavioral effects of the drug. The sleep suppressant action of fenfluramine may therefore result from a direct action of the drug on postsynaptic 5-HT receptors.
D000818:Animals; D004569:Electroencephalography; D010134:Fenclonine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D011814:Quipazine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012890:Sleep / Q000187:drug effects*; D013569:Synapses / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects
D011985:Receptors, Serotonin; D005473:Fluoxetine; D005277:Fenfluramine; D012701:Serotonin; D011814:Quipazine; D010134:Fenclonine