Y. Cohen

Ontogeny of brain monoamines in lean and obese female Zucker rats

Differences in monoamine and metabolite levels were previously observed between lean and obese 16 week-old female Zucker rats. In order to test whether these variations exist initially in young animals, catecholamines (CA), serotonin (5-HT) and some of their metabolites were assayed in brain areas of Zucker rats between 5 and 16 weeks of age. The levels of most compounds in all areas studied increased with age in both groups. At 5 weeks of age, there was no difference between lean and obese rats. At 8 weeks, a reduction of dopamine (DA) metabolites appeared in the striatum and cortex of obese rats and persisted up to 16 weeks. A reduction of the 5-HT metabolite, 5-hydroxyindolacetic acid (5-HIAA), occurred at 8 weeks only. At 16 weeks, increases of DA and 5-HT in the hypothalamus and decreases of norepinephrine (NE), 5-HT and 5-HIAA in the hippocampus appeared. These data suggest that the development of obesity occurs before any monoamine alterations.

Fenfluramine and brain transmitters in the obese zucker rat

Genetically obese Zucker rats and their lean litter mates were treated for 5 days with fenfluramine. Levels of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) and their metabolism were assayed in the hypothalamus, striatum, medulla-oblongata pons and remainder of the brain. Fenfluramine induced a slight increase in the level of NE in the hypothalamus in lean rats and a marked decrease in obese rats. No change in the synthesis of NE was found. Fenfluramine had no effect on the level and metabolism of DA. The levels of 5-HT were decreased by fenfluramine in obese and lean rats, and the metabolism was increased. The levels of GABA were not changed by fenfluramine. Synthesis of GABA was increased in the remainder of the brain of obese and lean rats. These data suggest that fenfluramine acts on 5-HT systems in both obese and lean rats and are consistent with reports of the pharmacological effects of fenfluramine.

Effects of chronic β-blockers treatment on catecholamine synthesizing enzymes in spontaneously hypertensive rats

Abstract In the present work the effects of two β-blocking agents (Propranolol: 40 mg/kg/day and S 2395: 20 mg/kg/day) on the activity of central and peripheral catecholaminergic (CA) structures were studied in SHR after 55 days of oral treatment. These effects were assessed by measuring the activity of tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH) and phenylethanolamine- N -methyl-transferase (PNMT) in different structures dissected out from treated and control SHR. At the peripheral level, the only significant change was a decrease in the DBH activity of the adrenal medulla in propranolol-treated SHR. The plasma DBH activity was not altered. In the pons medulla, propranolol and S 2395 increased the TH activity of the A 6 , C 1 and C 2 region, and propranolol decreased the DBH activity in the A 6 and the C 2 region. The PNMT activity of these 3 neuronal groups remained unchanged. In the hypothalamus, TH and DBH activity exhibited no consistent changes. On the other hand, the PNMT activity was significantly reduced by propranolol in the anterior hypothalamus and in the median eminence but not in the posterior hypothalamus. The effects of β-blockers on the activity of central and peripheral CA structures were markedly different from those observed in similar conditions after chronic treatment with hydralazine, a peripheral vasodilator. Therefore, it was concluded that the enzymatic changes observed were not a consequence of the treatment induced decrease in blood pressure, but might more probably reflect a specific action of β-blockers on the central and peripheral CA structures of the SHR.

GABA levels and synthesis index in different brain areas of two obese rat models

Abstract 1. 1. GABA levels and synthesis index were measured in different brain areas of ventromedian hypothalamic lesioned rats (VMH) and in genetically obese rats (Fatty) compared to lean controls. 2. 2. GABA level was decreased in VMH rats hypothalamus. 3. 3. GABA synthesis was accelerated in VMH rats hypothalamus as well as in the hypothalamus, the striatum and the medulla oblongata-pons of Fatty rats. 4. 4. These data are related to the role of GABA in food intake.

Effects of dexfenfluramine and opioid peptides, alone or in combination, on food intake and brain serotonin turnover in rats.

Dexfenfluramine (d-FF) and opiate agonists both act on food intake but in opposite ways. Serotonin is known to be involved in the pharmacological action of both d-FF and opiates, but not necessarily in the feeding effect of the latter. In order to test this hypothesis, the effects of three opioid agonists, beta-endorphin, dynorphin and D-Ser2-Leu-Enk-Thr6 (DSLET) and of an antagonist, naltrexone, were investigated individually and in combination with d-FF on food intake and brain serotonin turnover. The opioid agonist-d-FF combinations generally produced a similar anorectic effect to that of d-FF alone, with the exception of DSLET which showed a reciprocal antagonism. The serotonergic effects varied according to the opioid tested, alone or in combination with d-FF. This does not allow to highlight a general pattern of serotonin involvement in the feeding effects of these peptides. However, all the treatments which decreased feeding (d-FF, naltrexone and the combinations dynorphin-d-FF and beta-endorphin-d-FF) displayed similar trends in hypothalamic serotonergic variations. This study evidences a role of serotonin in the feeding effect of opiates, although not similar for all of them. The use of d-FF provides a tool for assessing this involvement.

Effects of opiate agonists and an antagonist on food intake and brain neurotransmitters in normophagic and obese “cafeteria” rats

The relationship between the effects of opiates on food intake and on central monoamines in various brain areas was investigated in normophagic and obese cafeteria rats. Three agonists, beta-endorphin, dynorphin, and D-Ser2-Leu-Enk-Thr6 (DSLET) and an antagonist, naltrexone, were used. The three agonists enhanced feeling in normophagic rats but had different dopaminergic effects. Serotonergic metabolism increased concomitantly with the enhancement of feeding by the agonists, whereas it decreased following treatment with the antagonist naltrexone. In the cafeteria rats, although the feeding effects of dynorphin and DSLET occurred earlier, there was a complete lack of monoaminergic effects. beta-Endorphin was completely devoid of effects in this model. There would, thus, appear to be a positive correlation between the behavioural effects of these opiates and serotonergic metabolism in normophagic rats, while stimulated feeding situations (cafeteria rats) the disruption of a monoaminergic modulation does not prohibit a direct effect on feeding.

Changes in brain neuropeptide Y induced by cholecystokinin peptides

Cholecystokinin (CCK) and neuropeptide Y (NPY) are two peptides with opposite effects on the regulation of feeding behaviour. The possible interaction between these two systems has always been controversial. In this study, rat brain NPY levels were assayed after treatment with CCK 8 S and with a potent CCK agonist (Boc-(Nle 28-Nle 31)-CCK 26-33). CCK 8 S and its agonist analogue (50 micrograms/kg i.p.) both decreased hypothalamic and hippocampal NPY levels. This result suggests a negative relationship between NPY and CCK-peptides which is not surprising given their opposite role in the control of feeding. The hypothalamus and secondarily the hippocampus appear to be the site of this interaction; no change in NPY levels was observed in other brain areas (striatum and cortex). The same pattern of variation was found in the plasma, suggesting a direct release from the brain via a mechanism which remains to be investigated. The effect appeared later with the CCK analogue than with CCK 8 S itself; this is not surprising with regard to other behavioural and biochemical effects of the analogue and provides further characterization of its action.

Effects of a new cholecystokinin analogue (JMV 236) on food intake and brain monoamines in the rat

JMV 236, a new cholecystokinin-octapeptide-sulfate (CCK 8 S) derivative (Boc-Tyr (SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2) has been synthesized in the Centre de Pharmacologie-Endocrinologie (Montpellier). This peptide has been shown to present the same activity as CCK 8 S on pancreatic amylase secretion and has the advantage of a better chemical stability. With a view to further characterization, the effect of JMV 236 on food intake and brain monoamine and metabolite variations was assayed in the rat after intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations. JMV 236 decreased food intake 2 and 3 hours after i.p. administration of 12.5 and 50 micrograms/kg but was inactive after i.c.v. injection. Its global action was similar to that of CCK 8 S, but was less marked with delayed onset of response. As in our previous work with CCK 8 S, JMV 236 was more potent in inducing monoaminergic variations after i.p. than after i.c.v. administration. The main effects were decreases in striatal dopamine metabolite levels and increases in hypothalamic and striatal serotonin metabolite (5-HIAA) levels. These effects are classically observed with CCK 8 S and are described in our previous reports. The interesting peptide will require further characterization and may serve as a possible reference compound for studies on CCK derivatives.

Unexpected responses of the obese “cafeteria” rat to the peptide FMRF-Amide

The relationship between the acute effects of FMRF-amide on central monoamines and feeding effects were investigated simultaneously in normophagic and cafeteria rats. This tetrapeptide is considered as being representative of an endogenous related peptides family with antagonistic properties on opioid-induced behavioural effects. In normophagic rats, no feeding effect was observed, but there was a decrease in serotonergic metabolism similar to that induced by the classical antagonist, naltrexone. However, in the cafeteria rats, FMRF-amide enhanced food intake and increased serotonergic metabolism, exhibiting the classical effects of opiate agonists. Since the effects of FMRF-amide differ according to the ponderal and/or nutritional status, this peptide would appear to act rather as a modulator than a true opiate antagonist on food intake. This raises the question as to the exact role of the recently-discovered endogenous FMRF-amide related family in obesity and/or stimulated feeding patterns.

Variability of changes in obese rat brain monoamines in response to cholecystokinin

The interactions between cholecystokinin (CCK) and brain monoamines have been investigated. The data found in the literature are quite dissimilar. Several reasons for these disparities have been suggested. We have sought to test some of them, such as the strain of rat, the nutritional state (by the use of two models of obesity), the length of the peptide (CCK 8 and CCK 33), the route of administration (i.p. and i.c.v.) and the time of sacrifice. We indeed found all these experimental conditions to be the cause of differential effects on brain monoamines and metabolites. However, by repeating the same experiments several times, we did not always obtain the same variations, even under the same conditions. In addition to the different parameters tested, another source of variability exists, possibly due to the molecule itself or to seasonal variations.