Dissociation of the anorexic effects of fenfluramine and amphetamine following intrahypothalamic injection (original) (raw)
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Diminished amphetamine anorexia and enhanced fenfluramine anorexia after midbrain 6-hydroxydopamine
Psychopharmacology, 1983
Rats were made hyperphagic by 6-hydroxydopamine (6-OHDA) injected bilaterally into the ventral midbrain; then they were restricted to a 6h/day feeding schedule and tested for appetite suppression with amphetamine and fenfluramine in randomized order. Amphetamine anorexia was diminished while fenfluramine anorexia was enhanced (both P < 0.001). The opposite effect on fenfluramine anorexia shows that the effect of 6-OHDA on amphetamine anorexia was not due to hyperphagia masking the anorexia. Norepinephrine in the forebrain was 90 % depleted, but DA and serotonin levels were within 9 % of normal. These results demonstrate a new way to dissociate amphetamine and fenfluramine anorexia, as others have done with lateral hypothalamic lesions or DA depletion. The 6-OHDA injections, which were of a type that cause hyperphagia, apparently destroyed a substrate for amphetamine anorexia and also facilitated a substrate for fenfluramine anorexia.
Fenfluramine anorexia: A peripheral locus of action☆
Physiology & Behavior, 1983
In a series of feeding pattern studies, amphetamine was shown to produce a period of complete anorexia often followed by a broken nibbling pattern of eating. Fenfluramine produced a regular feeding pattern in which a depressed meal size was not compensated for by an increase in meal frequency. The disproportionate lengthening of the post-meal interval relative to meal size was accompanied by a decrease in the rate of gastric emptying. Fenfluramine was most effective in lengthening post-meal interval when administered immediately after a meal, and was progressively less effective when the injection was delayed, allowing time for gastric emptying to occur. Amphetamine was shown to have similar but less pronounced effects, corresponding to its weaker effects on gastric emptying. Midbrain raphe lesions that abolished the fenfluramine effect on short-term intake of food-deprived rats did not attenuate fenfluramine's effect on gastric emptying, nor did the lesions attenuate the anorectic effect of fenfluramine on ad lib food intake. Lateral intracerebroventricular administration of fenfluramine did not reduce feeding. These results suggest that fenfluramine controls feeding primarily by short-term signals related to food in the upper gastro-intestinal tract.
Contribution of caudal brainstem to d -fenfluramine anorexia
Psychopharmacology, 1997
Of the central 5-HT substrates that may mediate the anorexic actions of systemically administered dfenfluramine (d-FEN), those in the forebrain have received the most attention. As a counterpoint to this forebrain focus, we evaluated the contribution of caudal brainstem substrates to the anorexic action of d-FEN. Two experimental protocols were employed. In one we compared the feeding response (intra-oral intake of 12.5% glucose) of intact and chronic supracollicular decerebrate (CD) rats to systemic administration of d-FEN.
Psychopharmacology, 1981
The purpose of this study was to determine whether repeated treatment (15 days) with d-amphetamine (AMP) or fenfluramine (FEN), administered after a daily 3 h feeding session (e. g. post-session), would result in tolerance or crosstolerance to the decrement in food consumption induced by treatment with either drug before feeding (e. g. pre-session). Groups of male rats were treated IP with 0.5 ml saline, 1.0, 2.0, or 4.0 mg/kg AMP, or 2.5, 5.0, or 10.0 mg/kg FEN prior to a 3 h feeding session. For the next 15 sessions, the respective groups were treated post-session with saline (0.5 ml), AMP (4.0 mg/kg), or FEN (10 mg/kg). Following the 15 day postsession phase, each group again received this pre-session treatment. The initial pre-session treatment with all dosages of these two drugs produced a significant decrease in food consumption. Tolerance to the food intake suppressant effect of FEN, but not AMP, resulted from repeated post-session treatment with the same agent. Repeated post-session treatment with AMP resulted in a significant decrement in the suppressant activity of FEN on food intake, whereas the corresponding post-session treatments with FEN did not alter the pre-session effects of AMP, except for an enhancement seen with higher AMP doses.
Pharmacology Biochemistry and Behavior, 1980
The effects of two doses of d-amphetamine and fenfluramine on male Zucker rats maintained ad lib on solid and liquid diets were investigated using the technique of meal pattern analysis. Amphetamine-induced anorexia was of short duration in both obese and lean rats. In the lean rats, anorexia was followed by rebound feeding resulting in little or no reduction in total daily intake. The drug reduced meal sizes of obese but not lean rats and caused a transient decrease in meal frequency. Increased spontaneous activity paralleled the decreased food intake. In contrast, anorexia following fenfluramine was greater, more prolonged and of equivalent magnitude in obese and in lean rats. No rebound feeding was observed. Reduction in intake was achieved primarily by changes in meal size rather than in meal frequency. These data demonstrate that food intakes of genetically obese Zucker rats are more susceptible to the action of d-amphetamine than those of lean rats, and are consistent with reports of differential neurotransmitter levels in the obese and lean rats.
Site of action of anorectic drugs: Glucoprivic- versus food deprivation-induced feeding
Pharmacology Biochemistry and Behavior, 1987
Feeding induced by 2-deoxyglucose was compared with feeding induced by food deprivation in terms of antagonism by anorectic drugs and of anatomical site of action. Glucoprivic feeding was completely blocked by microinjection of amphetamine, fenfluramine, and mazindol into the paraventricular nucleus of the hypothalamus (PVN). Deprivation-induced feeding was not blocked by amphetamine, fenfluramine, or mazindol microinjected into the PVN. Neither the feeding induced by 2-deoxygiucose nor its reversal by amphetamine were blocked by pretreatment with the p-adrenergic antagonist, propranolol. Amphetamine and fenfluramine blocked both glucoprivic-and deprivation-induced feeding when microinjected into the perifomical region of the lateral hypothalamus. These data suggest that food consumption induced by 2-deoxyglucose treatment can be antagonized by anorectic drugs acting at recognition sites present in several hypothalamic nuclei, while deprivationinduced feeding acts through different receptor mechanisms which may be specific to the perifomical region of the lateral hypothalamus. Hypothalamus Amphetamine 2-Deoxy-D-glucose Paraventricular hypothalamic nucleus Anorectic drugs Glucoprivic feeding
Gastromotor mechanism of fenfluramine anorexia
Appetite, 1986
A gastric slowing effect of fenfluramine accounts for most of the drug's suppressant effect on food intake in freely feeding rats. It is conceivable on the evidence to date that this gastromotor action of fenfluramine explains all its effects on appetite and metabolism, but additional peripheral and central effects-such as motor inhibition-are likely.
The effects of chronic fenfluramine administration on behaviour and body weight
Psychopharmacologia, 1973
Two experiments were conducted on the effects of chronic administration of fenfluramine on behaviour and body weight in rats. In Experiment One the effects of 28 day chronic administration were studied. A dose related rapid weight loss was observed in treated subjects, with development of tolerance to the effects of the drug on body weight after 14 days administration. Observations of behaviour were made on days 1, 14~ and 28 of chronic administration according to a "time sampling" procedure of behavioural eategorisation. The incidence of some behavioural patterns varied significantly between observation days, although observations of control subjects were never significantly different. By the 28 th day of administration tolerance to the behavioural effects of the drug had developed, no dose/response effects being noted in contrast to the results for prior observation days.
Pharmacological Research Communications, 1982
The anorectic effect of d-norfenfluramine, but not that of d-fenfluramine, was potentiated in reserpine-treated rats. Chlorimipramine reduced the effect of d-fenfluramine but not that of d-norfenfluramine. Parachlorophenylalanine and xylamidine, a peripheral serotonin antagonist, unlike metergoline, did mot modify the effect of either drug. The data suggest that d-fenfluramine and d-norfenfluramine depress food intake by acting on different serotonin mechanisms in the rat brain.
Behavioural microanalysis of the role of dopamine in amphetamine anorexia
Pharmacology Biochemistry and Behavior, 1988
of the role of dopamine in amphetamine anorexia. PHARMACOL BIOCHEM BEHAV 30(3) [641][642][643][644][645][646][647][648] 1988.--A microstructural analysis paradigm was used to study amphetamine anorexia. Doses above 0.40 mg/kg significantly reduced food intake by reducing eating time; in contrast, eating rate was increased at these doses. Examination of the frequency distribution ofinterresponse times (IRTs) revealed a significant shift to shorter IRTs at doses as low as 0.125 mg/kg. Pimozide blocked amphetamine anorexia at 0.5 and 1.0 mg/kg, suggesting that at both doses amphetamine anorexia has a dopaminergic substrate. However, the atypical neuroleptic thioridazine did not antagonize amphetamine. Furthermore, effects of amphetamine were additive with those of apomorphine, administered at a dose known to suppress feeding by inhibiting mesolimbic DA neurons. These results provide evidence against an involvement of the mesolimbic DA system in amphetamine anorexia.