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1.
ACS Chem Neurosci ; 5(10): 1020-31, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25141170

ABSTRACT

The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, ß-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic stability, thus minimizing their use as probes to characterize the overlapping pharmacological and physiological functions of the melanocortin receptor subtypes. In the present study, an engineered template, in which the peptide backbone was modified by a heterocyclic reverse turn mimetic at the Trp(7) residue, was synthesized using solid phase peptide synthesis and characterized by a ß-galactosidase cAMP based reporter gene assay. The functional assay identified a ∼5 nM mouse MC4R agonist (AST3-88) with more than 50-fold selectivity over the mMC3R. Biophysical studies (2D (1)H NMR spectroscopy and molecular dynamics) of AST3-88 identified a type VIII ß-turn secondary structure spanning the pharmacophore domain stabilized by the intramolecular interactions between the side chains of the His and Trp residues. Enzymatic studies of AST3-88 revealed enhanced stability of AST3-88 over the α-MSH endogenous peptide in rat serum. Upon central administration of AST3-88 into rats, a decreased food intake response was observed. This is the first study to probe the in vivo physiological activity of this engineered peptide-heterocycle template. These findings advance the present knowledge of pharmacophore design for potent, selective, and metabolically stable melanocortin ligands.


Subject(s)
Neurotransmitter Agents/pharmacology , Peptides, Cyclic/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Chromatography, Liquid , Drug Evaluation, Preclinical , Eating/drug effects , HEK293 Cells , Humans , Male , Mass Spectrometry , Mice , Molecular Dynamics Simulation , Molecular Structure , Neurotransmitter Agents/chemical synthesis , Peptides, Cyclic/chemical synthesis , Proton Magnetic Resonance Spectroscopy , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 3/agonists , Receptor, Melanocortin, Type 3/metabolism , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Transfection , alpha-MSH/metabolism
2.
Drug Metab Dispos ; 41(1): 79-88, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23034697

ABSTRACT

Rodent animal models have been widely used for studying neurologic and toxicological events associated with cocaine abuse. It is known that the mouse is more susceptible to cocaine-induced hepatotoxicity (CIH) than the rat. However, the causes behind this species-dependent sensitivity to cocaine have not been elucidated. In this study, cocaine metabolism in the mouse and rat was characterized through LC-MS-based metabolomic analysis of urine samples and were further compared through calculating the relative abundance of individual cocaine metabolites. The results showed that the levels of benzoylecgonine, a major cocaine metabolite from ester hydrolysis, were comparable in the urine from the mice and rats treated with the same dose of cocaine. However, the levels of the cocaine metabolites from oxidative metabolism, such as N-hydroxybenzoylnorecgonine and hydroxybenzoylecgonine, differed dramatically between the two species, indicating species-dependent cocaine metabolism. Subsequent structural analysis through accurate mass analysis and LC-MS/MS fragmentation revealed that N-oxidation reactions, including N-demethylation and N-hydroxylation, are preferred metabolic routes in the mouse, while extensive aryl hydroxylation reactions occur in the rat. Through stable isotope tracing and in vitro enzyme reactions, a mouse-specific α-glucoside of N-hydroxybenzoylnorecgonine and a group of aryl hydroxy glucuronides high in the rat were identified and structurally elucidated. The differences in the in vivo oxidative metabolism of cocaine between the two rodent species were confirmed by the in vitro microsomal incubations. Chemical inhibition of P450 enzymes further revealed that different P450-mediated oxidative reactions in the ecgonine and benzoic acid moieties of cocaine contribute to the species-dependent biotransformation of cocaine.


Subject(s)
Cocaine/metabolism , Metabolomics , Animals , Mice , Rats
3.
Neurosci Biobehav Rev ; 37(9 Pt A): 2047-58, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23237885

ABSTRACT

One of the defining characteristics of the research of Ann E. Kelley was her recognition that the neuroscience underlying basic learning and motivation processes also shed significant light upon mechanisms underlying drug addiction and maladaptive eating patterns. In this review, we examine the parallels that exist in the neural pathways that process both food and drug reward, as determined by recent studies in animal models and human neuroimaging experiments. We discuss contemporary research that suggests that hyperphagia leading to obesity is associated with substantial neurochemical changes in the brain. These findings verify the relevance of reward pathways for promoting consumption of palatable, calorically dense foods, and lead to the important question of whether changes in reward circuitry in response to intake of such foods serve a causal role in the development and maintenance of some cases of obesity. Finally, we discuss the potential value for future studies at the intersection of the obesity epidemic and the neuroscience of motivation, as well as the potential concerns that arise from viewing excessive food intake as an "addiction". We suggest that it might be more useful to focus on overeating that results in frank obesity, and multiple health, interpersonal, and occupational negative consequences as a form of food "abuse".


Subject(s)
Behavior, Addictive/physiopathology , Brain/physiopathology , Motivation/physiology , Neural Pathways/physiopathology , Obesity/physiopathology , Reward , Animals , Humans
4.
J Lipid Res ; 53(11): 2318-30, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22904346

ABSTRACT

During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury.


Subject(s)
Cocaine/toxicity , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Animals , Chemical and Drug Induced Liver Injury/metabolism , Chromatography, Liquid , Fatty Acids , In Vitro Techniques , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Oxidation-Reduction/drug effects , PPAR alpha/metabolism , Palmitoylcarnitine/metabolism
5.
Pharmacol Biochem Behav ; 100(3): 581-6, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21925200

ABSTRACT

Melanin concentrating hormone (MCH) stimulates feeding driven by energy needs and reward and modifies anxiety behavior. Orexigenic peptides of similar characteristics, including nociceptin/orphanin FQ, Agouti-related protein and opioids, increase consumption also by reducing avoidance of potentially tainted food in animals displaying a conditioned taste aversion (CTA). Herein, using real-time PCR, we assessed whether expression levels of genes encoding MCH and its receptor, MCHR1, were affected in CTA in the rat. We also investigated whether injecting MCH intracerebroventricularly (ICV) during the acquisition and retrieval of LiCl-induced CTA, would alleviate aversive responses. MCHR1 gene was upregulated in the hypothalamus and brain stem of aversive animals, MCH mRNA was significantly higher in the hypothalamus, whereas a strong trend suggesting upregulation of MCH and MCHR1 genes was detected in the amygdala. Despite these expression changes associated with aversion, MCH injected prior to the induction of CTA with LiCl as well as later, during the CTA retrieval upon subsequent presentations of the aversive tastant, did not reduce the magnitude of CTA. We conclude that MCH and its receptor form an orexigenic system whose expression is affected in CTA. This altered MCH expression may contribute to tastant-targeted hypophagia in CTA. However, changing the MCH tone in the brain by exogenous peptide was insufficient to prevent the onset or facilitate extinction of LiCl-induced CTA. This designates MCH as one of many accessory molecules associated with shaping an aversive response, but not a critical one for LiCl-dependent CTA to occur.


Subject(s)
Brain/metabolism , Dysgeusia/metabolism , Gene Expression Regulation , Hypothalamic Hormones/metabolism , Melanins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Pituitary Hormones/metabolism , Receptors, Somatostatin/metabolism , Animals , Brain Stem/metabolism , Conditioning, Psychological , Dysgeusia/drug therapy , Hypothalamic Hormones/administration & dosage , Hypothalamic Hormones/genetics , Hypothalamic Hormones/therapeutic use , Hypothalamus/metabolism , Injections, Intraventricular , Male , Melanins/administration & dosage , Melanins/genetics , Melanins/therapeutic use , Nerve Tissue Proteins/administration & dosage , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/therapeutic use , Organ Specificity , Pituitary Hormones/administration & dosage , Pituitary Hormones/genetics , Pituitary Hormones/therapeutic use , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Receptors, Somatostatin/genetics , Up-Regulation
6.
Biochem Biophys Res Commun ; 408(3): 422-6, 2011 May 13.
Article in English | MEDLINE | ID: mdl-21514276

ABSTRACT

Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.


Subject(s)
Brain/metabolism , Gene Expression Regulation , Oxo-Acid-Lyases/metabolism , Oxytocin/genetics , Oxytocin/metabolism , Satiety Response , Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mixed Function Oxygenases , Neurons/metabolism
7.
Peptides ; 31(7): 1346-52, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20399242

ABSTRACT

Increased tone of orexigens mediating reward occurs upon repeated consumption of sweet foods. Interestingly, some of these reward orexigens, such as opioids, diminish activity of neurons synthesizing oxytocin, a nonapeptide that promotes satiety and feeding termination. It is not known, however, whether consumption-related activity of the central oxytocin system is modified under chronic sugar feeding reward itself. Therefore, we examined how chronic consumption of a rewarding high-sucrose (HS) vs. bland cornstarch (CS) diet affected the activity of oxytocin cells in the hypothalamus at the time of meal termination. Schedule-fed (2h/day) rats received either a HS or CS powdered diet for 20 days. On the 21st day, they were given the same or the opposite diet, and food was removed after the main consummatory activity was completed. Animals were perfused 60 min after feeding termination and brains were immunostained for oxytocin and the marker of neuronal activity, c-Fos. The percentage of c-Fos-positive oxytocin cells in the hypothalamic paraventricular nucleus was significantly lower in rats chronically exposed to the HS than to the CS diet, regardless of which diet they received on the final day. A similar pattern was observed in the supraoptic nucleus. We conclude that the chronic rather than acute sucrose intake reduces activity of the anorexigenic oxytocin system. These findings indicate that chronic consumption of sugar blunts activity of pathways that mediate satiety. We speculate that a reduction in central satiety signaling precipitated by regular intake of foods high in sugar may lead to generalized overeating.


Subject(s)
Dietary Sucrose/administration & dosage , Neurons/metabolism , Oxytocin/metabolism , Satiation/physiology , Animals , Food Preferences , Immunohistochemistry , Male , Rats , Rats, Sprague-Dawley
8.
Physiol Behav ; 99(4): 529-33, 2010 Mar 30.
Article in English | MEDLINE | ID: mdl-20096717

ABSTRACT

The use of rats differing in the intake of sweet substances has highlighted some interesting parallels between taste preferences and drug self-administration. For example, rats selectively bred to consume high (HiS) or low (LoS) amounts of a 0.1% saccharin solution (when compared to water consumption), show corresponding differences across several measures of cocaine self-administration (HiS>LoS). In this study, we measured whether the two strains also differ when response requirements are imposed for obtaining a sucrose reinforcer. Male HiS and LoS rats were measured for operant responding for sucrose pellets under fixed-ratio (FR) schedules of 1, 3, 5 and 10 and under a progressive-ratio (PR) schedule, during which the response requirement for each successive pellet increased exponentially. The effect of systemic naltrexone (0.3, 1 and 3mg/kg) on PR responding for sucrose pellets was also tested. Under all FR and PR schedules, the number of pellets obtained by the LoS rats were significantly lower than those obtained by the HiS rats. Although the LoS weighed more than the HiS rats, this difference does not appear to explain differences in operant behavior. No strain differences in the effect of naltrexone were observed; the 3mg/kg dose reduced the number of pellets obtained in both strains. Measures of locomotor activity taken prior to operant trials suggest that the differences in responding were not due to differences in general activity levels. These studies provide further characterization of the HiS and LoS rat lines by demonstrating that motivation to consume sucrose is greater in HiS than in LoS rats.


Subject(s)
Behavior, Addictive/physiopathology , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Saccharin/adverse effects , Sucrose/pharmacology , Sweetening Agents/pharmacology , Animals , Behavior, Addictive/drug therapy , Behavior, Addictive/genetics , Dose-Response Relationship, Drug , Food Preferences/drug effects , Food Preferences/physiology , Male , Motor Activity/drug effects , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Rats , Reinforcement Schedule , Self Administration/methods , Sucrose/administration & dosage , Sweetening Agents/administration & dosage
9.
Biol Psychiatry ; 65(7): 607-13, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19103435

ABSTRACT

BACKGROUND: Weight gain has been associated with many second generation antipsychotics (SGAs). A variety of theories have been put forward as to the etiology of SGA-associated weight gain. Modafinil possesses pharmacologic effects that could influence the weight gain associated with SGAs. The objective of this trial was to determine the effect of modafinil on olanzapine-associated weight gain. METHODS: This study was a 3-week, randomized, double-blind, placebo-controlled trial. All subjects received olanzapine titrated to 10 mg/day. Concurrently, subjects were randomized to receive modafinil titrated to 200 mg/day or placebo. Weight and feeding lab assessments were conducted at baseline and endpoint. RESULTS: Fifty subjects were enrolled in the study with 20 subjects per group completing the trial. The primary outcome variable was change in the body mass index (BMI) over the 3 weeks of the trial. Increases in BMI were observed in both groups. However, analysis of covariance, controlled for baseline BMI, revealed that the olanzapine/placebo group had a greater increase in BMI at end point compared with the olanzapine/modafinil group (.89 +/- .59 vs. .47 +/- .50 kg/m(2), p < .05). When controlled for gender, the comparison showed a significant difference between groups at week 1 but not at weeks 2 or 3. CONCLUSIONS: The results of this trial should not be extrapolated to clinical practice at this time. These data do serve to support further evaluation in a patient population to determine if the weight modifying effect of modafinil can be demonstrated over a longer period of time.


Subject(s)
Antipsychotic Agents/adverse effects , Benzhydryl Compounds/pharmacology , Benzodiazepines/adverse effects , Central Nervous System Stimulants/pharmacology , Weight Gain/drug effects , Adult , Antipsychotic Agents/administration & dosage , Benzhydryl Compounds/administration & dosage , Benzodiazepines/administration & dosage , Body Mass Index , Central Nervous System Stimulants/administration & dosage , Female , Humans , Male , Modafinil , Olanzapine
10.
J Clin Psychopharmacol ; 28(1): 21-6, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18204336

ABSTRACT

To thoroughly investigate the phenomenon of atypical antipsychotic-associated weight gain, a feeding laboratory paradigm was developed that included obtaining plasma levels of the orexigenic peptide ghrelin that is associated with appetite and eating. This study is a randomized, double-blind, parallel group trial comparing the effects of a 2-week exposure to olanzapine, risperidone, or placebo on plasma ghrelin area under the plasma-time curve (AUC) in 28 healthy human subjects. Subjects were randomized to receive olanzapine, risperidone, or placebo and titrated over 4 days to 10 mg/d or 4 mg/d, respectively. The mean dose at end point was 8.6 + 1.8 mg/d for the olanzapine group and 2.8 + 0.8 mg/d for the risperidone group. Weight changes were significantly different between groups at end point (F2,44 = 10.193; P = 0.0001). The olanzapine group demonstrated a significant increase in weight at end point (2.25 + 1.84 kg) compared with placebo (0.13 + 1.05 kg; P = 0.007). Because of the small subject number, the comparisons between olanzapine and risperidone and risperidone and placebo did not reach statistical significance, although olanzapine's mean weight gain was numerically greater than that of risperidone (2.25 + 1.84 kg vs 1.10 + 0.99 kg) and risperidone's mean weight gain was numerically larger than placebo (1.10 + 0.99 kg vs 0.13 + 1.05 kg). The baseline adjusted Bonferroni corrected contrast of end point ghrelin AUC demonstrated a significant difference between groups (F2,24 = 4.40; P = 0.024), and the post hoc analysis revealed a significant decrease in ghrelin AUC for the olanzapine group in comparison with the risperidone group (P = 0.021) but not between risperidone and placebo or olanzapine and placebo. Ghrelin AUC values did not change significantly from baseline to end point in either of the other 2 groups. The difference between groups approached but did not reach significance (F2,23 = 3.299; P = 0.055) when body mass index change was included as a covariate, suggesting that the difference in ghrelin AUC change followed the change in body weight. Sedation associated with both active drugs (P = 0.006) and "stuffy nose" associated with risperidone (P = 0.020) were the only statistically different adverse reactions when compared with placebo. Thus, a human feeding laboratory paradigm using a brief exposure to atypical antipsychotics functions as a method to investigate pharmacologically induced weight gain and its association with changes in the orexigenic peptide ghrelin. This rejects the hypothesis that ghrelin levels are elevated by the antipsychotic and that this is a potential cause of the weight gain phenomenon.


Subject(s)
Antipsychotic Agents/pharmacology , Benzodiazepines/pharmacology , Ghrelin/blood , Risperidone/pharmacology , Adult , Antipsychotic Agents/administration & dosage , Area Under Curve , Benzodiazepines/administration & dosage , Benzodiazepines/adverse effects , Double-Blind Method , Feeding Behavior/drug effects , Female , Humans , Male , Olanzapine , Risperidone/administration & dosage , Risperidone/adverse effects , Weight Gain/drug effects
11.
J Clin Psychopharmacol ; 25(5): 413-8, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16160615

ABSTRACT

To thoroughly investigate the phenomenon of atypical antipsychotic associated weight gain, a feeding laboratory paradigm was developed. This study is a randomized, double-blind, parallel group trial comparing the tolerability and effects of a two-week exposure to olanzapine, risperidone or placebo on weight, resting energy expenditure (REE), and eating behaviors in 48 healthy human subjects. Subjects were randomized to receive olanzapine, risperidone, or placebo and titrated over four days to 10 mg/d, or 4 mg/d, respectively. The mean dose at endpoint was 8.75 mg/day for the olanzapine group and 2.88 mg/d risperidone group. Weight changes were significantly different between groups at midpoint (F = 5.477, df = 2, 44, P = .0001). The olanzapine group demonstrated a significant increase in weight at midpoint (1.59 + 1.80 kg, P = .002) and endpoint (2.25 + 1.62 kg, P = .0001) compared to placebo and at endpoint compared to risperidone (1.05 + 1.15 kg, P = .015). Resting energy expenditures corrected for fat free mass did not reveal any differences between groups. Olanzapine subjects demonstrated significantly more dry mouth and sedation versus placebo while risperidone subjects experienced significantly more sedation, dry mouth, dizziness stuffy nose and restlessness than placebo and more dizziness and stuffy nose versus olanzapine subjects. Thus, a human feeding lab paradigm utilizing a brief exposure to atypical antipsychotics functions as a method to investigate pharmacologically induced weight gain.


Subject(s)
Antipsychotic Agents/pharmacology , Feeding Behavior/drug effects , Risperidone/pharmacology , Adolescent , Adult , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Benzodiazepines/administration & dosage , Benzodiazepines/adverse effects , Benzodiazepines/pharmacology , Double-Blind Method , Energy Intake/drug effects , Female , Humans , Hunger/drug effects , Male , Middle Aged , Olanzapine , Risperidone/administration & dosage , Satiety Response/drug effects , Weight Gain/drug effects
12.
Brain Res ; 1031(2): 194-201, 2005 Jan 21.
Article in English | MEDLINE | ID: mdl-15649444

ABSTRACT

Many studies have reported relationships between the intake or preference for sweets and the effects or self-administration of drugs of abuse. This study was conducted to determine whether intermittent access to sucrose would alter the activity response to an injection of cocaine (15 mg/kg, i.p.) or the degree to which repeated cocaine injections produce behavioral sensitization. Nondeprived rats were given 1 h access to granulated sucrose, ground chow, or alternating sucrose and chow for 38 days. Activity levels were measured after injections of saline and cocaine. Rats were also tested after a total of seven cocaine injections, and again 14 days later with no intervening treatments. There was an on overall facilitation of the response to cocaine in rats exposed to sucrose, compared to rats exposed only to ground chow. Subsequent analyses indicated that after the seventh cocaine injection, there was a significant increase in activity of the sucrose group early in the session (compared to the chow group). When tested 14 days later, there was a prolongation of the effect of cocaine in the sucrose group. These results are in partial agreement with the results of others on amphetamine-elicited activity and suggest that some degree of potentiation or cross-sensitization between sucrose and psychostimulants is possible.


Subject(s)
Central Nervous System Stimulants/pharmacology , Cocaine/pharmacology , Motor Activity/drug effects , Sucrose/administration & dosage , Taste/physiology , Administration, Oral , Analysis of Variance , Animals , Drug Synergism , Feeding Behavior/physiology , Locomotion/drug effects , Male , Rats , Rats, Sprague-Dawley , Time Factors
13.
Am J Clin Nutr ; 78(4): 834S-842S, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14522747

ABSTRACT

The prevalence of obesity has increased dramatically in recent years in the United States, with similar patterns seen in several other countries. Although there are several potential explanations for this dramatic increase in obesity, dietary influences are a contributing factor. An inverse correlation between dietary sugar intake and body mass index has been reported, suggesting beneficial effects of carbohydrate intake on body mass index. In this review we discuss how sugars interact with regulatory neurochemicals in the brain to affect both energy intake and energy expenditure. These neurochemicals appear to be involved in dietary selection, and sugars and palatable substances affect neurochemical changes in the brain. For example, rats that drink sucrose solutions for 3 wk have major changes in neuronal activity in the limbic area of the brain, a region involved in pleasure and other emotions. We also investigate the relations between sucrose (and other sweet substances), drugs of abuse, and the mesolimbic dopaminergic system. The presence of sucrose in an animal's cage can affect the animals desire to self-administer drugs of abuse. Also, an animal's level of sucrose preference can predict its desire to self-administer cocaine. Such data suggest a relation between sweet taste and drug reward, although the relevance to humans is unclear. Finally, we address the influence of sugar on body weight control. For example, sucrose feeding for 2 wk decreases the efficiency of energy utilization and increases gene expression of uncoupling protein 3 in muscle, suggesting that sucrose may influence uncoupling protein 3 activity and contribute to changes in metabolic efficiency and thus regulation of body weight.


Subject(s)
Brain/drug effects , Carbohydrates , Neuropeptides , Obesity/chemically induced , Animals , Body Mass Index , Brain/metabolism , Carbohydrate Metabolism , Carbohydrates/adverse effects , Carbohydrates/pharmacology , Energy Metabolism , Humans , Neuropeptides/metabolism , Neuropeptides/physiology , Rats
14.
Obes Res ; 11(5): 599-602, 2003 May.
Article in English | MEDLINE | ID: mdl-12740447

ABSTRACT

OBJECTIVE: The purpose of this study was to evaluate the effects of sibutramine vs. placebo on binge-eating behavior, hunger, and satiety in patients who had problems with binge eating. RESEARCH METHODS AND PROCEDURES: Seven adult subjects who had problems with binge eating (mean age, 42 years) were randomly assigned to receive alternating sibutramine and placebo in a double-blind placebo-controlled crossover study. This involved two 4-week dosing periods separated by a 2-week washout. RESULTS: Subjects lost weight on sibutramine but not on placebo. There was a significant difference in the number of kilocalories consumed between the sibutramine and placebo conditions, with a significant reduction of intake during binge-eating episodes on sibutramine. DISCUSSION: Sibutramine suppresses intake during binge-eating episodes. This effect is demonstrable in a human feeding laboratory paradigm.


Subject(s)
Appetite Depressants/pharmacology , Bulimia/drug therapy , Cyclobutanes/pharmacology , Eating/drug effects , Hunger/drug effects , Satiety Response/drug effects , Adult , Cross-Over Studies , Double-Blind Method , Female , Humans , Male , Middle Aged , Weight Loss/drug effects
15.
J Nutr ; 133(3): 831S-834S, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12612162

ABSTRACT

The appetite for specific foods and nutrients may be under neuroregulatory control. In animal studies, fat intake is increased by both opioids and galanin and reduced by enterostatin, whereas carbohydrate intake is increased by neuropeptide Y (NPY). However, what may be affected is the consumption of preferred foods rather than macronutrients. Fat and sugars are highly preferred whether consumed separately or as mixtures in foods. Studies suggest that sustained consumption of sugars and fats may have additional metabolic consequences; among these are neurochemical changes in brain sites involved in feeding and reward, some of which are also affected by drugs of abuse. Furthermore, the consumption of fats and sugars alters tissue expression of uncoupling proteins, which are also influenced by neuroregulatory peptides and may be markers of energy expenditure. These data suggest that these palatable nutrients may influence energy expenditure through changes in central neuropeptide activity. Fats and sugars could affect central reward systems, thereby increasing food intake, and might have an additional effect on energy expenditure. Such palatable substances may contribute to the observed increase in the body weight of populations from affluent societies during the past few decades.


Subject(s)
Brain/physiology , Dietary Fats/administration & dosage , Dietary Sucrose/administration & dosage , Food Preferences/physiology , Animals , Brain Chemistry , Energy Metabolism , Humans , Narcotics/administration & dosage , Neuropeptides/physiology , Substance-Related Disorders , Taste
16.
Neuropharmacology ; 42(8): 1039-42, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12128005

ABSTRACT

The neural adaptations involved in initiating and maintaining the long-term consequences of utilizing drugs of abuse are the subject of intense investigation. It is commonly suggested that the neural plasticity mechanisms underlying physiological phenomena such as learning and memory may also be engaged when drug addiction occurs. The effect of cocaine on one prominent cellular mechanism for learning/memory, long-term potentiation (LTP), was assessed in the CA1 region of the rat hippocampus. Hippocampal slices obtained from animals treated in vivo for five days with cocaine (15 mg/kg i.p., daily) exhibited enhanced LTP vs saline treated controls. We suggest that this example of cocaine-induced enhancement of LTP provides an example of how synaptic plasticity mechanisms may be altered in a manner that contributes to the behavioral outcomes expressed, following exposure to psychostimulants.


Subject(s)
Cocaine/pharmacology , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Animals , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Hippocampus/physiology , In Vitro Techniques , Long-Term Potentiation/physiology , Male , Rats , Rats, Sprague-Dawley
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