Effects Of D-fenfluramine Research Articles

Forkhead Box, Class O Transcription Factors in Brain: Regulation and Behavioral Manifestation

The mammalian forkhead box, class O (FoxO) transcription factors function to regulate diverse physiological processes. Emerging evidence that both brain-derived neurotrophic factor (BDNF) and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant treatment and whether their genetic deletion affects behaviors. C57BL/6 mice were treated with D-fenfluramine to increase brain serotonergic activity or with the antidepressant imipramine. The functional status of brain FoxO1 and FoxO3a was audited by immunoblot analysis for phosphorylation and subcellular localization. The behavioral manifestations in FoxO1- and FoxO3a-deficient mice were assessed via the Elevated Plus Maze Test, Forced Swim Test, Tail Suspension Test, and Open Field Test. Increasing serotonergic activity by d-fenfluramine strongly increased phosphorylation of FoxO1 and FoxO3a in several brain regions and reduced nuclear FoxO1 and FoxO3a. The effect of D-fenfluramine was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Chronic, but not acute, treatment with the antidepressant imipramine also increased the phosphorylation of brain FoxO1 and FoxO3a. When FoxO1 was selectively deleted from brain, mice displayed reduced anxiety. In contrast, FoxO3a-deficient mice presented with a significant antidepressant-like behavior. FoxOs may be a transcriptional target for anxiety and mood disorder treatment. Despite their physical and functional relatedness, FoxO1 and FoxO3a influence distinct behavioral processes linked to anxiety and depression. Findings in this study reveal important new roles of FoxOs in brain and provide a molecular framework for further investigation of how FoxOs may govern mood and anxiety disorders.

The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux

Dexfenfluramine, a drug formerly prescribed for treatment of obesity, caused heart valve damage and pulmonary hypertension in some people. The cause of the toxicity has not been defined, but 5-HT has been implicated. The objective of this study was to evaluate the effect of the anorectic agent, d-fenfluramine, and its major metabolite, d-norfenfluramine, on intact human platelet serotonin (5-HT) transport in vitro. The effects of d-fenfluramine and d-norfenfluramine on platelet uptake and efflux of 3H-5-HT were measured in buffer at pH 6.7, to optimize serotonin transporter (SERT) function, and at pH 7.4. Uptake of 3H-5-HT at pH 6.7 and 7.4 was inhibited by both agents at micro m concentrations (IC50, d-fenfluramine approximately 3 microM; d-norfenfluramine approximately 10 microM). However, no efflux of 3H-5-HT from labeled platelets at either pH 6.7 or 7.4 occurred at similar concentrations of d-fenfluramine or d-norfenfluramine. With inhibition of platelet dense granule 3H-5-HT uptake by reserpine, efflux of 3H-5-HT was observed at pH 6, but not at pH 7.4. Fluoxetine, a SERT inhibitor, was a more potent inhibitor of uptake (IC50 0.05 microM) than d-fenfluramine, but the anorectic agent, phentermine, had no effect. Therefore, d-fenfluramine and d-norfenfluramine inhibit human platelet uptake of 5-HT in vitro at tissue concentrations attainable in vivo, but they do not stimulate 5-HT efflux due to dense granule sequestration. Inhibition of platelet 5-HT uptake may play a role in the cardiopulmonary toxicity of d-fenfluramine, but other factors probably contribute, since similar toxicity has not been observed with fluoxetine.

Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats.

Serotonin (5-HT) systems may play a role in modulating cocaine-seeking behavior. The present study examined the effects of acute administration of the 5-HT reuptake inhibitor (SRI) fluoxetine, and the SRI/releaser d-fenfluramine, on reinstatement of extinguished cocaine-seeking behavior elicited by either response-contingent presentations of cocaine-paired cues or cocaine priming. Separate groups of rats that had been trained to press a lever for a cocaine reinforcer (0.75 mg/kg per 0.1 ml, IV) with a light/tone stimulus complex paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e. neither cocaine nor the stimulus complex was available). Subsequently, the effects of fluoxetine (0-10.0 mg/kg, IP) on extinction and cue reinstatement of extinguished cocaine-seeking behavior were examined, as well as the effects of d-fenfluramine (0-3.0 mg/kg, IP) on cue reinstatement. Additionally, dose-dependent effects of fluoxetine (0-10.0 mg/kg, IP) and d-fenfluramine (0-1.0 mg/kg, IP) on cocaine-primed (0-15.0 mg/kg, IP) reinstatement of extinguished cocaine-seeking behavior were examined. Fluoxetine dose-dependently attenuated cocaine-seeking behavior during extinction. Both fluoxetine and d-fenfluramine dose-dependently attenuated cue-reinstated cocaine-seeking behavior. In contrast, neither drug reliably altered cocaine-seeking behavior reinstated by cocaine priming. These findings suggest that 5-HT indirect agonists effectively attenuate cocaine-seeking behavior elicited by cocaine-associated stimuli, but are much less effective in attenuating cocaine-seeking behavior elicited by cocaine priming.

The effect of d-fenfluramine on brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in male and female rats

Brain regional 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined in freely feeding male and female rats 7 days after giving a single dose of d-fenfluramine (3.8 mg/kg, p.o.) or vehicle. Males showed negligible effects except for a significant decrease of 5-HT in the rest of the cortex, whereas females showed significant decreases of 5-HT and 5-HIAA in the frontal cortex, the rest of the cortex, hippocampus and hypothalamus; 5-HT was also decreased in female midbrain. Females had substantially higher plasma and brain concentrations of fenfluramine and moderately but significantly lower concentrations of norfenfluramine than the males. Plasma fenfluramine+norfenfluramine concentrations of the females were significantly higher than those of the males. Corresponding brain values showed smaller but significant differences. Female brain and plasma areas under the curve for fenfluramine+norfenfluramine (0–24 h after administration of d-fenfluramine) were 20 and 35% higher than male values. However, results suggest that the sex difference in the effect of d-fenfluramine on brain 5-HT metabolism is not due to differences in the metabolism of the drug.

Behavioural and neuroendocrine responses to D-fenfluramine in rats treated with neurotoxic amphetamines

The amphetamine derivatives p-chloroamphetamine (pCA), 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and D-fenfluramine can, if given repeatedly in high doses to rats, produce a degeneration of serotonergic nerve terminals which we have previously shown to result in a reduction in D-fenfluramine-evoked release of 5-HT in vivo. It is therefore possible that fenfluramine-evoked responses may have value as a probe of 5-HT neurodegeneration in man. The present study examined the effect of pre-treatment with these three agents (pCA 12 mg/kg×2; MDMA 20 mg/kg×8; D-fenfluramine 12.5 mg/kg×8, 14 days prior to testing) on behavioural (5-HT syndrome) and neuroendocrine [prolactin and adrenocorticotrophin (ACTH)] responses in rats to acute administration of D-fenfluramine and other serotonergic agonists. All three pre-treatments attenuated the D-fenfluramine-evoked behavioural syndrome, but did not affect the prolactin or ACTH responses to acute challenge with D-fenfluramine (apart from a small effect of pre-treatment with pCA on the ACTH response to D-fenfluramine). For comparison, the effect of pCA pre-treatment on the behavioural responses to acute administration of pCA and the 5-HT(1A) and 5-HT(2) receptor agonists 8-hydroxy-2-(di- n- propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), respectively, were also examined. pCA pre-treatment attenuated all components of the behavioural response to pCA but had little or no effect on the behavioural responses to 8-OH-DPAT or DOI, suggesting that there was no alteration in post-synaptic 5-HT(1A) or 5-HT(2) receptor function. While the loss of behavioural effect of D-fenfluramine on rats pre-treated with neurotoxic amphetamines can be understood in terms of the loss of D-fenfluramine's 5-HT-releasing action following 5-HT neurodegeneration, the lack of change in the neuroendocrine responses to D-fenfluramine is not easily explicable in this way. These results emphasise the need for further research into the actions of D-fenfluramine before carrying it forward as a probe of neurodegeneration in man.

Effect ofd-fenfluramine on the indole contents of the rat brain after treatment with different inducers of cytochrome P450 isoenzymes

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and beta-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly beta-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and beta-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamintaion) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of D-fenfluramine on mood and performance, and on neuroendocrine indicators of 5-HT function

D-fenfluramine has multiple actions which enhance 5-HT transmission and make it a useful neuroendocrine challenge agent, but little is known of its effects on mood or performance. In this study, two doses (15 and 30 mg) and placebo were administered to six male and six female healthy volunteers according to a double blind, cross-over design. Blood was sampled and self-ratings completed pre- and hourly up to 5 h post-challenge. Performance tests were administered pre- and at 2 and 4 h. Plasma concentrations of prolactin and cortisol decreased after all treatments at 1 h and then increased post-drug to a peak at 4 h. Body temperature showed a similar pattern. D-fenfluramine was well tolerated with few side effects. It caused only minor sedation and little psychomotor impairment but there was some decrement in episodic memory. The 30 mg dose produced a mild anxiolytic and anti-aggressive action.

Effects of d-fenfluramine on feeding and hypothalamic 5-hydroxytryptamine and dopamine in male and female rats

Male and female rats were given d-fenfluramine and its effects on feeding and on hypothalamic concentrations of the drug, its metabolite norfenfluramine and 5-hydroxytryptamine (5-HT) and dopamine determined. ID 50 values (i.p.) for the hypophagic effect of the drug on 30-, 42- and 100-day-old rats measured over 2 h during the light phase after 24 h food deprivation did not vary significantly with sex but tended to decrease with age approximately in parallel with daily percentage increases and (after deprivation) of decreases in body weight. However, male but not female 30-day-old rats showed a rebound of feeding during the subsequent 2 h. ID 50 values of 42-day-old rats on a palatable diet or measured during the dark phase when freely feeding also did not vary with sex. Male 30-day-old rats killed at 2–10 h after an ID 75 (p.o.) dose of d-fenfluramine had substantially lower hypothalamic concentrations of the drug and comparable or slightly lower concentrations of its metabolite norfenfluramine than 30-day-old females. Similarily treated 100-day-old males also had lower concentrations of fenfluramine but significantly higher norfenfluramine levels than females so that drug plus metabolite concentrations were essentially independent of sex. 100-day-old females killed 2 h, 24 h and 7 days after d-fenfluramine (3.8 mg/kg p.o. = ID 75) had larger percentage decreases of hypothalamic 5-HT than identically treated males. Percentage decreases of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) tended to become less marked with time after injection in males but not females. In contrast, percentage decreases of dopamine were more prominent in the males and dihydroxyphenylacetic acid (DOPAC) values decreased in males only. Although rats and humans show major quantitative differences in the hypophagic potency, metabolism and distribution of d-fenfluramine, the above findings indicate the importance of further study of its effects in both sexes.

Effect of d-fenfluramine and 5,7-dihydroxytryptamine on the levels of tryptophan hydroxylase and its mRNA in rat brain

Repeated high doses of d-fenfluramine (dF; 10 mg/kg, i.p. twice daily for 4 days) markedly reduced serotonin (5-HT) concentrations in the hippocampus and striatum of rat brain up to 1 month after treatment, while tryptophan hydroxylase (TPH) levels were reduced only in the hippocampus 5 days after injection. Unlike dF, an intracerebroventricular (i.c.v.) injection of 5,7-dihydroxytryptamine (5,7-DHT 150 μg/20 μl) induced a marked and long-lasting reduction of 5-HT and TPH in both brain regions. Thirty days after injection, 5,7-DHT, but not dF, markedly reduced the number of labelled neurons in the dorsal and ventral regions of the nucleus raphe dorsalis (NRD) and raised the levels of TPH mRNA in the spared neurons at all times examined. TPH mRNA levels were raised 5 and 15 days after dF treatment in the NDR suggesting that changes in the TPH gene expression or transcript stability result following 5-HT depletion. These data are in agreement with the suggestion that 5,7-DHT damages 5-HT nerve terminals and perikarya, but leave unanswered the question of the mechanism of the long-lasting reduction of 5-HT levels caused by high, repeated doses of dF.

Effects of d-fenfluramine, MK-212, and ondansetron on saline drinking in two-choice tests in the rehydrating rat

The aim of the present studies was to investigate the effects of serotonergic compounds on preference for isotonic saline and aversion to hypertonic saline, respectively. Twenty-two-hour water-deprived rats were divided into two groups: The first was given a choice between 0.9% saline and water in a 30-min test; the second was given a choice between 1.8% saline and water. Animals were tested following administration of d-fenfluramine, the 5-HT 1C receptor agonist 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), and the 5-HT 3 receptor antagonist ondansetron. d-Fenfluramine (0.3–3.0 mg/kg) abolished the preference for isotonic saline whereas ondansetron (10–100 μg/kg) had no effect. d-Fenfluramine and MK-212 reduced hypertonic saline drinking, although at the highest dose for each drug water drinking was also reduced. These data add further to the evidence for an important serotonergic involvement in the control of saline drinking and preference in the rat.

Effect of D-fenfluramine on neuropeptide Y concentration and release in the paraventricular nucleus of food-deprived rats

Recent evidence indicates that Neuropeptide Y (NPY) is an important signal in the hypothalamic neural circuitry that stimulates feeding in the rat. Administration of d-fenfluramine (FEN) has been shown to rapidly inhibit feeding in the rat. Because food deprivation increases the levels and release of NPY in the paraventricular nucleus (PVN) of the hypothalamus, the aim of this study was to investigate whether the rapid anorectic effects of FEN in food-deprived (FD) rats are associated with alterations in the hypothalamic NPYergic system. In the first experiment, the effect of FEN (10 mg/kg) on NPY concentrations in nine microdissected hypothalamic sites was assessed by radioimmunoassay (RIA) in rats either food deprived for 3 days or fed ad lib during the experimental period. In response to food deprivation, NPY concentrations increased significantly in the PVN and arcuate nucleus, but NPY levels remained unchanged in the remaining seven hypothalamic sites. In control rats maintained on ad lib food supply, FEN injection produced little effect on NPY concentration in hypothalamic sites. However, FEN suppressed NPY levels selectively in the PVN of FD rats, so that NPY concentrations measured in the nucleus were within the range found in satiated control rats. In the second experiment, the effect of FEN on NPY release in the PVN was examined in FD rats by the push-pull cannula (PPC) technique. NPY levels in the PPC perfusate were unchanged in FD rats during the period 30–120 min after saline or FEN injection. Also, the mean rate of NPY release was similar in vehicle- and FEN-treated FD rats. These results raise the possibility that the immediate anorectic effects of FEN may not be due to decreased NPY release in the PVN, but may be due to either suppression of postsynaptic NPY action and/or activation of neural systems that inhibit feeding behavior. However, the decrease in NPY concentration seen selectively in the PVN implies that FEN may eventually affect NPY secretion in FD rats.

The effect of d-fenfluramine on intake of carbohydrate supplements is influenced by the hydration of the test diets

The effect of d-fenfluramine on carbohydrate intake in the rat has been investigated using a dietary paradigm in which a pure carbohydrate supplement is presented in addition to the normal balanced chow diet. This experimental strategy has been used as an alternative to the macronutrient selection model in an attempt to increase the sensitivity of the measurement of drug effects on carbohydrate intake. This issue is important because of the postulated theoretical relationship between brain serotonin (5-HT) and carbohydrate intake. The effect of d-fenfluramine was dependent upon the texture and density of the supplement (hydrated vs. non-hydrated) and upon the nature of the carbohyhdrate employed - either sucrose (sweet-tasting) or Polycose (bland-tasting). Selective carbohydrate suppression, by d-fenfluramine, was detected (as predicted by the 5-HT/carbohydrate theory) but only under specific environmental conditions, namely hydrated chow supplemented with dry Polycose. Therefore, suppression of carbohydrate may depend, not on any inherent biological link between carbohydrate consumption and brain 5-HT activity, but on a shift in relative preference for the diet choices available.

Weight cycling alters the effects of d-fenfluramine on activity-based anorexia

Weight cycling alters the effects of d-fenfluramine on activity-based anorexia

Role of 5-HT receptors in the effect of d-fenfluramine on feeding patterns in the rat

The effect of d-fenfluramine, 1.5 mg/kg i.p., on meal patterns was studied in rats treated i.p. with 1 mg/kg metergoline or 0.5 mg/kg ritanserin or s.c. with 3 mg/kg (±)cyanopindolol. d-Fenfluramine significantly reduced eating rate, meal size and total intake in the first 4 h of testing and the effects were antagonized by metergoline. (±)Cyanopindolol reduced total intake and the effect of d-fenfluramine on this measure; the effect of d-fenfluramine on meal size (but not on eating rate) was also reduced by (±)cyanopindolol. Ritanserin only reduced the rate of eating and the effect of d-fenfluramine on this measure. The results suggest that 5-HT 1 receptors, possibly of the 5-HT 1B type, are involved in the ability of d-fenfluramine to cause satiety in freely feeding rats.

Feeding pattern studies suggest that d-fenfluramine and sertraline specifically enhance the state of satiety in rats

The effects of d-fenfluramine (1.5 mg/kg) and sertraline (10 mg/kg), administered intraperitoneally once daily for seven days were studied on feeding parameters of rats over various periods. On the first day of treatment both drugs markedly reduced meal size and meal duration during the first hour and, to a lesser extent, the first 4 h. No effects were seen later. The size and duration of eating bouts were also markedly reduced by both drugs in the first hour. There was no significant effect of either drug on meal frequency in any period. Only d-fenfluramine significantly reduced the rate of eating within 4 h from the start of testing. Sertraline, but not d-fenfluramine, markedly increased locomotor activity in the first 4 h after the start of testing. The d-fenfluramine effect on eating rate disappeared by the second day whereas total intake and meal size were still reduced on day five. By days six and seven however the d-fenfluramine-treated rats did not differ from the controls. During the seven-day treatment sertraline always reduced total food eaten and meal size but caused only transient changes of locomotor activity and eating rate. Since the effects of d-fenfluramine and sertraline on meal size and food intake could be separated from the effects on eating rate and arousal, it appears that at appropriate doses these drugs specifically increase the satiating effect of food. Tolerance to this effect appears to develop more rapidly for d-fenfluramine than for sertraline.

Role of 5-HT receptors in the effect of d-fenfiuramine on gastric emptying and feeding behaviour as examined in the runway test

In one experiment, the effect of d-fenfluramine (DF) on gastric emptying was studied in rats treated i.p. with metergoline, a non-selective serotonin (5-HT) receptor antagonist, ritanserin, a selective 5-HT 2 and 5-HT 1C receptor antagonist, and xylamidine, a 5-HT antagonist which has poor access to the brain. Metergoline (1 mg/kg) but not ritanserin (0.5 mg/kg) or xylamidine (3 mg/kg) blocked the effect of 2.5 mg/kg DF studied 2 and 4 h after injection. In a second experiment, we studied the ability of metergoline to antagonise the effect of DF, administered after a meal, on runway performance, food intake and gastric emptying assessed 4 h later. Metergoline at a dose of 1 mg/kg did not antagonise the effect of DF (2.5 mg/kg) on runway performance but completely blocked the effect on gastric emptying. The data clearly show that DF delays gastric emptying by indirectly activating 5-HT 1 receptors; this effect is not important for the ability of DF to reduce runway performance and food intake when the drug is injected after a pre-feeding period. While there is evidence that DF hastens the termination of the meal by a 5-HT mechanism, the data suggest that DF may prolong the satiating effect of food during the post-absorptive phase by mechanisms other than 5-HT.

Effects of intracerebroventricular administration of d-fenfluramine and d-norfenfluramine, as a single injection or 2-HR infusion, on serotonin in brain: Relationship to concentrations of drugs in brain

The effects of d-fenfluramine (DF) and d-norfenfluramine (DNF), administered intracerebroventricularly (i.c.v.) on levels of serotonin (5-HT) in the brain, was assessed in relation to levels of drugs in brain. d-Fenfluramine, as single injection (500 μg/20 μl), caused no significant changes in 5-HT in whole brain from 15 to 480 min after injection. When infused intraventricularly for 2 hr, DF and DNF at 500 but not at 125–250 μg/hr, markedly reduced concentrations of 5-HT in brain 4 hr after the end of the infusion. At this time levels of DNF in brain were similar (between 4 and 5 μg/g) with both compounds, whereas levels of DNF after single intraventricular injections of DF were below 2 μg/g at all times after injection. Infusion of 500 μg/hr of DNF for 2-hr reduced concentrations of 5-HT in various regions of the brain, with the exception of the brainstem, whereas 250 μg/hr of DNF significantly lowered levels of 5-HT only in the cortex. The effect of infusion of 500 μg/hr of DNF was specific for 5-HT (no effect on dopamine and norepinephrine) and lasted for at least 168 hr. The results suggest that the effect on 5-HT in brain of intraventricular infusion of DF, but not a single injection, was due to the fact that, only in the former condition were adequate levels of DNF, the active metabolite of DF, reached in the brain. These results are relevant to the interpretation of studies in which biochemical changes in the brain after intraventricular administration, are reported without any measurement of the drug or its active metabolites, in plasma and brain.

Effect of d-fenfluramine on basal glucose turnover and fat-feeding-induced insulin resistance in rats

Effect of d-fenfluramine on basal glucose turnover and fat-feeding-induced insulin resistance in rats

Effect of d-fenfluramine on basal glucose turnover and fat-feeding-induced insulin resistance in rats.

There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg.kg-1.day-1) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (approximately 140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [3H]-2-deoxyglucose and [14C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P less than .05) in fat-fed rats receiving d-fenfluramine (fat + fen). The glucose infusion rate to maintain euglycemia was 22.0 +/- 1.1 mg.kg-1.min-1 in the high-carbohydrate-fed rats, 8.2 +/- 1.0 in fat-fed rats, and 15.1 +/- 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.

Do serotoninergic drugs decrease energy intake by reducing fat or carbohydrate intake? Effect of d-fenfluramine with supplemented weight-increasing diets

The capacity of serotoninergic drugs to selectively suppress carbohydrate (CHO) intake was investigated using a procedure sensitive to drug action. The drug d-fenfluramine was administered chronically to rats whose weight had been increased by exposure to either a fat or CHO-supplemented hyperphagia-inducing diet. The drug exerted a more potent anorexic effect and weight-reducing action in rats given the dietary supplements than in control chow-fed rats. Tolerance to the drug was not apparent even after 40 days of treatment. However, there was no evidence for a selective inhibition of CHO intake, nor was the drug more potent with the CHO-supplemented diet. d-Fenfluramine was equally effective against the hyperphagia and weight gain induced by either fat or CHO supplements.