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August 2010

Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.

We found that development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs. Moreover, lentivirus-mediated knockdown of striatal D2Rs rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.

Nat Neurosci. 2010 May;13(5):635-41

Behavioural satiety sequence (BSS): Separating wheat from chaff in the behavioural pharmacology of appetite.

The history of anti-obesity drug development is far from glorious, with transient magic bullets and only a handful of agents currently licensed for clinical use. In view of recent progress in our understanding of the multiplicity of signalling pathways involved in appetite regulation, and the resultant deluge of reports on the anorectic efficacy of novel therapies, it seems timely to stress the need to differentiate treatments that suppress intake by primary means from those that only indirectly achieve this endpoint. The current article reviews the conceptual history of the behavioural satiety sequence (BSS), also known as the behavioural sequence of satiety, post-ingestive satiety, and the postprandial satiety sequence. Early research confirmed that natural satiation, produced by a caloric load on the gut, is associated with a predictable transition from feeding through grooming to resting. Although many less naturalistic manipulations are also capable of reducing food intake, very few do so without disrupting the normal structure of this feeding cycle. Thus, while CCK and d-fenfluramine reduce intake by accelerating but otherwise maintaining the integrity of the BSS, other anorectic interventions disrupt the BSS through response competition (e.g. d-amphetamine), nausea/discomfort (e.g. lithium chloride) and/or interference with taste-mediated positive feedback (e.g. quinine adulteration of the diet). A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B) and 5-HT(2C) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine. Recent BSS analyses have also identified rather selective anorectic profiles for the dual noradrenaline and 5-HT reuptake inhibitor sibutramine, the orexin-1 receptor antagonist SB-334867, and the broad spectrum opioid receptor antagonist naloxone. However, similar analyses have offered little/no support for the anorectic potential of the gut peptide PYY(3-36) while the acute anorectic efficacy of cannabinoid CB1 receptor antagonist/inverse agonists appears largely to be secondary to response competition. In contrast, studies with low-dose combinations of naloxone and CB1 receptor antagonist/inverse agonists have very recently confirmed the potential of drug polytherapies not only in appetite suppression but also in attenuating/eliminating unwanted side-effects. In sum, as BSS analysis offers a reliable means of differentiating the wheat (primary anorectics) from the chaff (secondary anorectics), it should form an integral part of early phase testing in any anti-obesity drug screening programme.

Pharmacol Biochem Behav. 2010 Mar 7

Valvular heart disease associated with fenfluramine-phentermine.

BACKGROUND: Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS: We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS: Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS: These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

N Engl J Med. 1997 Aug 28;337(9):581-8

Serotonin delivery into the ventromedial nucleus of the hypothalamus affects differently feeding pattern and body weight in obese and lean Zucker rats.

AIM: To determine if central serotonin (5-HT)-induced satiety is altered in obesity. METHODS: Obese and lean Zucker rats received infusion of 5-HT (5 microg/0.5 microl/h) or saline into the ventromedial nucleus of the hypothalamus (VMN) for 2 weeks. RESULTS: In lean rats, 5-HT decreased body weight (7%) and total food intake (15%) which was due to a decreased meal size during the dark phase. In obese rats, a decrease of food intake was also observed in the dark phase, but it was compensated by an increased food intake during the light phase, resulting in no significant changes of total food intake and body weight. In obese rats, meal number but not meal size was affected by 5-HT delivery. Body fat content was not affected by 5-HT in obese rats, while cessation of 5-HT delivery in lean rats resulted in 13% increase. CONCLUSION: Intra-VMN 5-HT in obese rats did not increase meal-associated satiety as it did in lean rats, but modulated hunger. These results show that the Zucker obese phenotype is characterized by VMN resistance to 5-HT, which may contribute to neurobiological mechanisms of increased meal size and food intake and may diminish anti-obesity effects of serotonergic anorexiants.

Appetite. 2010 Apr;54(2):346-53

Effects of serotonin (5-HT)(1B) receptor ligands on cocaine-seeking behavior in rats.

Numerous data indicated a significance for the brain dopaminergic pathways in the behavioral effects of cocaine, however recent research also demonstrated involvement of serotonin (5-HT) neurotransmission and particularly 5-HT(1B) receptors in the reinforcing, discriminative stimulus and sensitizing effects of cocaine. In order to substantiate a role of these receptors in incentive motivation for cocaine, we used the extinction/reinstatement model to examine the effects of the 5-HT(1B) receptor ligands on reinstatement of extinguished cocaine-seeking behavior and food-taking behavior. Rats trained to self-administer cocaine (0.5 mg/kg/infusion) subsequently underwent extinction procedures. They were then tested for the cocaine-primed or cocaine-associated cue-induced reinstatement of extinguished cocaine-seeking behavior. Other groups of rats were trained to self-administer food (sweet milk), and after extinction they were tested for the reinstatement of food-taking behavior induced by contingent food presentation. The 5-HT(1B) receptor antagonists SB 216641 (2.5-7.5 mg/kg) and GR 127935 (2.5-10 mg/kg) dose-dependently attenuated the cocaine (10 mg/kg)- and cocaine-associated cue-induced reinstatement of cocaine-seeking behavior whereas they failed to alter reinstatement of food-taking behavior. The 5-HT(1B) receptor agonist CP 94253 (2.5 or 5 mg/kg) combined with a subthreshold priming dose of cocaine (2.5 mg/kg) potentiated reinstatement of the drug seeking-behavior, but inhibited cocaine seeking induced by a submaximal dose (10 mg/kg) of cocaine or the cocaine-associated cue. Moreover, the 5-HT(1B) receptor agonist attenuated reinstatement of food-taking behavior. Facilitatory effect of CP 94253 on cocaine-seeking behavior and its inhibitory effect on food-taking behavior were blocked by SB 216641, but its inhibitory effect on cocaine-seeking behavior remained unaffected by this 5-HT(1B) receptor antagonist. Our results indicate that tonic activation of 5-HT(1B) receptors is involved in cocaine- and cue-induced reinstatement of cocaine-seeking behavior and that the inhibitory effects of 5-HT(1B) receptor antagonists on these phenomena are directly related to motivational aspects of cocaine abuse. The facilitatory 5-HT(1B) receptor-mediated effect of the 5-HT(1B) receptor agonist on cocaine seeking may be related to the earlier reported enhancement of the rewarding properties of cocaine, while its inhibitory effect on cocaine-seeking behavior, unrelated to the 5-HT(1B) receptor activation, may result from a general reduction of motivation.

Pharmacol Rep. 2008 Nov-Dec;60(6):798-810

Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction.

BACKGROUND: Plasma tryptophan concentrations and the ratio of tryptophan to other large neutral amino acids (plasma tryptophan ratio) are reportedly low in obese subjects. The plasma tryptophan ratio predicts brain tryptophan uptake and serotonin production. If this ratio is low in obese subjects, serotonin function may also be low. Plasma tryptophan concentrations and ratios have been measured only at single time points in obese subjects; it is not known whether low values for these 2 variables persist throughout a 24-h period. OBJECTIVE: Our objective was to determine whether plasma tryptophan concentrations and ratios in obese subjects are lower than those in normal-weight subjects throughout a 24-h period and whether they increase when body weight is reduced. DESIGN: Plasma tryptophan concentrations and ratios were examined in obese subjects before and after weight loss and in nonobese control subjects. Blood samples were drawn frequently throughout the 24-h period. An insulin tolerance test was also used to determine whether weight loss altered the ability of insulin to modify plasma concentrations of tryptophan and of the other large neutral amino acids. RESULTS: Plasma tryptophan concentrations and ratios in obese subjects were low at all times; these effects persisted after weight reduction. Plasma concentrations of all the large neutral amino acids decreased during insulin infusion in all the groups. CONCLUSIONS: The low 24-h plasma tryptophan ratios in obese and formerly obese subjects suggest that brain tryptophan uptake may be continuously diminished and may remain below normal despite weight reduction.

Am J Clin Nutr. 2003 May;77(5):1112-8

Meal-induced changes in tryptophan:LNAA ratio: effects on craving and binge eating.

This study investigated the effects of meals varying in macronutrient composition on plasma tryptophan/large neutral amino acid (tryp:LNAA) ratios and subsequent appetite and mood in women defined as “food cravers.” Nine women consumed one of each of a high protein, high carbohydrate and mixed meal on three separate days. Blood samples and appetite and mood ratings were taken before and at intervals up to 150 min after meal consumption. The first subsequent ad libitum food intake was recorded in diaries. The tryp:LNAA ratio increased significantly after the carbohydrate meal compared to protein and mixed meals. No significant correlations between change in tryp:LNAA ratio and mood or macronutrient intake at the ad libitum eating episode were observed. There was a negative correlation between tryp:LNAA ratio and desire to binge eat (p=0.03) and a trend towards a negative correlation between tryp:LNAA ratio and craving for carbohydrate-rich foods (p=0.07). Participants whose ad libitum eating episode was categorized as a binge had a trend (p=0.06) toward lower plasma tryp:LNAA ratio than those who did not binge. Regression analysis showed that the effects of change in tryp:LNAA ratio on desire to binge eat was independent of meal type and changes in insulin and glucose concentrations. These findings suggest that reducing plasma tryp:LNAA ratio, via consumption of a protein-rich meal, may mediate the desire to binge eat in susceptible women.

Eat Behav. 2000 Sep;1(1):53-62

Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan.

Previous observations have shown that oral administration of 5-hydroxytryptophan (5-HTP) without dietary prescriptions causes anorexia, decreased food intake, and weight loss in obese subjects. To confirm these data over a longer period of observation and to verify whether adherence to dietary restriction could be improved by 5-HTP, 20 obese patients were randomly assigned to receive either 5-HTP (900 mg/d) or a placebo. The study was double-blinded and was for two consecutive 6-wk periods. No diet was prescribed during the first period, a 5040-kJ/d diet was recommended for the second. Significant weight loss was observed in 5-HTP-treated patients during both periods. A reduction in carbohydrate intake and a consistent presence of early satiety were also found. These findings together with the good tolerance observed suggest that 5-HTP may be safely used to treat obesity.

Am J Clin Nutr. 1992 Nov;56(5):863-7

Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients.

OBJECTIVE: In obese patients, brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan (5-HTP), the precursor of serotonin, causes decreased carbohydrate intake and weight loss. Since diabetes mellitus is associated with depressed brain serotonin, hyperphagia and carbohydrate craving, we hypothesized that in diabetic patients, orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour. To test this hypothesis, we investigated whether in diabetic patients: 1) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor, tryptophan; and 2) oral 5-HTP is effective in reducing energy and carbohydrate intake. SUBJECTS AND METHODS: 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double-blind, placebo-controlled study, and randomized to receive either 5-HTP (750 mg/d) or placebo for two consecutive weeks, during which no dietary restriction was prescribed. Energy intake and eating behaviour, as expressed by macronutrient selection, were evaluated using a daily diet diary. Plasma amino acid concentrations and body weight, as well as serum glucose, insulin and glycosylated haemoglobin were assessed. RESULTS: 20 patients (nine from the 5-HTP group and 11 from the Placebo group) completed the study. Brain tryptophan availability in diabetic patients was significantly reduced when compared to a group of healthy controls. Patients receiving 5-HTP significantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight. CONCLUSIONS: These data confirm the role of the serotonergic system in reducing energy intake, by predominantly inhibiting carbohydrate intake, and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus.

Int J Obes Relat Metab Disord. 1998 Jul;22(7):648-54

Food intake and energy expenditure in obese female bingers and non-bingers.

Since compulsive eating occurs in approximately 30% of obese females and is associated with earlier relapse following weight loss, we compared daily energy intake, dietary composition and energy expenditure among obese binge eaters and obese non-bingers. Nine obese bingers (33 +/- 4 yrs, 95 +/- 6 kg, 39 +/- 1% fat) and nine obese non-bingers (47 +/- 3 yrs, 93 +/- 5 kg, 40 +/- 1% fat) were admitted for 12 days to a metabolic unit. Binge eaters were defined as scoring > 25 on the binge eating scale (BES). During the initial 8 days, subjects ate ad libitum from two computerized vending machines offering a variety of foods and beverages. A weight maintenance diet was then provided for the next 4 days. Twenty-four hour energy expenditure (24EE) and respiratory quotient (24Q) were measured on the last day of both feeding periods in a respiratory chamber. Obese bingers showed a wider range of energy intake compared to non-bingers, but the mean daily energy intake was similar between the two groups (2,587 +/- 454 vs 2,386 +/- 201 kcal/d) during 8 days of ad libitum intake. 24EE was not different between bingers and non-bingers after 8 days of ad libitum intake (2,298 +/- 147 vs 2109 +/- 97 kcal/d, P = 0.3) or 4 days of weight maintenance diet, even more so after adjustment for differences in fat-free mass, fat mass and age. Resting metabolic rate, sleeping metabolic rate, and macronutrient intake and oxidation were also similar between groups.

Int J Obes Relat Metab Disord. 1995 Jan;19(1):11-6

Personality traits and eating behavior in the obese: poor self-control in emotional and external eating but personality assets in restrained eating.

Personality traits can give a fuller understanding for eating behaviors in obesity. The objective was to describe eating behavior (Dutch Eating Behaviour Questionnaire) in terms of the Big Five personality traits (NEO Personality Inventory-Revised) in obesity patients (n=442). Emotional eating was strongly positively associated to Neuroticism, in particular impulsiveness and depression, and further linked to lower Conscientiousness mainly seen in lower self-discipline, and lower Extraversion. External eating was likewise mainly associated to the facets impulsiveness and lower self-discipline. Restrained eating was on the other hand related to higher Conscientiousness, Extraversion and Openness, and lower Neuroticism. These results imply that poor self-control seen in impulsiveness and lower self-discipline was most important for eating due to negative emotions as well as in response to external food stimuli, suggesting that the inhibition of eating and difficulties to govern ones behavior are major aspects of these eating behaviors. Attempts to control food intake and body weight seen in restrained eating were associated with more character strengths and ambitions, and also a more outgoing personality style with more stable emotions.

Eat Behav. 2008 Aug;9(3):285-93

Emotional eating, depressive symptoms and self-reported food consumption. A population-based study.

We examined the associations of emotional eating and depressive symptoms with the consumption of sweet and non-sweet energy-dense foods and vegetables/fruit, also focusing on the possible interplay between emotional eating and depressive symptoms. The participants were 25-64-year-old Finnish men (n=1,679) and women (n=2,035) from the FINRISK 2007 Study (DILGOM substudy). The Three-Factor Eating Questionnaire-R18, Center for Epidemiological Studies Depression Scale, and a 132-item Food Frequency Questionnaire were used. Emotional eating and depressive symptoms correlated positively (r=0.31 among men and women), and both were related to a higher body mass. Emotional eating was related to a higher consumption of sweet foods in both genders and non-sweet foods in men independently of depressive symptoms and restrained eating. The positive associations of depressive symptoms with sweet foods became non-significant after adjustment for emotional eating, but this was not the case for non-sweet foods. Depressive symptoms, but not emotional eating, were related to a lower consumption of vegetables/fruit. These findings suggest that emotional eating and depressive symptoms both affect unhealthy food choices. Emotional eating could be one factor explaining the association between depressive symptoms and consumption of sweet foods, while other factors may be more important with respect to non-sweet foods and vegetables/fruit.

Appetite. 2010 Feb 4