Reversal of fenfluramine and fluoxetine anorexia by 8-OH-DPAT is attenuated following raphe injection of 5,7-dihydroxytryptamine.

Drugs that enhance serotonergic neurotransmission reduce food intake by directly or indirectly activating serotonergic receptors. In contrast drugs that inhibit serotonergic neurotransmission such as the 5-HT1A agonist 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) stimulate food intake. The present study examined the effects of 8-OH-DPAT on the feeding suppressant action of the indirect 5-HT agonists fenfluramine (FEN; 0.63-2.5 mg/kg) and fluoxetine (FLU; 2.5-10 mg/kg), as well as the 5-HT1B/2C agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP; 0.5-2 mg/kg). 8-OH-DPAT (62.5-250 microg/kg) was administered 5 min prior to FEN, FLU or TFMPP, injected 30 min before food access. While FEN, FLU and TFMPP dose-dependently reduced 2 h food intake, 8-OH-DPAT stimulated eating behavior. 8-OH-DPAT (62.5-250 microg/kg) pretreatment reversed the anorectic action of FEN (1.25 mg/kg) and FLU (5 mg/kg) but not TFMPP (1 mg/kg). Separate groups of rats were injected with 5,7-dihydroxytryptamine (5,7-DHT; 3 microg free base) into both the dorsal and median raphe, which resulted in extensive 5-HT depletion in hypothalamus (80%), striatum and hippocampus (90%). In both 5, 7-DHT and vehicle-injected rats, FEN (1.25 mg/kg) and FLU (5 mg/kg) suppressed feeding. In 5,7-DHT treated rats, however, the ability of 8-OH-DPAT (125 microg/kg) to block FEN and FLU induced anorexia was attenuated. That is, 8-OH-DPAT pretreatment did not reverse the feeding inhibitory effects of either FEN or FLU. Further, the ability of FEN and FLU to suppress food intake was not altered by the 5,7-DHT lesion. These findings suggest that the reversal of FEN and FLU anorexia by 8-OH-DPAT is partially dependent on the integrity of brain 5-HT systems since their disruption compromises the ability of this 5-HT1A agonist to antagonize the feeding suppressant action of either FEN or FLU. However, the ability of treatments which impair 5-HT neurotransmission to reverse FEN and FLU induced suppression of food intake may depend upon whether this impairment is acute and reversible (8-OH-DPAT), or chronic and irreversible (5,7-DHT).

The 5-HT1B receptor mediates the effect of d-fenfluramine on eating caused by intra-hypothalamic injection of neuropeptide Y.

d-Fenfluramine (0.63 mg/kg i.p.), a serotonin (5-hydroxytryptamine, 5-HT) releaser and re-uptake inhibitor, reduced the eating caused by neuropeptide Y (235 pmol) injected into the paraventricular nucleus of the hypothalamus. The 5-HT1 and 5-HT2 receptor antagonist metergoline (1.0 and 2.0 mg/kg i.p.) and the 5-HT1A and 5-HT1B receptor antagonist (+/-)-cyanopindolol (3.0 and 8.0 mg/kg s.c.) significantly antagonized the effect of d-fenfluramine. The 5-HT2A and 5-HT2C receptor antagonist mesulergine (0.1 and 0.3 mg/kg s.c.) and the 5-HT2A receptor antagonist ketanserin (2.5 and 5.0 mg/kg i.p.) did not significantly modify the effect, nor did the 5-HT1A and 5-HT1B receptor antagonist (-)-propranolol (20-40 nmol), injected bilaterally into the paraventricular nucleus of the hypothalamus. The results suggest that d-fenfluramine reduces neuropeptide Y's hyperphagia by indirectly stimulating 5-HT1B receptors outside the paraventricular nucleus of the hypothalamus.

5-HT and carbohydrate suppression: effects of 5-HT antagonists on the action of d-fenfluramine and DOI.

The effects of several 5-hydroxytryptamine (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine and the 5-HT2/5-HT1C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were examined in a dietary paradigm that appears to be sensitive to 5-HT-induced carbohydrate suppression. In this paradigm, deprived rats are provided with a nutritionally complete hydrated chow mash diet together with an optional carbohydrate supplement of powdered Polycose. Both d-fenfluramine and DOI produced a clear suppression of total energy intake and carbohydrate (Polycose) intake. However, the mechanisms underlying these effects are different. The effect of d-fenfluramine in this paradigm was attenuated by the 5-HT1/5-HT2 receptor antagonist metergoline and partially attenuated by the 5-HT1A/5-HT1B receptor antagonist (+/-)cyanopindolol. In contrast, d-fenfluramine's effect was not antagonised by the 5-HT2 receptor antagonist ketanserin, the 5-HT3 receptor antagonist (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS-205,930), the 5-HT2/5-HT1C receptor antagonist ritanserin, or the peripheral 5-HT receptor antagonist xylamidine. However, the effect of DOI in this paradigm was significantly attenuated by ketanserin but was not antagonised by either ritanserin or (+/-)cyanopindolol. Therefore, the suppressive effect of these two 5-HT drugs on total and Polycose intake appears to be mediated, respectively, by 5-HT1B/5-HT1C receptors (d-fenfluramine) and 5-HT2 receptors (DOI).

Tissue ascorbic acid, fenfluramine, and changes in fat metabolism.

Following initial weight gain, reduction in appetite and pronounced weight loss occurred in scorbutic unsupplemented guinea-pigs. Hepatic ascorbic acid levels were significantly reduced and cholesterol concentration increased in the liver. Fenfluramine administration caused immediate loss of weight and appetite in the scorbutic guinea-pigs, these changes being more pronounced in the males. Hepatic ascorbic acid, cholesterol and triglycerides were reduced to lower levels in the fenfluramine-treated scorbutic animals than in the scorbutic guinea-pigs receiving diet alone. In contrast, weight and appetite increased in vitamin-C-supplemented animals while they were receiving fenfluramine. Their hepatic cholesterol and triglyceride levels became significantly reduced. It has been shown that supplementary vitamin C can inhibit the anti-obesity and anorectic actions of fenfluramine and counteract its effect in raising tissue cholesterol.

Vitamin C and the anti-obesity effect of fenfluramine.

Increasing doses of fenfluramine were given to female guinea-pigs on a scorbutogenic diet with or without Ascorbic Acid (AA) supplementation. AA alone increased weight and appetite, hepatic and plasma AA. AA deficiency reduced weight after an initial rise. 10 mg/kg fenfluramine in association with the diet produced a gain in weight. Larger doses caused weight loss and reduced appetite. These effects were prevented by AA supplementation. Fenfluramine reduced hepatic and plasma AA significantly in comparison with the animals receiving the diet alone, or the diet with AA supplementation in the absence of fenfluramine administration. It is concluded that AA release plays an important role in the anti-obesity and anorectic actions of fenfluramine.

Hyperthermia induced by amphetamine, p-chloroamphetamine and fenfluramine in the rat-1.

Hyperthemia was elicited in rats by the subcutaneous injection of 4 mg/kg (+)-amphetamine, 4 mg/kg (+)-p-chloroamphetamine, or 8 mg/kg fenfluramine. This hyperthermia could be abolished by oral pretreatment with 300 mg/kg p-chlorophenylalanine. Cyproheptadine, at a dose of 0.05 mg/kg, completely inhibited the response induced by p-chloroamphetamine, but a dose of 0.4 mg/kg was necessary in the case of amphetamine and fenfluramine. Protection against hyperthermia by p-chloroamphetamine was also provided by chloroimipramine. Hypothalamic turnover of 5-HT was enhanced by all three amphetamines. alpha-Methyltyrosine and disulfiram had no effect on the hyperthemia induced by the amphetamines, FLA-63 seemed even to enhance it. Haloperidol, in the dose range of 0.1 -0.4 mg/kg, attenuated the hyperthermia induced by amphetamine and p-chloroamphetamine, but not that induced by fenfluramine. The results point to a central origin of the hyperthemia induced by amphetamine, p-chloroamphetamine and fenfluramine. In the mediation of this effect, 5-HT and, to a lesser degree, dopamine seem to play an important role.