Injection Of Fenfluramine Research Articles

Metabolism of fenfluramine to norfenfluramine in guinea-pigs

After injection of fenfluramine into guinea-pigs, the N-dealkylated metabolite norfenfluramine was present in brain at higher concentrations and persisted longer than the parent drug, fenfluramine. Contrary to a claim in previous literature, the guinea-pig does metabolize fenfluramine to norfenfluramine, hence the ability of fenfluramine to cause acute and long-term depletion of brain 5-hydroxytryptamine in this species does not prove that fenfluramine, instead of nonfenfluramine, can produce these effects.

Ephedrine decreases vesicular monoamine transporter‐2 function

Ephedrine decreases vesicular monoamine transporter‐2 function

Serotonin (5‐HT) Transporter Ligands Affect Plasma 5‐HT in Rats

Dual dopamine (DA)/serotonin (5-HT)-releasing agents are promising candidate medications for stimulant addiction and other disorders. However, certain 5-HT transporter (SERT) substrates are associated with development of idiopathic pulmonary arterial hypertension (IPAH) and valvular heart disease (VHD). According to the "5-HT hypothesis," SERT substrates increase the risk for developing IPAH and VHD by increasing plasma 5-HT. To test this hypothesis directly, we determined the effects of acute and chronic fenfluramine, and other SERT ligands, on plasma 5-HT in male rats. For acute treatments, rats received i.v. vehicle or test drug (0.3 and 1.0 mg/kg), and serial blood samples were withdrawn. For chronic treatments, vehicle or test drug was infused via osmotic minipump (3 and 10 mg/kg/d) for 2 weeks. On the last day of infusion, rats received i.v. fenfluramine challenge (1 mg/kg), and serial blood samples were withdrawn. Plasma 5-HT was measured using ex vivo microdialysis in whole-blood samples. Baseline plasma 5-HT was <1.0 nM. Acute injection of fenfluramine or other SERT substrates caused large (up to 24-fold) dose-dependent increases in plasma 5-HT. Chronic fenfluramine at 3 and 10 mg/kg/d produced 1.7- and 3.5-fold increases in baseline plasma 5-HT, while chronic fluoxetine had no effect. Chronic infusions of fenfluramine or fluoxetine diminished the ability of acute fenfluramine to elevate dialysate 5-HT, and both drugs markedly reduced whole-blood 5-HT. Acute fenfluramine increases plasma 5-HT to concentrations that are below the micromolar levels necessary to produce adverse cardiovascular effects. Chronic fenfluramine and fluoxetine have minimal effects on plasma 5-HT, suggesting that the increased risk for IPAH associated with fenfluramine does not depend upon elevations in plasma 5-HT.

Effect of fenfluramine-induced increases in serotonin release on [18F]MPPF binding: A continuous infusion PET study in conscious monkeys

[(18)F]MPPF is a selective and reversible antagonist to the serotonin-1A (5-HT(1A)) receptor. The aim of the present study was to investigate whether the binding of [(18)F]MPPF is sensitive to increases in 5-HT levels. We used the 5-HT releasing agent and reuptake inhibitor fenfluramine (FEN) to increase the concentration of 5-HT. [(18)F]MPPF binding was assessed using positron emission tomography (PET) in conscious monkeys. Possible effects of blood flow on ligand binding were excluded by using a bolus-infusion paradigm. Control scans were obtained to assess the state of ligand equilibrium. FEN (5 or 10 mg/kg, i.v.) was administered between 90 and 130 min after the start of the [(18)F]MPPF infusion. The binding potential (BP) was calculated for an early interval (30 min preceding FEN administration) and late interval (20-50 min after administration of FEN). Microdialyses results showed a 20- and 35-fold increase in extracellular 5-HT levels in the prefrontal cortex after injection of FEN at a dose of 5 mg/kg and 10 mg/kg respectively. However, despite these large increases in 5-HT levels, no differences in BP were found between the control and FEN scans. These results may imply that the majority of 5-HT(1A) receptors is in the low affinity state in the living brain.

The potential of the beta-Microprobe, an intracerebral radiosensitive probe, to monitor the [(18)F]MPPF binding in the rat dorsal raphe nucleus.

The aim of this study was to demonstrate the ability of a recently developed beta(+)-range sensitive intracerebral probe (beta-Microprobe) to measure the binding kinetics of [(18)F]MPPF, a well-documented 5-HT(1A) serotoninergic receptor ligand, in the dorsal raphe nucleus (DRN) of the anaesthetised rat. This midbrain nucleus presents a high concentration of 5-HT(1A) receptors known to be implicated in the effects of antidepressants. The difficulty confronting this study lay in the fact that the dimensions of the DRN are smaller than the detection volume of the beta-Microprobe. In the first part of the study, we studied the feasibility of this measurement from a theoretical point of view by autoradiography and a Monte Carlo simulation. We determined the optimal beta-Microprobe location close to the DRN and verified that this configuration allowed accurate determination of [(18)F]MPPF specific binding in the nucleus. In the second part of our study, we measured the in vivo time-concentration curves of [(18)F]MPPF binding in the DRN in comparison with the cerebellum. The specificity of [(18)F]MPPF binding in the DRN was confirmed by its displacement after non-labelled 5-HT(1A)antagonist injection (MPPF or WAY-100635). Moreover, we verified the feasibility of using beta-Microprobe monitoring and simultaneous validation by microdialysis to study the effect of an increase in extracellular serotonin, induced by fenfluramine injection, on [(18)F]MPPF binding in the DRN. Our theoretical simulations, confirmed by our experimental results, demonstrate the ability of this new device to monitor in vivo the binding of [(18)F]MPPF in the DRN of anaesthetised rodents.

Effect of 5-HT on binding of [(11)C] WAY 100635 to 5-HT(IA) receptors in rat brain, assessed using in vivo microdialysis nd PET after fenfluramine.

By using a combination of positron emission tomography (PET) and postmortem tissue dissection, the effect of increased endogenous serotonin on specific binding of [(11)C]WAY 100635 to the 5-HT(1A) receptor was investigated in rat brain in vivo. The binding studies were complemented by in vivo microdialysis to monitor 5-HT levels in similarly treated isoflurane-anaesthetised rats, with the dialysis probe locations corresponding to two of the tissues sampled for specific binding of the radioligand. Fenfluramine treatment (10 mg/kg i.p.) resulted in a approximately 5-fold increase in extracellular 5-HT in medial prefrontal cortex and a approximately 15-fold increase in lateral hippocampus, maximal at approximately 40 min after injection. PET scan duration was either 60 or 90 min, beginning 30 min after fenfluramine injection. The specific binding of [(11)C]WAY 100635 was reduced by 10-20% in hippocampus, which showed highest binding in control animals. Specific binding, however, was unaffected in both prefrontal cortex and midbrain raphe, each additional high binding regions. The minimal effects are consistent with a low baseline occupancy of the 5-HT(1A) receptor by 5-HT in vivo, so that only a large change in endogenous agonist concentration will affect radioligand binding. This implies that utilisation of [(11)C]WAY 100635 in human PET to quantify 5-HT(1A) receptor expression can be extended to pathology where synaptic 5-HT levels are altered as a consequence of the disease state.

Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum: Interaction between the serotonergic, glutamatergic, and dopaminergic systems

Fenfluramine (FE) is a halogenated amphetamine derivative that has been used in the treatment of obesity. It has been suggested that the effects of FE on the striatum are mediated by serotonergic mechanisms. However, several major afferent systems may be involved, and administration of FE may be useful to study interactions between these systems. In this work, the effects of FE on striatopallidal neurons and the possible involvement of the major striatal afferent systems were studied in rats by determination of FE-induced changes in striatal levels of preproenkephalin (PPE) mRNA using in situ hybridization. Injection of FE induced a significant increase (60%) in striatal levels of PPE mRNA. This increase was blocked by pretreatment with the D(1) dopamine receptor antagonist SCH-23390 or with the NMDA glutamate receptor antagonist MK-801, or by lesion of the serotonergic system with 5,7-dihydroxytryptamine or p-chlorophenylalanine. In 6-hydroxydopamine lesioned rats, the lesion-induced increase in PPE mRNA levels was not affected by injection of FE, but was reduced by simultaneous serotonergic deafferentation. The results suggest that the serotonergic, glutamatergic, and dopaminergic system interact to increase striatal PPE mRNA levels after FE administration.

Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function

High-dose administrations of amphetamine, methamphetamine, cathinone, methcathinone or methylenedioxymethamphetamine rapidly decrease dopamine and serotonin transporter function in vivo, as assessed in striatal synaptosomes obtained from drug-treated rats. In contrast, high-dose injections of fenfluramine, cocaine or methylphenidate had little or no effect on the activity of these transporters. Interestingly, the capacity of these agents to directly alter dopamine and serotonin uptake, as assessed in vitro by direct application to rat striatal synaptosomes, did not predict their potential to modulate transporter activity following in vivo administration. These findings demonstrate heretofore-unreported differences in the effects of these agents on monoamine transporter function, and a distinction between drug effects after direct application in vitro vs. administration in vivo.

In vivo evidence for free radical involvement in the degeneration of rat brain 5-HT following administration of MDMA ('ecstasy') and p-chloroamphetamine but not the degeneration following fenfluramine.

1. Administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') to several species results in a long lasting neurotoxic degeneration of 5-hydroxytryptaminergic neurones in several regions of the brain. We have now investigated whether this degeneration is likely to be the result of free radical-induced damage. 2. Free radical formation can be assessed by measuring the formation of 2,3- and 2,5-dihydroxybenzoic acid (2,3-DHBA and 2,5-DHBA) from salicylic acid. An existing method involving implantation of a probe into the hippocampus and in vivo microdialysis was modified and validated. 3. Administration of MDMA (15 mg kg-1, i.p.) to Dark Agouti (DA) rats increased the formation of 2,3-DHBA (but not 2,5-DHBA) for at least 6 h. Seven days after this dose of MDMA, the concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) was reduced by over 50% in hippocampus, cortex and striatum, reflecting neurotoxic damage. There was no change in the concentration of dopamine or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. 4. p-Chloroamphetamine (PCA), another compound which produces a neurotoxic loss of cerebral 5-HT content, when given at a dose of 5 mg kg-1 also significantly increased the formation of 2.3-DHBA (but not 2,5-DHBA) in the dialysate for over 4.5 h. post-injection starting 2 h after treatment. 5. In contrast, fenfluramine administration (15 mg kg-1, i.p.) failed to increase the 2,3-DHBA or 2,5-DHBA concentration in the dialysate. A single fenfluramine injection nevertheless also markedly decreased the concentration of 5-HT and 5-HIAA in the hippocampus, cortex and striatum seven days later. 6. When rats pretreated with fenfluramine (15 mg kg-1, i.p.) seven days earlier were given MDMA (15 mg kg-1, i.p.) no increase in 2,3-DHBA was seen in the dialysate from the hippocampal probe. This indicates that the increase in free radical formation following MDMA is occurring in 5-HT neurones which have been damaged by the prior fenfluramine injection. 7. Administration of the free radical scavenging agent alpha-phenyl-N-tert-butyl nitrone (PBN; 120 mg kg-1, i.p.) 10 min before and 120 min after an MDMA (15 mg kg-1, i.p.) injection prevented the acute rise in the 2,3-DHBA concentration in the dialysate and attenuated by 30% the long term damage to hippocampal 5-HT neurones (as indicated by a smaller MDMA-induced decrease in both the concentration of 5-HT and 5-HIAA and also the binding of [3H]-paroxetine). 8. These data indicate that a major mechanism by which MDMA and PCA induce damage to 5-hydroxytryptaminergic neurones in rat brain is by increasing the formation of free radicals. These probably result from the degradation of catechol and quinone metabolites of these substituted amphetamines. In contrast, fenfluramine induces damage by another mechanism not involving free radicals; a proposal supported by some of our earlier indirect studies. 9. We suggest that these different modes of action render untenable the recent suggestion that MDMA will not be neurotoxic in humans because fenfluramine appears safe at clinical doses.

Behavioural and neurochemical characteristics of phentermine and fenfluramine administered separately and as a mixture in rats.

Clinical case studies suggest that combined administration of the serotonergic agent fenfluramine (FEN) and the weak amphetamine-like anorexic agent phentermine (PHEN) may be useful in the treatment of alcohol and cocaine addictions. The present experiment examined the nature of the interaction between the two agonists using the drug discrimination paradigm. In vivo microdialysis served to examine the neurochemical profile of dopamine and serotonin release in the nucleus accumbens. In conscious rats, acute injections of FEN (1.0-2.0 mg/kg i.p.) or PHEN (1.0-2.0 mg/kg i.p.) selectively elevated levels of serotonin and dopamine in the nucleus accumbens, respectively. A mixture (1 mg/kg of each) increased levels of both amines by similar magnitudes to those observed with each individually. Three groups of Sprague-Dawley rats were trained to discriminate (1) FEN (1.0 mg/kg i.p.) alone, (2) PHEN (1.0 mg/kg i.p.) alone or a mixture (3) PHEN+FEN (1 mg/kg of each, i.p.) from saline under a fixed ratio (FR-10) schedule of food reinforcement. Rats acquired the mixture discrimination rapidly, while for the other groups the training dose had to be increased to 2.0 mg/kg to attain stimulus control. The individual components of the mixture at the training dose generalized partially to the mixture, and complete generalisation was observed following 3.0 mg/kg FEN or PHEN. Rats trained to discriminate the individual components showed respective cross-generalisation profiles. Generalisation to cocaine (0.3-10.0 mg/kg i.p.), amphetamine (0.1-3.0 mg/kg i.p.) and nicotine (0.1-0.8 mg/kg s.c.) was greatest in the MIX-trained rats, while partial or no generalisation was observed in rats trained to discriminate the individual compounds. From the present results, it may be concluded that the two drugs given as a mixture do not produce a novel cue. Rather, these aminergics appear to interact additively. Furthermore, the dual stimulation of the amines by the mixture may be the basis for the cueing effects of the FEN+PHEN drug mixture, and its effectiveness in treating drug addictions.

Reinforcing effects of certain serotonin-releasing amphetamine derivatives

The present study was designed to characterize further the rewarding and aversive properties of 3,4-methylenedioxymethamphetamine (MDMA), the α-ethyl homologue of MDMA (MBDB), fenfluramine, and the selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan (MMAI) using the conditioned place preference paradigm (CPP). Extracellular dopamine (DA) and its metabolite DOPAC were also measured in the nucleus accumbens after systemic drug administration, using in vivo microdialysis in freely moving rats. MDMA produced a positive dose-dependent effect in the CPP test, which was maximal at doses of 5 and 10 mg/ kg. MBDB also induced a positive CPP, with a maximum effect at 10 mg/kg. The conditioning effect of MBDB was more than 2.5-fold weaker compared with MDMA. Fenfluramine evoked place aversion at doses of 4, 6, and 10 mg/kg. This effect of fenfluramine was independent of dose. MMAI at doses of 1.25, 2.5, and 5 mg/kg produced no significant effect on place conditioning. At doses of 10 and 20 mg/kg, MMAI produced an effect similar to fenfluramine: Place aversion was independent of dose. In the microdialysis experiments, MDMA significantly elevated extracellular DA and induced a decrease of DOPAC in the nucleus accumbens. Thus, activation of dopaminergic systems may be responsible for the rewarding properties of MDMA-like drugs. In contrast to the effects seen with MDMA, no difference in extracellular DA or DOPAC was seen after injection of MBDB, fenfluramine, or MMAI, even though MBDB weakly induced a place preference. The mechanism responsible for the development of place aversion by fenfluramine or MMAI is unknown at this time and requires further study.

Effects of systemic phenylpropanolamine and fenfluramine on serotonin activity within rat paraventricular hypothalamus

Phenylpropanolamine (PPA) anorexia has been linked to activation of α1-adrenergic receptors within rat paraventricular hypothalamus (PVN) by studies documenting that intra-PVN injection of PPA and other α1-adrenergic agonists suppress food intake. The present experiments examine the hypothesis that PPA may suppress appetite indirectly via release of serotonin (5-HT) within the PVN. In Experiment 1, we compare the effects of PPA (20 mg/kg, IP) and of d,l-fenfluramine (FEN: 7.5 mg/kg, IP), relative to a vehicle treatment, on extracellular levels of 5-HT and the 5-HT metabolite 5-HIAA in adult male rats prepared with concentric microdialysis probes aimed at either the PVN or the perifornical hypothalamus (PFH). Injection of either vehicle or 20 mg/kg PPA had no significant effect on extracellular 5-HT within the PFH or the PVN. In contrast, a subsequent injection of 7.5 mg/kg FEN produced significant increases in 5-HT and significant decreases in 5-HIAA within the PVN and the PFH. In Experiment 2, the 5-HT 1a autoreceptor agonist 8-OH-DPAT (0.25 mg/kg, SC) was used to suppress presynaptic release of 5-HT prior to systemic injection of either fenfluramine (5 mg/kg, IP) or PPA (5, 10, 20, and 30 mg/kg, IP). The anorexic action of FEN, but not PPA, was reduced by pretreatment with 8-OH-DPAT. These results suggest that the anorexic action of PPA is not mediated by an indirect effect of PPA on presynaptic release of 5-HT.

Serotonin and stress-induced increases in renin secretion are not blocked by sympathectomy/adrenal medullectomy but are blocked by β antagonists

The present study examined the role of the sympathetic nervous system as a mediator of the message from the CNS to the kidneys to stimulate the secretion of renin. Two procedures that increase the secretion of renin were tested: administration of the serotonin releaser fenfluramine, which increases renin release without altering blood pressure [53], and subjecting the rats to the ‘psychological’ stressor of conditioned emotional response (CER) stress. Pretreatment of rats with either the β antagonist sotalol or the β 1-selective antagonist atenolol completely prevented the increase in plasma renin activity and concentration caused by fenfluramine (5 mg/kg i.p.) injection. However, chemical sympathectomy with 6-hydroxydopamine (6-OHDA) combined with surgical adrenal medullectomy did not prevent the increase in plasma renin activity and concentration following fenfluramine injection. Since β-antagonists have been previously shown to prevent the renin response to CER stress, we also tested whether the sympathetic nervous system mediates the renin response to CER stress. Chemical sympathectomy combined with adrenal medullectomy did not prevent the effect of CER stress on renin release. The completeness of the sympathectomy/adrenal medullectomy was verified biochemically by measuring plasma epinephrine and both plasma and renal norepinephrine concentrations. Plasma epinephrine and renal norepinephrine levels were reduced to below 1% of control while plasma norepinephrine ws reduced to below 8% of control values. In conclusion, our data previous reports suggesting that activation of CNS pathways increases the secretion of renin. However, the message from the brain to release renin from the kidneys does not exclusively involve either the sympathetic innervation of the kidneys or adrenal epinephrine. Although β 1 receptors are involved in mediating this phenomenon, their location or mechanisms remains unknown and will be discussed.

Brain catecholamines mediate the delayed reduction in renin release after injection of fenfluramine

The present studies examined whether brain or peripheral catecholaminergic mechanisms mediate the fenfluramine-induced reduction in plasma renin activity and concentration. Fenfluramine reduced plasma renin activity and concentration to 35% of basal levels in vehicle pretreated rats. This reduction was prevented in rats whose central catecholaminergic neurons were destroyed by i.c.v. injection of 6-hydroxydopamine (6-OHDA) two weeks prior to the experiment. In contrast, the suppressive effects of fenfluramine on plasma renin activity and concentration was not altered in rats that were surgically adrenal medullectomized and chemically sympathectomized by 6-OHDA. To determine whether α 2 adrenoceptors mediate the suppressive effects of fenfluramine, rats were pretreated with increasing doses of the α 2 adrenoceptor antagonist yohimbine 1 h before the administration of fenfluramine. Although yohimbine alone increased plasma renin activity and concentration, it did not prevent the suppressive effects of fenfluramine. In conclusion, the data suggest that central, but not peripheral catecholamines mediate the suppressive effect of fenfluramine on renin secretion. This effect is not mediated by α 2 adrenoceptors.

Ethanol consumption following acute fenfluramine, fluoxetine, and dietary tryptophan

Male Sprague-Dawley rats fed a commercial diet with or without tryptophan supplementation (0.5% L-TRP) were treated with single IP injections of fenfluramine or fluoxetine. Rats had been water deprived prior to injection and food was removed during the period of fluid availability. They were offered, following drug or saline injection, water, a 5% ethanol solution, or an isocaloric sucrose solution (8.75%) for 1 h. Fenfluramine injection significantly reduced intake of all fluids, but its effect on ethanol was significantly greater than for water or sucrose solutions. Fluoxetine suppressed water and ethanol intake but not that of sucrose; the reduction in ethanol intake was significantly greater than for water. Ingestion of the tryptophan-supplemented diet in the absence of any drug treatment had no effect on fluid intake. However, the tryptophan supplementation significantly enhanced the reduction in ethanol intake induced by fenfluramine and fluoxetine. It appears that both fenfluramine and fluoxetine decrease ethanol intake more so than that of water or sucrose and that this effect is exacerbated by tryptophan supplementation.

5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine

1. The present study has investigated whether the neurotoxic effects of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxins, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), p-chloroamphetamine (PCA) and fenfluramine on hippocampal and cortical 5-HT terminals in rat brain could be prevented by administration of either chlormethiazole or dizocilpine. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in an approximate 30% loss of cortical and hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content 4 days later. Injection of chlormethiazole (50 mg kg-1) 5 min before and 55 min after the MDMA provided complete protection in both regions, while dizocilpine (1 mg kg-1, i.p.) protected only the hippocampus. 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx +2.5 degrees C) induced by the MDMA injection. 4. Injection of PCA (5 mg kg-1, i.p.) resulted in a 70% loss of 5-HT and 5-HIAA content in hippocampus and cortex 4 days later. Injection of chlormethiazole (100 mg kg-1, i.p.) or dizocilpine (1 mg kg-1, i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg-1, i.p.) was given which produced only a 30% loss of 5-HT content. Chlormethiazole did prevent the hyperthermia induced by PCA (5 mg kg-1), while the lower dose of PCA (2.5 mg kg-1) did not produce a change in body temperature.5. Neither chlormethiazole nor dizocilpine prevented the neurotoxic loss of hippocampal or cortical 5-HT neurones measured 4 days following administration of fenfluramine (25 mg kg-1, i.p.).6. In general, chlormethiazole and dizocilpine were effective antagonists of the 5-HT-mediated behaviours of head weaving and forepaw treading which appeared following injection of all three neurotoxins.7. Both chlormethiazole and dizocilpine have previously been shown to prevent the neurotoxic effects ofa high dose of methamphetamine on cerebral 5-HT and dopamine pathways. These drugs also prevent MDMA-induced neurotoxicity of 5-HT pathways, but not that induced by injection of PCA or fenfluramine. This suggests that the mechanisms of neurotoxic damage to 5-HT pathways produced by substituted amphetamines cannot be identical. The monoamine loss does not appear to result from the hyperthermia produced by the neurotoxic compounds.

Thermogenic, thermoregulatory and activity effects of fenfluramine, a 5-hydroxytryptamine agonist, in immature domestic fowl ( Gallus domesticus)

1. 1. dl-Fenfluramine, a 5-hydroxytryptamine (5-HT) agonist, increases the metabolic rate of the adult domestic fowl and also stimulates heat loss mechanisms. Since thermogenic mechanisms vary qualitatively and quantitatively with age, this series of experiments was designed to measure the effects of fenfluramine on immature, growing, ‘broiler’ chickens. 2. 2. The work was also designed to distinguish any direct effect of fenfluramine on respiratory quotient (RQ) from the indirect effects of reduced food intake. 3. 3. Female commercial broilers were used (5–7 weeks old; 1.1–1.8 kg), at an ambient temperature of 25°C and on a 14 hr light: 10 hr dark cycle. dl-Fenfluramine was injected intramuscularly at 80 μmol/kg body weight (20 mg/kg), in 0.5 ml of 9 g/l saline per kg bodyweight. 4. 4. When the effects on heat production (H) of differences in food intake were eliminated by fasting, fenfluramine increased H by up to 20% within about 20 min. 5. 5. RQ decreased four times more rapidly after fenfluramine injection than after the control treatment whether the birds were fed or fasted, reaching 0.70 in about 3 hr. 6. 6. Wing-drooping and polypnea occurred within 10 min of injection. Maximal response was in 30 min to 1 hr for polypnea and 30 min to 2 hr for wing-drooping, depending on experimental procedure. Both responses ceased in 5–7 hr. 7. 7. Physical activity was greatly reduced by fenfluramine, particularly in the first 4hr. This effect occurred whether food was available or not. 8. 8. The effects of fenfluramine were, therefore, qualitatively and quantitatively similar to those seen in adults, but were initiated more rapidly and generally persisted for a shorter period in the younger birds.

Fenfluramine-induced thermogenesis in adult domestic fowl ( Gallus domesticus): Elimination by propranolol, a beta-blocker

1. Intra-muscular injection of DL-fenfluramine, a 5-hydroxytryptamine agonist, increased heat production by a mean of 16% over the following 6hr in adult domestic fowl. 2. Propranolol, a beta-receptor blocker, completely eliminated the effect of fenfluramine on thermogenesis. 3. Respiratory quotient (RQ) was significantly reduced by fenfluramine injection, whether or not this was preceded by injection of propranolol. Injection of propranolol alone produced a decline of RQ to 0.71 within 1 hr, followed by an immediate steady increase to 0.90 over the next 5 hr. 4. Extension and lowering of the wings, which augments surface area for heat loss, was observed within 30 min of fenfluramine injection and persisted for several hours. This thermolytic effect of fenfluramine was not eliminated by prior injection of propranolol. Polypnea occurred only when both propranolol and fenfluramine had been injected. 5. Food intake over the whole day of measurement was significantly reduced by fenfluramine injection, whether or not this had been preceded by injection of propranolol. Water intake over the same period was unaffected by any of the treatments. 6. Fenfluramine reduced spontaneous activity by almost half. The reduction was slightly greater when fenfluramine injection followed propranolol. Propranolol given alone had no effect on activity.

Ethanol intake of chickens treated with fenfluramine, fluoxetine, and dietary tryptophan.

Male, white leghorn chickens fed a standard diet with or without tryptophan supplementation were treated with single injections of 8 mg/kg fenfluramine in one series of experiments, or 8 mg/kg fluoxetine in another series. The birds had been food- and water-deprived prior to injection. They were offered, following the drug or saline injection, water, a 5% ethanol solution, or an isocaloric sucrose solution (8.75%) for 1 hr. Both fluoxetine and fenfluramine significantly reduced consumption of the ethanol solution, an effect exacerbated by tryptophan supplementation. Water or sucrose solution intake was also significantly reduced, but significantly less so than ethanol after fenfluramine injection. Since the birds drank significantly more of the sucrose solution after saline injection than of water, the consumption decrease caused by fenfluramine resulted, nevertheless, in a higher intake than that of either water or ethanol. Body temperature was decreased by ethanol intake and/or fluoxetine injection. Fenfluramine injection had an opposite, body temperature-increasing effect. It appears that both fenfluramine and fluoxetine decrease ethanol intake in a manner more specific than for water or sucrose, and that this effect is amplified by dietary tryptophan supplementation.

The 5-hydroxytryptamine agonist fenfluramine increases fos-like immunoreactivity in the brain

This study was designed to assess the effects of the 5-hydroxytryptamine (5-HT) indirect agonist fenfluramine on the brain distribution of Fos- and corticotropin-releasing factor-like immunoreactivity (F-LI and CRF-LI). A single intraperitoneal injection of either dl-fenfluramine (25 mg/kg) or saline was given to resting Sprague-Dawley rats housed on a 12-12 h light-dark cycle and fed libitum. Sixty min following injections, rats were killed and brains removed and sliced (40 μm thick) in a coronal plane from the anterior olfactory bulb to the brainstem. Brain slices were then stored at −40°C pending the tissue localization of F-LI and CRF-LI were determined by means of a double immunostaining procedure using the peroxidase-avidin: biotin complex (ABC) method. Fenfluramine injection led to a marked increase in F-LI in the caudate-putamen (CPu), the parvocellular division of the hypothalamic paraventricular nucleus (PVN), and the central amygdaloid nucleus (CeA). In the PVN, most of the F-LI was co-localized with CRF-LI. There was no attempt to identify which types of neurons displayed F-LI in CPu and CeA. While F-LI was readily observable in all rats treated with fentluramine, it was not discernible in the control animals. This study provides evidence for an involvement of the immediate-early genes c- fos in the central action of fenfluramine.