Effects of central administration of distinct fatty acids on hypothalamic neuropeptide expression and energy metabolism.

OBJECTIVE: To investigate the differential effects of acute central administration of distinct fatty acids (FA) on food intake, body weight and energy metabolism. DESIGN: Male Sprague-Dawley rats were treated with bolus intracerebroventricular injections of control hydroxypropyl-ß-cyclodextrin (HPB) or HPB complexed with 30 nmol of saturated palmitic acid (PA), monounsaturated oleic acid (OA) or polyunsaturated ω-3 docosahexaenoic acid (DHA). Food intake, body weight, neuropeptide expression and various serum parameters were assessed. RESULTS: When compared with controls, rats injected with either OA or DHA had significantly reduced food intake and body weight for 48 h following injections. No significant changes in food intake or body weight were observed in the PA group. In conjunction with reduced food intake, hypothalamic anorexigenic pro-opiomelanocortin (POMC) gene expression was significantly augmented in the OA and DHA groups, with essentially no changes observed in the PA group. Changes in serum measures of energy metabolism also changed coinciding with the observed differences in food intake. Moreover, central administration of SHU9119, a melanocortin-4-receptor (MC4R) antagonist, completely abolished the anorexigenic actions of OA, suggesting a role for OA-induced augmentation of hypothalamic POMC expression in mediating its central inhibition of food intake. CONCLUSIONS: The hypothalamus differentially senses FA and, specifically, that OA and DHA, but not PA, reduce food intake and body weight, which may be mediated through POMC/MC4R signaling.

Reward systems and food intake: role of opioids.

Humans eat for many reasons, including the rewarding qualities of foods. A host of neurotransmitters have been shown to influence eating behavior and some of these appear to be involved in reward-induced eating. Endogenous opioid peptides and their receptors were first reported more than 30 years ago, and studies suggesting a role of opioids in the regulation of food intake date back nearly as far. Opioid agonists and antagonists have corresponding stimulatory and inhibitory effects on feeding. In addition to studies aimed at identifying the relevant receptor subtypes and sites of action within the brain, there has been a continuing interest in the role of opioids on diet/taste preferences, food reward, and the overlap of food reward with others types of reward. Data exist that suggest a role for opioids in the control of appetite for specific macronutrients, but there is also evidence for their role in the stimulation of intake based on already-existing diet or taste preferences and in controlling intake motivated by hedonics rather than by energy needs. Finally, various types of studies indicate an overlap between mechanisms mediating drug reward and palatable food reward. Preference or consumption of sweet substances often parallels the self-administration of several drugs of abuse, and under certain conditions, the termination of intermittent access to sweet substances produces symptoms that resemble those observed during opiate withdrawal. The overconsumption of readily available and highly palatable foods likely contributes to the growing rates of obesity worldwide. An understanding of the role of opioids in mediating food reward and promoting the overconsumption of palatable foods may provide insights into new approaches for preventing obesity.

Modulation of long-term potentiation in the rat hippocampus following cocaine self-administration.

Long-lasting neuroadaptations that occur during drug use and remain after withdrawal are thought to contribute to the persisting and compulsive nature of drug addiction and relapse. At the molecular and cellular levels, mechanisms that have been implicated in the normal process of memory formation are increasingly being identified as potential contributors to the persistence of the addicted state. To investigate the effect of cocaine self-administration on synaptic plasticity, rats were allowed to self-administer 0.5 mg/kg/infusion cocaine or 0.9% NaCl during 90 min sessions for 15 consecutive days. These cocaine and saline self-administration subjects were then restricted to their home cages for 3, 30, or 100 days (3, 30, and 100 day cocaine/saline withdrawal groups) before the assessment of the induction and reversal of long-term potentiation (LTP) in the CA1 region of hippocampal slices. The magnitude of LTP was increased in the 3-day cocaine withdrawal group as compared with the 3-day saline withdrawal group, but this effect was short lived, as the 30-day cocaine and saline withdrawal groups exhibited similar LTP magnitudes. Interestingly, LTP was significantly decreased in the 100-day cocaine withdrawal group compared with the 100-day saline withdrawal group. These results support the hypothesis that the capacity for LTP is persistently altered after withdrawal from exposure to an addictive substance. In addition, this alteration can be differentially expressed such that depending upon the duration of the withdrawal period following the last drug exposure, LTP may be enhanced, unchanged, or suppressed.

Food presentation and energy intake in a feeding laboratory study of subjects with binge eating disorder.

OBJECTIVE: The purpose of this study was to examine the influence of the number of foods presented and the amount of food presented on overeating or binge eating behavior in obese subjects with and without binge eating disorder (BED). METHOD: Ten subjects (5 BED, 5 non-BED), male and female, aged 18-65, participated. Their body weight was > or =130% of their ideal body weight (IBW). They were evaluated in a feeding laboratory setting on four occasions when they were presented with (a) either one or two binge foods presented in (b) either two or four times the amount of their self-reported usual intake during a binge/overeating episode. Measurement included energy intake and self-recorded measures of hunger, fullness, anxiety, and depression. RESULTS: The results indicated that the number and amount of food presented influenced significantly the amount of food consumed. Although subjects with BED tended to eat more than the non-BED obese, the differences did not reach statistical significance. DISCUSSION: The results have implications for the interpretation of results obtained in feeding laboratory settings, suggesting that attention needs to be given to both the number and amount of foods presented because both variables have an impact on the amount of food eaten during overeating or binge eating episodes.

Long-term follow-up of patients' status after gastric bypass.

BACKGROUND: We report a long-term (13-15 year) follow-up of a cohort of 100 patients who underwent gastric bypass for morbid obesity. METHODS: Sources of information include baseline data collected before surgery and information obtained at follow-up interview including data on weight history, psychosocial functioning, and medical complications. RESULTS: Mean age at follow-up was 56.8 years. The mean weight loss at long-term follow-up was 29.5 kg (range -13.6 to 93.6 kg). Three subjects weighed more at long-term follow-up than before the operation. Overall, 74% of those interviewed indicated that the gastric bypass had benefited them in terms of their physical health. However, 68.8% reported continued problems with vomiting and 42.7% with "plugging". Eight had died. CONCLUSION: The findings in this study suggest that at long-term follow-up the majority of individuals who have undergone gastric bypass feel that the procedure benefited them, although some complications including difficulties with "plugging" and vomiting were present at long-term follow-up.

Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms.

Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17beta-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors alpha and beta in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor alpha in males and females, but there was a significant increase in expression levels in response to 17beta-estradiol. Stimulation of benign and malignant thyroid cells with 17beta-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G(1)/S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17beta-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17beta-estradiol. In addition, 17beta-estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17beta-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17beta-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17beta-estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.

Sucrose intake predicts rate of acquisition of cocaine self-administration.

RATIONALE: A number of studies have indicated a relationship between the intake of palatable foods or fluids and drug self-administration. OBJECTIVES: Two experiments were conducted to determine whether the intake of sucrose or fat was related to subsequent cocaine self-administration. METHODS: In separate groups of rats, sucrose or fat was presented for 60 min daily for 7 days. On day 8, a mild stressor (saline injection) was given just prior to sucrose or fat presentation. Rats were then catheterized and tested for cocaine self-administration on a fixed ratio schedule at doses from 0.2 mg/kg to 1.0 mg/kg per infusion and on a progressive ratio schedule at doses from 0.2 mg/kg to 1.5 mg/kg per infusion. RESULTS: Sucrose intake after a mild stressor was significantly related to time to acquisition, with those rats consuming the most sucrose meeting the acquisition criterion sooner than those rats consuming lower amounts of sucrose. Subsequent to acquisition, however, low and high sucrose feeders did not consistently differ in the amount of cocaine self-administered. No relationship was observed between fat intake and rate of acquisition. CONCLUSION: These results provide additional evidence of a relationship between sucrose intake and drug reward, and suggest that stress reactivity may be an important component of this relationship.

Cardiovascular regulatory actions of the hypocretins in brain.

The hypocretins, also known as the orexins, are alternate translation products of a single gene. The recognition of their production in neurons of the rostral diencephalon, and their axonal localization in brain sites known to be important in the control of appetite, led to the demonstration of their orexogenic actions. However, these peptides are not as potent as other appetite stimulating neuropeptides and they have been localized in areas of brain more related to cardiovascular function. We verified the orexogenic actions of hypocretin-1 (Hcrt-1) and hypocretin-2 (Hcrt-2) in an ad libitum feeding model and identified the threshold dose to be 1 nmol when given into the lateral cerebroventricle (i.c. v.). Even at threshold doses for feeding, both Hcrt-1 and Hcrt-2 given i.c.v. into conscious, unrestrained rats stimulated significant elevations in mean arterial blood pressure, that appeared dose related. These elevations were relatively long lasting, mirroring the time course of a pressor dose of angiotensin II (0.1 nmol i.c.v.); however, the magnitude of blood pressure elevation to hypocretin did not equal that of A II. These data suggest an additional, non-appetitive action of the hypocretins and indicate that the peptide and receptor mapping studies may have predicted important roles for the peptides in the central nervous system control of cardiovascular function.

The relationship between intravenous cocaine self-administration and avidity for saccharin.

Two experiments were conducted to determine whether measures of saccharin intake could be used as a predictor of intravenous cocaine self-administration. Saccharin avidity, defined as the ratio of total daily fluid intake when saccharin and water were available to total intake when only water was available, was measured in male rats. Cocaine self-administration (0.4 mg/kg/infusion) was subsequently measured in an initial 18-h session, followed by daily 1-h sessions in which the infusion dose and the reinforcement schedule were varied. In the initial overnight session, some rats obtained the maximum or near-maximum number of infusions; this high level of cocaine intake was unrelated to saccharin avidity. In the remaining rats, there was a pattern somewhat resembling an "inverted-U," in which rats with low or high avidity self-administered less cocaine than those with intermediate avidity. This pattern reemerged later in the experiment when rats were tested at a low cocaine infusion dose combined with a FR-6 reinforcement schedule. In a second experiment, no significant relationship was observed between the self-administration of a lower cocaine dose (0.125 mg/kg/infusion) and avidity for either saccharin or the artificial sweetener SC-45647. Although these results are consistent with a previous report indicating no simple relationship between saccharin preference and the acquisition of cocaine self-administration, they do suggest that a more complex relationship may be observed under some conditions. Additional research with other drugs, as well as with caloric and noncaloric sweeteners, will be needed to determine the usefulness of taste measures in identifying or treating substance abuse.

Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens.

The present study was designed to further investigate the nature of feeding induced by opioid stimulation of the nucleus accumbens through an examination of the effects of intra-accumbens (ACB) opioids on macronutrient selection. In 3-hr tests of free-feeding (satiated) rats, intra-ACB administration of the mu receptor agonist D-Ala2,N,Me-Phe4, Gly-ol5-enkephalin (DAMGO; 0, 0.025, 0.25 and 2.5 micrograms bilaterally) markedly enhanced the intake of fat or carbohydrate when the diets were presented individually (although the effect on fat intake was much greater in magnitude). Intra-ACB injections of DAMGO, however, produced potent preferential stimulatory effects on fat ingestion with no effect on carbohydrate ingestion when both fat and carbohydrate diets were present simultaneously. Moreover, this selective stimulation of fat intake was independent of base-line diet preference and could be blocked by systemic injection of naltrexone (5 mg/kg). We also examined the effect of 24-hr food deprivation on the pattern of macronutrient intake in rats with access to both carbohydrate and fat. In contrast to the DAMGO-induced selective enhancement of fat intake, food deprivation significantly increased the intake of both diets to the same extent; however, in this case, only the stimulated fat intake was blocked by systemic naltrexone. Intra-ACB administration of DAMGO in hungry rats produced an effect similar to that observed in free-feeding rats; preference was strongly shifted to fat intake. Similarly, the opioid antagonist naltrexone (20 micrograms) infused directly into ACB preferentially decreased fat intake in hungry rats. These findings suggest that endogenous opioids within the ventral striatum may participate in the mechanisms governing preferences for highly palatable foods, especially those rich in fat.

Intravenous self-administration of cathinone by rats.

Cathinone is the principal psychoactive constituent in leaves of the khat shrub. In some parts of the world, khat leaves are commonly chewed for their stimulant effects. While it has been demonstrated that rhesus monkeys will self-administer cathinone, there has been no demonstration of cathinone self-administration in rats. Two experiments were therefore conducted on rats fitted with intravenous catheters. On an FR 1 reinforcement schedule, the dose response curve for cathinone was shifted to the left of that for cocaine by a factor of approximately two. Within the sessions, cocaine infusions tended to be spaced evenly, whereas cathinone infusions were generally more frequent in the early portions of the session than later. In a second experiment, pretreatment with the dopamine D1-type receptor antagonist SCH 23390, at 10mg/kg, significantly increased the number of infusions obtained. Pretreatment with the D2-type receptor antagonist spiperone caused only a slight, non-significant increase in cathinone self-administration. These results demonstrate that cathinone is a potent reinforcer in rats and suggest a role for D1-type dopamine receptors in mediating its reinforcing effects.

Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters.

To test the hypothesis that endogenous opiate peptides selectively influence hedonic response to sweet and high-fat foods, the opiate antagonist naloxone, opiate agonist butorphanol, and a saline placebo were administered by intravenous infusion to 16 obese and 25 normal-weight women. Twenty of the women (10 obese, 10 lean) fulfilled DSM-III-R diagnostic criteria for bulimia nervosa, as determined by psychiatric interview. During drug infusion the women tasted and rated 20 sweetened dairy products and were presented with eight snack foods of varying sugar and fat content. Naloxone suppressed hedonic responses in all subject groups and suppressed the consumption of sweet and high-fat foods in binge eaters, but not in nonbingers. Food intakes of obese women were not affected by naloxone. Butorphanol had no effect on either hedonic response or on food consumption in any group. Although opiate blockade is not a viable strategy for weight reduction in the treatment of obesity, it may be useful in the clinical management of the binge-eating disorder.

Clinical characteristics of eating disorder patients who report sexual or physical abuse.

At initial contact in an eating disorders clinic, 712 female eating disorder patients were asked if they had been physically or sexually abused as children. They also completed a Beck Depression Inventory (BDI) and an Eating Disorders Inventory (EDI). Their eating disorder symptom frequency and severity was determined. They were asked if they had alcohol problems, had attempted suicide, or had shoplifting problems. Twenty-nine percent reported sexual abuse. Twenty-five percent reported physical abuse. There was no correlation between reports of abuse and symptom frequency or severity. The abused subjects were more depressed on the BDI and showed more psychological disturbance on the EDI. Abused subjects were much more likely than nonabused subjects to report alcohol problems, suicide attempts, or shoplifting.

Intravenous morphine self-administration by rats with low versus high saccharin preferences.

An experiment was performed to determine the relationship between saccharin preference and the self-administration of morphine via the oral and intravenous routes. On the basis of voluntary intake of a saccharin solution by male rats, low and high preference groups were formed. Rats selected for high saccharin preference self-administered more morphine intravenously than rats selected for low preference. The two groups did not differ in oral morphine intake. The positive relationship between the intake of saccharin and intravenous morphine self-administration may be due to their mediation by a common mechanism. Measures of taste sensitivity or preference may be useful in identifying individuals at risk for drug abuse.

Ethanol reinforcement and its relationship to saccharin preference in Wistar rats.

Forty rats were given a choice between 0.1% sodium saccharin and water. Based on their intakes, three groups of six rats representing high, intermediate, and low saccharin preferences were selected. These rats were reduced to 80% of their free-feeding weights. Ethanol was established as a reinforcer by use of a food-induced drinking procedure. Between-group differences were assessed based on response rates across acquisition sessions (0, 1, 2, 4, 5.7, 8%, w/v), a fixed-ratio series (1, 2, 4, 8, 1), and a concentration series (8, 5.7, 4, 2, 2, 4, 5.7, 8, 11.3, 16, 22.6, 32, 8%, w/v). In 29 of 32 conditions which were analyzed, the mean number of responses for ethanol was higher for the high saccharin preference group than for the low, and in 25 of 32 conditions, the intermediate group fell between the high and the low. However, there was considerable variability within groups across all conditions, such that mean between-group differences were not significant. This variability may be reduced by considering diet preferences in addition to saccharin preference. Nonetheless, these results offer limited support for the increasing body of evidence indicating a relationship between the factors mediating ethanol self-administration and those involving ingestion of palatable foods and fluids.

Morphine enhances hedonic taste palatability in rats.

The question of whether opiates stimulate feeding by enhancing taste pleasure was investigated by examining the effect of morphine upon hedonic and aversive reactions to taste (tongue protrusions, gapes, etc.). Rats (n = 12) were given SC injections of morphine (4 mg/kg) or equal volumes of isotonic saline 2 h after the start of their daily light cycle. Food intake was measured in a 2-h test. On days when they were given morphine, rats ate significantly more food than when given saline. Hedonic and aversive taste reactions were elicited by an infusion of sucrose-quinine solution into the mouth and were measured subsequently in a slow-motion video analysis. The same rats that showed an increase in food intake after treatment with morphine showed a significant increase in their positive hedonic responses. Aversive reactions were unchanged by morphine. The results support the hypothesis that morphine enhances feeding by increasing the hedonic palatability of food.

The effects of continuous morphine infusion on diet selection and body weight.

The administration of morphine causes a short-term increase in food intake, and repeated administration of morphine has been shown to cause progressively larger increases in intake and/or the relative intake of dietary fat. In this experiment, we measured the effects of continuous morphine infusions on diet choice and total intake. Male rats were given ad lib access to two diets: a high-carbohydrate diet (80% carbohydrate, 20% protein) and a high-fat diet (80% fat, 20% protein). Diet intakes were measured daily for 21 days. Via the implantation of osmotic minipumps, one group received continuous infusions of morphine sulfate (approx. 2.8 mg/kg/h) for days 1-7 and of saline for days 8-14. A second group was infused with saline for days 1-7 and with morphine for days 8-14. A third group received sham surgery but no minipumps. Total caloric intake was significantly decreased on the final 6 days of morphine infusions. The percentage of total caloric intake consumed from the high-fat diet was significantly increased for the first 2-3 days of morphine treatment; this effect was due to an initial reduction in carbohydrate intake and an increase in fat intake. Over the course of the infusion period, fat intake gradually decreased and carbohydrate intake increased. The effects of morphine when infused on days 1-7 were similar to those observed when the drug was infused during days 8-14.(ABSTRACT TRUNCATED AT 250 WORDS)

Centrally administered mu- and delta-opioid agonists increase operant responding for saccharin.

In previous reports, ICV administration of selective mu- or delta-opioid receptor agonists was found to stimulate the intake of saccharin and salt solutions in nondeprived rats. In the present study, we measured the effects of selective mu-, delta-, and kappa-agonists on operant responding for saccharin. The selective mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and the selective delta-agonist [D-Thr2]-leucine enkephalin-Thr (DTLET) increased responding, whereas the kappa-agonist dynorphin A analog kappa ligand (DAKLI) had no significant effect. These results agree with previous studies on saccharin and salt intake and are consistent with the possibility that the effects of opioids on the intake of these fluids are mediated via enhancement of activity in brain reward pathways.

Morphine-induced feeding: a comparison of the Lewis and Fischer 344 inbred rat strains.

Rats of the Lewis inbred strain have been shown to self-administer more morphine than rats of the inbred Fischer 344 (F344) strain. Because morphine reward and opioid-induced feeding may involve a common mechanism, we measured whether these strains also differ in their feeding response to morphine. In Experiment 1, rats were maintained on powdered rat chow and given SC injections of morphine sulfate (1, 3, and 10 mg/kg) and saline; all rats were tested with all doses. Food intake was measured 2, 4, and 6 h after injection. In Experiment 2, rats were given a choice of two diets: a fat/protein diet and a carbohydrate/protein diet. Feeding responses to morphine were measured in a manner identical to that in Experiment 1. In both experiments, the feeding response to morphine was greater in Lewis rats than in F344 rats. To determine whether these responses might be explained by differences in the levels of morphine achieved in the blood or brain, rats of each strain were given SC injections of morphine sulfate (3 mg/kg) and sacrificed either 30 min or 3 h after injection. Serum and brain morphine levels were determined by radioimmunoassay. Lewis rats had significantly less brain morphine than F344 rats at 30 min; they did not differ in morphine content at 3 h. Serum levels were similar at 30 min; at 3 h, F344 rats had slightly lower levels than Lewis rats. Thus, differences in tissue levels cannot readily explain the differences in feeding responses to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)