Role of monoamine oxidase inhibition and monoamine depletion in fenfluramine-induced neurotoxicity and serotonin release

The role of both monoamine synthesis and monoamine oxidase inhibition in mediating the fenfluramine-induced damage to serotonin neurones was examined; as pretreatment agents, both alpha-methyl-para-tyrosine (AMPT) and parachlorophenylalanine (PCPA) were used to deplete dopamine and serotonin, respectively, while clorgyline and deprenyl were used to inhibit monoamine oxidase types A and B. While both AMPT and deprenyl did not alter fenfluramine induced serotonin or 5-hydroxyindoleacetic acid (5-HIAA) depletion in any area, PCPA did partially reduce the serotonin depletion in the hippocampus and hypothalamus. Although pretreatment with clorgyline did not significantly alter fenfluramine-induced serotonin depletion, it did produce a 65% mortality rate in animals treated with both drugs. Both PCPA and clorgyline significantly increased the depletion of striatal 5-HIAA concentration consequent to fenfluramine; however, these drugs also produced a long-term depletion of striatal 5-HIAA when administered alone, therefore, the changes seen after the coadministration with fenfluramine may be viewed as additive. Finally, acute PCPA pretreatment attenuated the rapid rise in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (homovanillic acid) induced by fenfluramine, and acute clorgyline reversed the drop in serotonin and rise in 5-HIAA induced by fenfluramine. These results indicate that the rapid increase in dopamine activity induced by fenfluramine is partially dependent on serotonin concentration and release and that the mechanism of fenfluramine-induced toxicity is unlike that of the other substituted amphetamines.     

Sympathetic activation by fenfluramine depletes brown adipose tissue norepinephrine content in rats

The antiobesity agent fenfluramine (FEN) has been reported to produce an activation of sympathetic neurons to brown adipose tissue (BAT) resulting in thermogenesis. The present study was conducted to determine if FEN-induced activation of BAT is affected by the ambient temperature at which animals are maintained. Body temperature was determined in conscious male Sprague-Dawley rats using implanted temperature transmitters, and sympathetic activation of BAT was determined by measuring norepinephrine (NE) content. Animals maintained at 22 and 4 degrees C incurred a significant decline in core body temperature following FEN administration. FEN produced a significant depletion of BAT NE content, and the magnitude of BAT NE depletion was related to the dose of FEN (-57.4% at 3 mg/kg dose and -75.9% at 10 mg/kg dose). However, the extent of BAT NE depletion was equal at 22 and 4 degrees C. BAT NE depletion by FEN appears to depend on activation of sympathetic neurons because it was prevented by pretreatment with the ganglionic blocker pentolinium (10 mg/kg ip). Furthermore, NE depletion by FEN could be blocked with fluoxetine (10 mg/kg ip) pretreatment, indicating that the action of FEN is mediated through the release of serotonin.     

Studies on the effect of MDMA ('ecstasy') on the body temperature of rats housed at different ambient room temperatures

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (Ta) conditions (>or=20 degrees C), but hypothermia when in cool conditions (Ta相似文献   

Chlordecone-induced effects on thermoregulatory processes in the rat

To investigate the mechanism(s) involved in chlordecone (CLD)-induced hypothermia, we examined colonic (Tcol) and tail skin (Tsk) temperatures, preferred ambient temperature (Ta), evaporative water loss, and metabolic rate following CLD exposure in the rat. Single ip dosages (0, 50, and 75 mg/kg) in corn oil were administered to Fischer-344 rats. At a Ta of 22.5 degrees C, Tcol was reduced by 50 and 75 mg/kg as early as 0.5 hr, and this effect persisted for 4 hr after dosing. Tcol was increased 24 hr after both CLD dosages. Tsk was elevated 2, 3, 4, and 6 hr after 75 mg/kg and 2 hr after 50 mg/kg. At Ta of 30.5 degrees C, Tcol was decreased at early exposure times after both dosages and was increased 3, 4, and 6 hr after 75 mg/kg. At 10.0 degrees C, an enhanced hypothermia was observed 1-6 hr following 50 and 75 mg/kg CLD. The preferred Ta was significantly decreased by approximately equal to 2.8 degrees C following CLD exposure while activity within the temperature gradient was unchanged. At 25.0 degrees C, evaporative water loss was decreased while metabolic rate was not affected by CLD administration. To study the enhanced hypothermia at 10.0 degrees C, metabolic rate was measured continuously for 2 hr following 75 mg/kg CLD and found to be significantly different from controls. The intensified hypothermia in the cold may be due to the inability of the CLD-treated rat to stimulate metabolic thermogenesis in response to cold in addition to the loss of body heat following cutaneous vasodilation. These data suggest that CLD-induced hypothermia at a neutral Ta is associated with cutaneous vasodilation and not with a decreased metabolic rate or increased evaporative water loss.     

The effects of a decarboxylase inhibitor, benserazide, on both thermoregulation and chlorpromazine-induced hypothermia in rats.

Intraperitoneal administration of a peripheral decarboxylase inhibitor benserazide (Ro4-4602) to unanesthetized rats produced alterations in body temperature which depended on ambient temperature. In the cold, hypothermia was brought about by a decrease in metabolic heat production. At room temperature, a dose-dependent hypothermia was preceded by a slight hyperthermia. The hypothermia was due to an increase in skin temperature (tail) and a decrease in metabolic heat production, while the hyperthermia was due to a decrease in skin temperatures (both tail and footsole) and an increase in metabolic heat production. In the heat, hyperthermia responses to benserazide were associated with decrease in skin temperature (both tail and footsole). Benserazide treatment produced no significant change in brain 5-HT content. Chlorpromazine-induced hypothermia was greatly enhanced after pretreatment of the animals with benserazide at room temperature (22 degrees).     

Antagonism of fenfluramine-induced hyperthermia in rats by some, but not all, selective inhibitors of 5-hydroxytryptamine uptake

The injection of fenfluramine (7.5 mg kg-1,i.p.) to rats housed at 27-28 degrees C was associated with an elevation of core body temperature which peaked at approximately 1 h post-injection. One h pretreatment with citalopram (20 mg kg-1, i.p.), chlorimipramine (10 mg kg-1, i.p.), femoxetine (10 mg kg-1, i.p.) and fluoxetine (20 mg kg-1, i.p.) resulted in an attenuated response to fenfluramine. In contrast, Org 6582 (20 mg kg-1) and zimelidine (20 mg kg-1) were devoid of an effect on fenfluramine-induced hyperthermia. The response to fenfluramine was was also blocked by i.p. injections of metergoline (0.2 mg kg-1), methysergide (5 mg kg-1) and mianserin (0.5 mg kg-1). Rectal temperature was unaltered by both the 5-hydroxytryptamine (5-HT) uptake inhibitors and the 5-HT receptor antagonists. The IC50 values (nM) for in vitro inhibition of [3H]-5-HT uptake into rat hypothalamic synaptosomes were for citalopram 2.4, chlorimipramine 8.8, femoxetine 14, fluoxetine 16, Org 6582 75 and zimelidine 250. The injection of all six compounds (20 mg kg-1, i.p.) 1 h before death was associated with an inhibition of [3H]-5-HT uptake into rat hypothalamic synaptosomes which ranged from 47.2% for chlorimipramine to 83.3% for citalopram. Rat hypothalamic 5-HT levels were decreased by approximately 50% 3 h after the injection of fenfluramine (15 mg kg-1, i.p.). This effect was blocked by a 1 h pretreatment with fluoxetine, Org 6582 and zimelidine (all 20 mg kg-1, i.p.). Ki values for displacement of specifically bound [3H]-5-HT (1 nM) to rat hypothalamic membranes were for metergoline 26 nM, methysergide 1.1 microM, mianserin 3.6 microM, chlorimipramine 9.2 microM and fluoxetine 32.7 microM. Values for citalopram, femoxetine, Org 6582 and zimelidine were in excess of 65.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of fenfluramine on the pulmonary disposition of 5-hydroxytryptamine in the isolated perfused rat lung: a comparison with chlorphentermine

A possible mechanism for fenfluramine-induced pulmonary hypertension has been investigated. Fenfluramine, like chlorphentermine, may inhibit the pulmonary uptake and/or metabolism of 5-hydroxytryptamine (5-HT). This allows more 5-HT to remain in the pulmonary circulation, where it may exert a greater vasoconstrictor action resulting in pulmonary hypertension. Chlorphentermine has been shown to inhibit the uptake and metabolism of 5-HT. The effect of fenfluramine on the pulmonary disposition of [14C]5-HT has been investigated, in comparison with chlorphentermine, using a recirculating isolated perfused rat lung system. The pulmonary disposition of [14C]5-HT was assessed by measuring the change in [14C]5-HT concentration in the perfusion medium during the experiment and at the end, and the concentration in the lung at the end of the experiment. The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, was measured in perfusate and lung samples. Mean pulmonary clearance of 5-HT for the control lung and lungs challenged with either fenfluramine (2.5 microM) or chlorphentermine (25 microM) was 4.514, 1.316 and 1.007 mL min(-1), respectively (n = 5). The concentration of 5-HT found in the lungs at the end of the experiment for the control and the lungs preloaded with fenfluramine or chlorphentermine was 695.05+/-9.69, 638.65+/-10.27 and 617.3+/-14.38 ng g(-1), respectively. Fenfluramine, like chlorphentermine, inhibited the pulmonary disposition of 5-HT resulting in an elevated perfusate level of 5-HT. This is a possible contributing mechanism for fenfluramine-induced pulmonary hypertension. The effect of fenfluramine was less pronounced than chlorphentermine.     

Fenfluramine-induced immunosuppression: an in vivo analysis

We examined the immunomodulatory potential of acute fenfluramine administration, by measuring production of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in response to an in vivo challenge with bacterial lipopolysaccharide in rats. Fenfluramine (2.5-10 mg/kg) suppressed tumor necrosis factor-alpha production, but only fenfluramine (5 and 10 mg/kg) suppressed interleukin-1beta production. Fenfluramine (10 mg/kg)-induced suppression of interleukin-1beta and tumor necrosis factor-alpha production persisted for 6 and 24 h, respectively. Using in vitro analyses, we demonstrated that the immunosuppressive effect of fenfluramine was not due to a direct effect on immune cells. As fenfluramine activates the hypothalamic pituitary adrenal axis, we examined the ability of the glucocorticoid receptor antagonist mifepristone to block fenfluramine-induced immunosuppression. However, mifepristone (10 mg/kg) failed to attenuate the suppressive effect of fenfluramine on interleukin-1beta and tumor necrosis factor-alpha production, indicating that glucocorticoids do not mediate fenfluramine-induced immunosuppression. We also assessed the effect of fenfluramine on production of the anti-inflammatory cytokine interleukin-10, as interleukin-10 can suppresses pro-inflammatory cytokine production. Fenfluramine (10 mg/kg) increased interleukin-10 production following an in vivo lipopolysaccharide challenge. However, the ability of fenfluramine to suppress tumor necrosis factor-alpha production cannot be accounted for by increased interleukin-10 production, as pretreatment with the beta-adrenoceptor antagonist nadolol completely blocked the increase in interleukin-10 without altering the suppression of tumor necrosis factor-alpha induced by fenfluramine. Taken together, these data demonstrate that fenfluramine promotes an immunosuppressive cytokine phenotype in vivo. The suppression of pro-inflammatory cytokines is not due to a direct effect the drug on immune cells, and also occurs independently of glucocorticoid receptor activation. In addition, whilst fenfluramine increases production of the anti-inflammatory cytokine interleukin-10, this cannot account for the suppression of the pro-inflammatory cytokine tumor necrosis factor-alpha induced by fenfluramine.     

INHIBITION OF SEROTONIN-INDUCED ACTH RELEASE IN MAN BY CLONIDINE

1. Clonidine, an alpha 2-adrenergic agonist, is thought to inhibit noradrenergic neuronal activity (NNA) in the central nervous system (CNS) by a presynaptic alpha 2-receptor mechanism. Central NNA is thought to be the primary monoaminergic stimulus to pituitary ACTH release. Fenfluramine, a serotonin releasing agent and uptake inhibitor, causes ACTH release in normal man. 2. The present study investigated the effect of clonidine on fenfluramine-induced ACTH release in six normal volunteers. Four protocols were used: 1.5 mg/kg body weight oral fenfluramine; 4.3 micrograms/kg body weight oral clonidine; oral clonidine + oral fenfluramine 1 h later; placebo clonidine. Plasma ACTH and cortisol were measured at intervals for 5 h after clonidine and for 4 h after fenfluramine. 3. The mean plasma ACTH and cortisol levels and the mean maximal changes in these levels were significantly lower during the clonidine + fenfluramine test than during fenfluramine alone. Plasma ACTH and cortisol levels were not lowered significantly more by clonidine than by placebo. 4. In conclusion, clonidine blocked the ACTH-releasing activity of fenfluramine in normal humans. This inhibition of active ACTH release may result from clonidine blockade of fenfluramine-induced activation of central NNA. Clonidine alone was no more effective than placebo in lowering plasma ACTH and cortisol.     

Pharmacological evaluation of central adrenergic involvement in chlordecone-induced hypothermia

Adrenergic involvement in the hypothermia produced by systemically administered chlordecone (CLD) was evaluated in the rat using intracisternal pretreatment with 6-hydroxydopamine (6-OHDA), alpha-adrenergic receptor antagonists (phenoxybenzamine and phentolamine) and beta-adrenergic antagonists (propranolol and atenolol). The effect of intraperitoneal administration of 75 mg/kg of chlordecone on colonic temperature (Tcol) in male Fischer-344 rats was measured 7 days after administration of 6-OHDA and 30 min following pretreatment with the receptor antagonists. Prior depletion of catecholamines in brain with 250 micrograms of 6-OHDA administered intracerebrally attenuated hypothermia induced by chlordecone, without affecting basal Tcol. Phenoxybenzamine (10 or 20 micrograms) and phentolamine (5 or 10 micrograms) also reduced the hypothermic response to chlordecone. The beta-adrenergic receptor antagonists propranolol (50 or 100 micrograms) and atenolol (10 or 20 micrograms) did not attenuate chlordecone-induced hypothermia. These data suggest that the hypothermia induced by chlordecone is a result of alterations in central alpha-adrenergic functions, possibly involved with the sympathetic control of vasomotor tone.     

Fenfluramine-induced suppression of food intake and locomotor activity is differentially altered by the selective type A monoamine oxidase inhibitor clorgyline

Administration of fenfluramine to rats produced decreases in 1-h food intake and locomotor activity. Short-term (2–6 days) or long-term (21–25 days) treatment with the monoamine oxidase (MAO) type A inhibiting antidepressant clorgyline potentiated fenfluramine-induced suppression of food intake but did not affect fenfluramine-induced suppression of locomotor activity. Although daily (4 h) food intake was not significantly less in clorgyline-treated animals relative to saline-treated controls, body weight gain was significantly less in clorgyline-treated animals relative to controls. These findings demonstrate a differential effect of clorgyline treatment on fenfluramine-induced suppression of food intake and locomotor activity. Offprint requests to: C. S. Aulakh     

Clonidine-induced hypothermia: Possible involvement of cholinergic and serotonergic mechanisms

The thermoregulatory effects (including metabolic, vasomotor and respiratory activities) produced by an injection of clonidine (1-3 micrograms in 0.5 microliter) into the preoptic anterior hypothalamus were assessed in conscious rats at ambient temperatures (Ta) of 8, 22 and 30 degrees C. Intrahypothalamic administration of clonidine caused a dose-dependent fall in rectal temperature at Ta 8 degrees C and 22 degrees C. The hypothermia in response to clonidine was due to decreased metabolic heat production and/or cutaneous vasodilation. There was no change in respiratory evaporative heat loss. The clonidine-induced hypothermic response was attenuated by pretreatment of the rats with either 5,7-dihydroxytryptamine (10 micrograms, administered intrahypothalamicly, 14 days before clonidine injection), yohimbine (0.2 microgram, administered intrahypothalamicly, 10 min before clonidine injection), cyproheptadine (1 microgram, administered intrahypothalamicly, 10 min before clonidine injection), or atropine (0.1 microgram, administered intrahypothalamicly, 10 min before clonidine injection). The data indicate that clonidine may act on alpha-adrenoceptors located on a serotonin-acetylcholine pathway within the preoptic anterior hypothalamus to induce hypothermia by promoting a reduction in metabolic heat production and/or an enhancement in dry heat loss in rats.     

The effects of a decarboxylase inhibitor,benserazide, on both thermoregulation and chlorpromazine-induced hypothermia in rats

Intraperitoneal administration of a peripheral decarboxylase inhibitor benserazide (Ro4–4602) to unanaesthetized rats produced alterations in body temperature which depended on ambient temperature. In the cold, hypothermia was brought about by a decrease in metabolic heat production. At room temperature, a dose-dependent hypothermia was preceded by a slight hyperthermia. The hypothermia was due to an increase in skin temperature (tail) and a decrease in metabolic heat production, while the hyperthermia was due to a decrease in skin temperatures (both tail and footsole) and an increase in metabolic heat production. In the heat, hyperthermia responses to benserazide were associated with decrease in skin temperature (both tail and footsole). Benserazide treatment produced no significant change in brain 5-HT content. Chlorpromazine-induced hypothermia was greatly enhanced after pretreatment of the animals with benserazide at room temperature (22°).     

Beta-adrenergic responsiveness in the rat following acute administration of ethanol

Ethanol has been shown to induce a hypothermia in rats maintained in air at 26 degrees C. The objective of the present study was to assess the metabolic responsiveness of ethanol-treated rats to administration of isoproterenol, a beta-adrenoceptor agonist, and to assess whether ethanol per se, or the hypothermia accompanying its administration, contribute to changes in beta-adrenergic responsiveness. In the present study, administration of ethanol (3 g/kg, i.p.) reduced both colonic temperature (Tco) and rate of oxygen consumption (metabolic rate) of rats maintained at 26 degrees C to levels below those of saline-treated controls within 20 min after treatment. Maximal decreases in both parameters occurred within approximately 40 min. Administration of isoproterenol (50 micrograms/kg, s.c.) 10 min after treatment with either ethanol or saline was accompanied by an increase in the metabolic rates of both groups, although the magnitude of the increase in the ethanol-treated group was less than that of controls. Maximal increases in tail skin temperatures (Tsk) following treatment with isoproterenol were similar in both groups but an increase in Tsk occurred earlier in the ethanol-treated group. Tco increased after treatment with isoproterenol in the saline-treated group but decreased in the ethanol-treated group. When isoproterenol was administered 90 min after treatment with ethanol, increases in metabolic rate, Tsk, and Tco were similar in both groups, although the increase in Tsk of ethanol-treated animals was delayed until Tco reached pretreatment level. Exposure to 30 degrees C minimized ethanol-induced hypothermia. At this temperature the metabolic responses to administration of isoproterenol at 90 min after treatment with ethanol did not differ significantly between the two groups. These results suggest that the metabolic responsiveness to administration of a beta-adrenoceptor agonist is not altered by prior treatment with ethanol but is affected by the hypothermia accompanying its administration.     

Antagonism of apomorphine-induced cage climbing behaviour and methamphetamine stereotypy by fenfluramine in mice

Pretreatment with fenfluramine (5 and 10 mg/kg, ip) in doses which induced head twitches was found to antagonize apomorphine-induced cage climbing behaviour and methamphetamine stereotypy in mice. Since fenfluramine (5 and 10 mg/kg) did not induce catalepsy it indicates that fenfluramine lacks postsynaptic striatal and mesolimbic dopamine receptor blocking activity and it is possible that the fenfluramine-induced enhancement of central 5-hydroxytryptamine neuronal transmission may be responsible for its antagonistic effect on apomorphine-induced climbing behaviour and methamphetamine stereotypy.     

Release of endogenous catecholamines from isolated rat brain tissue by fenfluramine and N-ethylamphetamine—effects of pargyline

The influence of the monoamine oxidase inhibitor, pargyline. upon the release of endogenous norepinephrine from chopped rat cerebral cortex and endogenous dopamine from chopped rat corpus striatum by fenfluramine and N-ethylamphetamine was examined. Endogenous norepinephrine and dopamine were measured using an enzymatic-isotopic assay. Both fenfluramine and N-ethylamphetamine released significant amounts of each catecholamine. Fenfluramine-induced catecholamine release was associated with the decrease in the total content (i.e. catecholamine in media + catecholamine in tissue) of both cortical norepinephrine and striatal dopamine; N-elhylamphetamine decreased only total striatal dopamine content. In brain tissue obtained from rats pretreated with pargyline HCl (100 mg/kg, 12 hr prior to sacrifice), total cortical norepinephrine content was approximately twice that in the absence of pargyline: striatal dopamine was unchanged. Pargyline pretreatment also resulted in a marked potentiation of the amounts of both catecholamines released by each drug. and in an antagonism of the above drug-induced reductions in catecholamine content. Additionally, after pargyline pretreatment. N-ethylamphetamine reduced total cortical norepinephrine content. When pargyline (2.56 × 10^?1 M) was added to the media containing chopped cortical tissue from unpretreated animals, control content was slightly increased. Only fenfluramine-induced norepinephrine release was potentiated and the degree of potentiation was less than that observed after pargyline pretreatment. As with pargyline in vivo, pargyline in vitro also resulted in an antagonism of the fenfluramine-induced decrease in total norepinephrine and was associated with an N-ethylamphetamine-induced decrease in norepinephrine content. Since the locomotor stimulant effects of both fenfluramine and N-ethylamphetamine are potentiated after pargyline. the data are consistent with the importance of catecholamines to these effects. The data also suggest that pargyline potentiates the behavioral effects of fenfluramine and N-ethylamphetamine in part by increasing the pool of norepinephrine available for release by these drugs and in part by inhibiting the deamination of the released norepinephrine and dopamine by monoamine oxidase. Decreases in total norepinephrine produced by N-ethylamphetamine may reflect alterations in the formation of O-methylated amines.     

Ambient temperature modulation of fenfluramine-induced thermogenesis in the rat

The anti-obesity drug fenfluramine, promotes loss of weight by reducing food intake; however, there is controversy as to whether the drug can also elevate expenditure of energy. Resting consumption of oxygen (VO2) was measured in conscious rats to determine whether the injection of fenfluramine increased metabolic rate and whether prior fasting, or ambient temperature altered the response. Regardless of whether the rats were fed or had been fasted for 22 hr, in a thermoneutral environment (28 degrees C), the intraperitoneal injection of dl-fenfluramine (20 mg/kg) caused a raised oxygen consumption. This elevation was sustained to the end of the 60-min period of measurement after the injection, at which point the colonic temperature was found to be increased. This metabolic response to fenfluramine was largely attenuated when the drug was administered at 23 degrees C, and the colonic temperature of the rats was decreased by 60 min after the injection. At 4 degrees C, the injection of fenfluramine inhibited thermogenesis against cold, the oxygen consumption fell and the rats exhibited hypothermia. It was concluded that fenfluramine can increase the metabolic rate, but that this effect is not conditional on associated food intake, as has been reported. Rather, the ambient temperature governs whether stimulation or inhibition of thermogenesis will be evoked. These metabolic effects of fenfluramine explain, in part, its divergent effects on body temperature, reported previously.     

The catecholamine mechanisms of prostaglandin E1-induced hypothermia in rats

Intraperitoneal administration of prostaglandin E1 (PGE1) produced a hypothermia in rats at room temperatue (22 degrees C). The hypothermia in response to PGE1 was due to cutaneous vasodilatation and decreased metabolic heat production. Depletion of brain 5-hydroxytryptamine (with 5,6-dihydroxytryptamine and p-chlorophenylalanine) did not alter the PGE1-induced hypothermia. However, depletion of bran catecholamines (with 6-hydroxydopamine) and blockade of central catecholaminergic receptors (with phentolamine and propranolol) both greatly reduced the PGE1-induced hypothermia. The data indicate that PGE1 lowers body temperature in rats by acting on the central catecholaminergic systems.     

The involvement of brain serotonin in the clonidine-induced hypothermia in rats

The effects of manipulation with brain serotonergic (5HT) activity on clonidine-induced hypothermia in rats were investigated. Lesion to the median raphe nucleus as well as p-chlorophenylalanine pretreatment significantly potentiated the temperature decrease after 0.2 mg/kg of clonidine. Pretreatment with a 5HT releasing agent--fenfluramine, or a 5HT receptor agonist--m-chlorophenylpiperazine (mCPP) antagonized the effect of clonidine. Additionally, both fenfluramine and mCPP given alone produced an elevation in body temperature. These results are discussed in terms of an involvement of the 5HT neuronal system in clonidine hypothermia, and the dissociation of the role of 5HT system in clonidine-induced behavioral and vegetative effects is suggested.     

Long-term imipramine treatment differentially affects fenfluramine-induced suppression of food intake and locomotor activity

Administration of fenfluramine to rats produced decreases in one-hour food intake and locomotor activity. Short-term (2-6 days) or long-term (21-25 days) treatment with the tricyclic antidepressant, imipramine, did not affect daily food intake, body weight gain or baseline locomotor activity when compared to saline treatment. However, long-term but not short-term imipramine treatment attenuated fenfluramine-induced decreases in one-hour food intake. On the other hand, neither short-term nor long-term imipramine treatment affected fenfluramine-induced decreases in locomotor activity. These findings demonstrate a differential effect of long-term imipramine treatment on fenfluramine-induced suppression of food intake and locomotor activity.