Article
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Obesity is typically associated with abnormal eating behaviors. Brain imaging studies in humans implicate the involvement of dopamine (DA)-modulated circuits in pathologic eating behavior(s). Food cues increase striatal extracellular DA, providing evidence for the involvement of DA in the nonhedonic motivational properties of food. Food cues also increase metabolism in the orbitofrontal cortex indicating the association of this region with the motivation for food consumption. Similar to drug-addicted subjects, striatal DA D2 receptor availability is reduced in obese subjects, which may predispose obese subjects to seek food as a means to temporarily compensate for understimulated reward circuits. Decreased DA D2 receptors in the obese subjects are also associated with decreased metabolism in prefrontal regions involved in inhibitory control, which may underlie their inability to control food intake. Gastric stimulation in obese subjects activates cortical and limbic regions involved with self-control, motivation, and memory. These brain regions are also activated during drug craving in drug-addicted subjects. Obese subjects have increased metabolism in the somatosensory cortex, which suggests an enhanced sensitivity to the sensory properties of food. The reduction in DA D2 receptors in obese subjects coupled with the enhanced sensitivity to food palatability could make food their most salient reinforcer putting them at risk for compulsive eating and obesity. The results from these studies suggest that multiple but similar brain circuits are disrupted in obesity and drug addiction and suggest that strategies aimed at improving DA function might be beneficial in the treatment and prevention of obesity.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The insignificant r-values of the correlation of reduced r-OPFC D2R-BP and intake of the CCD or total calories for choice females (Table 4) were greater than the r-value for all females combined ( Table 2). Regardless of this statistical nuance, the association between decreased D2R-BP in the r-OPFC and increased overall caloric intake is consistent with the notion that a down-regulation of D2R within the PFC increases risk for overeating in obese humans [ 67 ]. The OPFC is involved in goaldirected behavior, reward coding, and the inhibitory control of behavior [68]. ...
... Furthermore, the activation of the OPFC in response to food receipt is less activated in women with food addiction [70]. Importantly, dopaminergic transmission via D2R in the OPFC has been implicated in the inhibitory control of behavior [67]. States associated with decreased D2R levels in the PFC, including the OPFC, are associated with deficiencies in impulse control and regulation of goal-directed behaviors [67,71]. ...
... Importantly, dopaminergic transmission via D2R in the OPFC has been implicated in the inhibitory control of behavior [67]. States associated with decreased D2R levels in the PFC, including the OPFC, are associated with deficiencies in impulse control and regulation of goal-directed behaviors [67,71]. Taken together, these data along with the current finding that decreased D2R-BP in the r-OPFC was predictive of augmented overall caloric intake, suggest that decreased D2R in the OPFC is a risk factor for uncontrolled eating regardless of dietary environment. ...
... Most importantly, nicotine stimulates the release of DA in the mesolimbic area, the corpus striatum, and the frontal cortex [68,69]. These DAergic pathways are critical in nicotine-induced rewarding behaviors [70], as well as in regulating reward, motivation, decision-making, learning, and memory [71]. ...
... Several brain regions, such as the amygdala, hippocampus, insula, orbitofrontal cortex, and striatum, are also involved with the regulation of feeding and appetite [49]. These brain structures are involved in learning about food, allocating attention and effort towards food, conditioning reward with specific food cues in the environment, and integrating homeostatic information such as hunger with availability of food in the environment [49,71]. For a recent review of potential mechanisms for food addiction (in the presence of obesity) using a systems approach, see [87]. ...
Article
Full-text available
As food addiction is being more commonly recognized within the scientific community, parallels can be drawn between it and other addictive substance use disorders, including tobacco use disorder. Given that both unhealthy diets and smoking are leading risk factors for disability and death, a greater understanding of how food addiction and tobacco use disorder overlap with one another is necessary. This narrative review aimed to highlight literature that investigated prevalence, biology, psychology, and treatment options of food addiction and tobacco use disorder. Published studies up to August 2020 and written in English were included. Using a biopsychosocial lens, each disorder was assessed together and separately, as there is emerging evidence that the two disorders can develop concurrently or sequentially within individuals. Commonalities include but are not limited to the dopaminergic neurocircuitry, gut microbiota, childhood adversity, and attachment insecurity. In addition, the authors conducted a feasibility study with the purpose of examining the association between food addiction symptoms and tobacco use disorder among individuals seeking tobacco use disorder treatment. To inform future treatment approaches, more research is necessary to identify and understand the overlap between the two disorders.
... In a recent study, Rapuano et al., 14 measured total body fat using bioelectric impedance, and found a positive association between body fat levels and activation of the somatosensory cortex, which is functionally connected with the brain reward system through dopaminergic pathways. 15,16 The somatosensory cortex has also been linked to reward feedback processing in the context of tactile and monetary-based decision-making, and its activity is modulated by dopaminergic function. 17,18 A related question concerning the link between brain reward function and adiposity is if the responsivity of the brain reward system differs between males and females, which naturally have different levels of body fat. ...
... 18 In addition, PET studies have shown that higher baseline metabolism in S1 is associated with decreased availability of dopamine D2-type receptors in the striatum in obesity. 16 The aforementioned study on brain reactivity to food commercials found a significant association between body fat and higher activation of S1 during passive observation of ads containing highly palatable food. 14 Although our result was in the opposite direction (that is, more body fat, less activation of S1), both findings might be seen as complementary according to the reward prediction error theory (for example, Schultz 32 ). ...
Article
Full-text available
Background and aims: The brain reward system is key to understanding adolescent obesity in the current obesogenic environment, rich in highly appetising stimuli, to which adolescents are particularly sensitive. We aimed to examine the association between body fat levels and brain reward system responsivity to general (monetary) rewards in male and female adolescents. Method: Sixty-eight adolescents (34 females; mean age [standard deviation]=16.56 [1.35]) were measured for body fat levels with bioelectric impedance, and underwent a functional magnetic resonance imaging (fMRI) scan during the Monetary Incentive Delay (MID) task. The MID task reliably elicits brain activations associated with two fundamental aspects of reward processing: anticipation and feedback. We conducted regression analyses to examine the association between body fat and brain reward system responsivity during reward anticipation and feedback, while controlling for sex, age and socioeconomic status. We also analysed the moderating impact of sex on the relationship between fat levels and brain responsivity measures. Brain imaging analyses were corrected for multiple comparisons, with a cluster-defining threshold of P<0.001, and minimum cluster size of 38 contiguous voxels. Results: Higher body fat levels were associated with lower activation of the primary somatosensory cortex (S1) and the supramarginal gyrus during reward feedback after controlling for key sociodemographic variables. Although we did not find significant associations between body fat and brain activations during reward anticipation, S1/supramarginal gyrus activation during feedback was linked to increased negative prediction error, i.e., less reward than expected, in illustrative post-hoc analyses. Sex did not significantly moderate the association between body fat and brain activation in the MID task. Conclusions: In adolescents, higher adiposity is linked to hypo-responsivity of somatosensory regions during general (monetary) reward feedback. Findings suggest that adolescents with excess weight have blunted activation in somatosensory regions involved in reward feedback learning.International Journal of Obesity accepted article preview online, 18 August 2017. doi:10.1038/ijo.2017.207.
... Additionally, individuals seeking treatment for weight management are commonly prescribed pharmacotherapies that target the dopamine transporter (DAT), highlighting the involvement of the dopamine system in feeding and food seeking behaviors. Mesolimbic dopamine signaling contributes to the reinforcing efficacy of psychostimulants ( Baik, 2013), and elevated dopamine in the nucleus accumbens (NAc) is a neurochemical hallmark of all abused substances, including food ( Wang et al., 2009Wang et al., , 2011). Adaptations in the dopamine system following drug abuse are well documented by neuroimaging studies in humans showing reduced D 2 receptor binding ( Volkow et al., 1990) and reduced responsiveness to abused drugs ( Volkow et al., 1997). ...
... Adaptations in the dopamine system following drug abuse are well documented by neuroimaging studies in humans showing reduced D 2 receptor binding ( Volkow et al., 1990) and reduced responsiveness to abused drugs ( Volkow et al., 1997). Similar changes have been reported in clinical neuroimaging studies with obese patients, suggesting that they exhibit a comparable dopaminergic phenotype to drug addicts ( Wang et al., 2009;Volkow and Wise, 2005). Obese individuals display significantly less D 2 binding than normal weight healthy subjects ( Wang et al., 2001) and show reduced striatal activation during the consumption of highly palatable food ( Stice et al., 2008). ...
Article
High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3 d/week) or extended (24 h 7 d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations.
... The dopaminergic system has been extensively evaluated in the pathogenesis of obesity. In obese subjects, similarly to drug addicts, DA receptors, in particular D2 subtype, are hypo-expressed and hypo-functioning in thestriate nucleus [159][160][161][162]. Furthermore, a polymorphism of the D2 receptor, leading to significantly reduced expression [163], has been associated with a greater food reinforcement, which leads to an increased energy intake, more evident in obese subjects [164,165]. ...
Article
Full-text available
Prolactin (PRL) has been long deemed as a hormone involved only in female reproduction. However, PRL is a surprising hormone and, since its identification in the 1970s, its attributed functions have greatly increased. However, its specific role in male health is still widely unknown. Recently, low PRL has been associated with reduced ejaculate and seminal vesicle volume in infertile subjects. In addition, in men consulting for sexual dysfunction, hypoprolactinemia has been associated with erectile dysfunction and premature ejaculation, findings further confirmed in the general European population and infertile men. Several metabolic derangements, recapitulating metabolic syndrome, have also been associated with low PRL both in men with sexual dysfunction and from the general European population. In men with sexual dysfunction, followed-up for more than 4 years, low PRL was identified as an independent predictor of the incidence of major adverse cardiovascular events. Finally, an association with anxiety or depressive symptoms has been found in men with sexual dysfunction and from the general European population. While a direct role for impaired PRL function in the pathogenesis of these reproductive, sexual, metabolic and psychological disorders is conceivable, the possibility that low PRL is a mirror of an increased dopaminergic or a decreased serotonergic tone cannot be ruled-out. Hyperactivity of the dopaminergic system can explain only a few of the aforementioned findings, whereas a hypo-serotonergic tone fits well with the clinical features associated with low PRL, and there is significant evidence supporting the hypothesis that PRL could be a mirror of serotonin in the brain.
... At rest, the brain of an individual with a normal genetic trait, or epigenetic (environmental) state, has background working connections, which is a good thing illustrated in the figure as American cheese ( Figure 13). Certainly, it is now known that drug addiction and other nondrug addictive and RDS behaviors, like gambling, compulsive sexual behavior, overeating and ADHD all reduce rsFC [42][43][44][45][46][47][48][49][50][51]. These changes are thought to be epigenetic. ...
Article
Full-text available
Dopamine along with other chemical messengers like serotonin, cannabinoids, endorphins and glutamine, play significant roles in brain reward processing. There is a devastating opiate/opioid epidemicin the United States. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day due to narcotic overdose and alarmingly heroin overdose is on the rise. The Food and Drug Administration (FDA) has approved some Medication-Assisted Treatments (MATs) for alcoholism, opiate and nicotine dependence, but nothing for psychostimulant and cannabis abuse. While these pharmaceuticals are essential for the short-term induction of "psychological extinction," in the long-term caution is necessary because their use favors blocking dopaminergic function indispensable for achieving normal satisfaction in life. The two institutions devoted to alcoholism and drug dependence (NIAAA & NIDA) realize that MATs are not optimal and continue to seek better treatment options. We review, herein, the history of the development of a glutaminergic-dopaminergic optimization complex called KB220 to provide for the possible eventual balancing of the brain reward system and the induction of "dopamine homeostasis." This complex may provide substantial clinical benefit to the victims of Reward Deficiency Syndrome (RDS) and assist in recovery from iatrogenically induced addiction to unwanted opiates/opioids and other addictive behaviors.
... Moreover , compared with their lean littermates, obese rats exhibit a decreased number of D2 receptors (D2Rs) in their ventral striatum (Johnson and Kenny 2010). Likewise, morbidly obese persons have fewer D2Rs in their ventral striatum than persons with a normal body mass index (BMI) (Wang et al. 2009). Although these data point to an important role of DA in feeding, it is unknown to what extent the above-mentioned anorectic drugs produce their behavioral and neuronal effects via activation of DA receptors in the NAc shell. ...
Article
Full-text available
Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds.
... Although glucose has been previously linked to metabolic and motivational roles for glucose in performance enhancement, we investigate whether cognitive resources can be replenished by the simple act of anticipating food intake, prior to sensing or consuming actual food. This question is important because a necessary condition in the addiction literature relates to the dopamine reward system, which intensifies the "reward" in anticipation of the addictive action and not necessarily in the action itself [38,39]. In this regard, recent neurobiological evidence has shown that obese individuals are prone to an "anticipatory food reward", in which they exhibit greater activity in somatosensory and gustatory brain regions in response to anticipating food intake [40][41][42]. ...
Article
Full-text available
By randomizing the order in which participants perform a cognitive test and a food choice task in a controlled experiment, we investigate whether cognitive capacity can be enhanced by the simple act of anticipating food intake. Our findings show that overweight and obese participants exhibit an anticipatory food reward effect, which helped enhance their mental resources and improve their performance in a cognitive test. However, we find no anticipation effect among normal weight participants. Furthermore, eye tracking data reveal that food temptation, in the form of visual attention and emotional arousal is higher for overweight and obese individuals when they are cognitively impaired.
... While much attention has been given to obesity in the Western world (Gold, 2011), developing countries are not immune to the global obesity epidemic . Causes of obesity are multiple (Dietrich and Gold et al., 2009;Liu et al., 2010;Volkow and Wise, 2005;Wang et al., 2009;Zhang et al., 2011) and overconsumption of caloric dense foods is apparently one causal factor in obesity (Holsen et al., 2006;Volkow et al., 2011). ...
... Previous theories and traditional methods including psychosocial models, individual or group therapy, and CBT in the treatment of obesity and eating disorders are now being challenged with additional contemporary theories and concepts such as FA. Recent research approaches to FA have included: animal models (Avena, Rada, & Hoebel, 2009); biochemical models (Volkow & Wise, 2005;Wang et al., 2001); neurological theories (Blumenthal & Gold, 2010;Wang, Volkow, Thanos, & Fowler, 2009); standardised test batteries (YFAS; Gearhardt et al., 2009), and addiction models (Ifland et al., 2009). These recent avenues of research have produced empirical findings supporting the concept of FA. ...
... Imaging studies using positron emission tomography showed an important involvement of dopamine in normal and pathological food intake in humans. In comparison to healthy controls, pathologically obese subjects show reduced availability of striatal D2 receptors that were inversely associated with the weight of the subject [62][63][64]. Our theory suggests that the ability to restrain from taking actions and learn from negative consequences of actions such as overeating may be diminished when D2 receptors are activated to a lesser extent. ...
Article
Full-text available
Decision making relies on adequately evaluating the consequences of actions on the basis of past experience and the current physiological state. A key role in this process is played by the basal ganglia, where neural activity and plasticity are modulated by dopaminergic input from the midbrain. Internal physiological factors, such as hunger, scale signals encoded by dopaminergic neurons and thus they alter the motivation for taking actions and learning. However, to our knowledge, no formal mathematical formulation exists for how a physiological state affects learning and action selection in the basal ganglia. We developed a framework for modelling the effect of motivation on choice and learning. The framework defines the motivation to obtain a particular resource as the difference between the desired and the current level of this resource, and proposes how the utility of reinforcements depends on the motivation. To account for dopaminergic activity previously recorded in different physiological states, the paper argues that the prediction error encoded in the dopaminergic activity needs to be redefined as the difference between utility and expected utility, which depends on both the objective reinforcement and the motivation. We also demonstrate a possible mechanism by which the evaluation and learning of utility of actions can be implemented in the basal ganglia network. The presented theory brings together models of learning in the basal ganglia with the incentive salience theory in a single simple framework, and it provides a mechanistic insight into how decision processes and learning in the basal ganglia are modulated by the motivation. Moreover, this theory is also consistent with data on neural underpinnings of overeating and obesity, and makes further experimental predictions.
... models, notably rat models, in which the overconsumption of sweet food led to specific behavioral modifications (bingeing, withdrawal and cross-sensitization) [2,3] and neurochemical signs were also observed in models of substance dependence [2][3][4]. In humans, neuroimaging studies, notably those conducted with obese patients with FA, have also suggested the involvement of brain dopamine (DA) pathways and reward circuitry, and similarities with substance dependence have been observed as well [3,5,6]. ...
Article
Full-text available
The concept of “food addiction” (FA) has aroused much focus because of evidence for similarities between overeating and substance use disorders (SUDs). However, few studies have explored this concept among the broad spectrum of eating disorders (ED), especially in anorexia nervosa (AN). This study aimed to assess FA prevalence in ED female patients and to determine its associated factors. We recruited a total of 195 adult women with EDs from an ED treatment center. The prevalence of FA diagnosis (Yale Food Addiction Scale) in the whole ED sample was 83.6%; AN restrictive type (AN-R), 61.5%; AN binge-eating/purging type (AN-BP), 87.9%; bulimia nervosa (BN), 97.6%; and binge-eating disorder (BED), 93.3%. The most frequently met criteria of FA were “clinically significant impairment or distress in relation to food”, “craving” and “persistent desire or repeated unsuccessful attempts to cut down”. An FA diagnosis was independently associated with three variables: presence of recurrent episodes of binge eating, ED severity, and lower interoceptive awareness. In showing an overlap between ED and FA, this study allows for considering EDs, and AN-R in particular, from an “addictive point of view”, and thus for designing therapeutic management that draws from those proposed for addictive disorders.
... [13] Studies suggest that foods containing excess fat/sugar overstimulate reward pathways, and increase dopamine release, which leads to compulsive food consumption, i.e. to food addiction. [9,14,15] The present study aimed to determine the prevalence of obesity among adolescents in different high schools in an urban area and the effect of food addiction on obesity. ...
Article
Full-text available
Background: People may develop addiction to hyperpalatable foods, which may be a cause of obesity. This study aimed to determine the prevalence of obesity among adolescents and the effect of food addiction on obesity. Materials and methods: In this cross-sectional study, food addiction and obesity status of high school students were investigated. Among 17,000 10th and 11th grade students, assuming the design effect as 2.0, with obesity prevalence of 10%, with 3% error, and 95% confidence interval, at least 752 participants were included. Obesity was the dependent variable, whereas sociodemographic characteristics, body image, eating habits, and food addiction were the independent variables. Food addiction was assessed using the Yale Food Addiction Scale. Obesity was determined by age- and sex-specific body mass index (BMI) percentiles for adolescents < 18 years of age and BMI ≥ 30.0 for those aged ≥ 18. Data were collected through face-to-face interviews. Statistical analyses were performed using SPSS 25.0. After adjustment for age, sex, and other variables, the effect of food addiction on obesity was determined through logistic regression. P <0.05 was deemed statistically significant. Results: Among adolescents (n = 874), 18.9% were food addict, 25.1% were overweight, and 12.1% were obese. After adjusted for age, sex, and other variables, food addiction significantly increased the risk of obesity (odds ratio: 1.9; 95% confidence interval: 1.167-3.335). Having a fragmented family, working mother, overweight father, and participants not knowing their weight correctly significantly increased obesity. Conclusion: While quarter of the adolescents had weight problems, one-fifth suffered from food addiction. After adjusting for confounders, food addiction significantly increased obesity. Identifying individuals with food addiction, providing treatment to overcome that, paying special attention to adolescents with obese parents or living in fragmented families, and providing support to both parents and adolescents could be useful in tackling obesity.
... In our study, when assessing [ 3 H]DA uptake in striatal synaptosomes, we found that the HFD reduced the overall [ 3 H]DA uptake in both the A-HFD and W-HFD groups, implicating diet in the regulation of DA function, which can lead to functional modifications in DA signaling (South and Huang, 2008;Cone et al., 2013). By decreasing DA uptake, HFD consumption could promote adaptations such as downregulation of DA receptors, a feature of both human and rodent models of obesity (Wang et al., 2009;Johnson and Kenny, 2010). Cone et al. (2013) described that prolonged HFD appears to reduce dopamine transporter (DAT) trafficking or perhaps maturation but not DAT gene expression. ...
Article
Full-text available
Backgroud: Prenatal alcohol exposure is a leading cause of neurobehavioral and neurocognitive deficits collectively known as fetal alcohol spectrum disorders (FASD), including eating disorders and increased risk for substance abuse as very common issues. In this context, the present study aimed to assess the interaction between alcohol exposure during gestation and lactation periods (PLAE) and a high fat diet (HFD) during childhood and adolescence. Methods: Pregnant C57BL/6 mice underwent a procedure for alcohol binge drinking during gestation and lactation periods. Subsequently, PLAE female offspring were fed with a HFD for 8 weeks and thereafter, nutrition-related parameters as well as their response to cocaine were assessed. Results: In our model, feeding young females with a HFD increased their triglyceride blood levels but did not induce an overweight compared to those fed with a standard diet. Moreover, PLAE affected how females responded to the fatty diet as they consumed less amount of food than water-exposed offspring, consistent with a lower gain of body weight. HFD increased the psychostimulant effects of cocaine. Surprisingly, PLAE reduced the locomotor responses to cocaine without modifying cocaine-induced reward. Moreover, PLAE prevented the striatal overexpression of cannabinoid 1 receptors induced by a HFD and induced an alteration of myelin damage biomarker in the prefrontal cortex, an effect that was mitigated by a HFD-based feeding. Conclusion: Therefore, in female offspring, some effects triggered by one of these factors, PLAE or a HFD, were blunted by the other, suggesting a close interaction between the involved mechanisms.
... The latter regions are part of the basal ganglia complex that receive dopaminergic projections from midbrain nuclei and are involved in higher-level processing of gustatory information such as reward value. Dopamine modulates the experience of reward, and decreased dopamine efficiency has been implicated in overeating (Wang et al., 2009). The current results suggest less activation of reward-related brain regions in individuals with MetS during the physiological state of hunger. ...
Article
Metabolic syndrome (MetS) is a constellation of cardiometabolic abnormalities that commonly occur together and increase risk for cardiovascular disease and type II diabetes. Having MetS, especially during middle-age, increases the risk for dementia in later life. Abdominal obesity is a central feature of MetS; therefore, increased efforts to prevent obesity and identify predictors of weight gain are of extreme importance. Altered processing of food reward in the brain of obese individuals has been suggested to be a possible mechanism related to overeating. We scanned fifteen healthy middle-aged controls (aged 44-54) and sixteen middle-aged adults with MetS after a fast (hungry) and after a preload (sated), while they rated the pleasantness of sucrose (sweet) and caffeine (bitter) solutions. Data were analyzed using voxelwise linear mixed-effects modeling, and a region of interest analysis to examine associations between hypothalamic activation to sweet taste and BMI during hunger and satiety. The results indicate that middle-aged individuals with MetS respond with significantly less brain activation than controls without MetS during pleasantness evaluation of sweet and bitter tastes in regions involved in sensory and higher-level taste processing. Participants with higher BMI had greater hypothalamic response during pleasantness evaluation of sucrose in the sated condition. Importantly, this study is the first to document differential brain circuitry in middle-aged adults with MetS, a population at risk for poor physical and cognitive outcomes. Future research aimed at better understanding relationships among MetS, obesity, and brain function is warranted to better conceptualize and develop interventions for overeating in these disorders. Copyright © 2015 Elsevier B.V. All rights reserved.
... In the fight against obesity and eating disorders, improved knowledge about the pathophysiological and neurobehavioral mechanisms underlying these diseases is needed to better prevent risky behaviors, diagnose and treat patients, and develop new therapies that are safer and adjustable to each patient. As noted by Schmidt and Campbell (2013), treatment of eating disorders cannot remain 'brainless', and the same applies to obesity when we consider the growing amount of literature highlighting the behavioral and brain changes/plasticity induced by obesity (Wang et al., 2009b;Burger and Berner, 2014), effective bariatric surgery (Geliebter, 2013;Scholtz et al., 2014), and neuromodulatory interventions (McClelland et al., 2013a;Gorgulho et al., 2014) in animal models and human subjects. ...
Article
Full-text available
Functional, molecular and genetic neuroimaging has highlighted the existence of brain anomalies and neural vulnerability factors related to obesity and eating disorders such as binge eating or anorexia nervosa. In particular, decreased basal metabolism in the prefrontal cortex and striatum as well as dopaminergic alterations have been described in obese subjects, in parallel with increased activation of reward brain areas in response to palatable food cues. Elevated reward region responsivity may trigger food craving and predict future weight gain. This opens the way to prevention studies using functional and molecular neuroimaging to perform early diagnostics and to phenotype subjects at risk by exploring different neurobehavioral dimensions of the food choices and motivation processes. In the first part of this review, advantages and limitations of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), pharmacogenetic fMRI and functional near-infrared spectroscopy (fNIRS) will be discussed in the context of recent work dealing with eating behavior, with a particular focus on obesity. In the second part of the review, non-invasive strategies to modulate food-related brain processes and functions will be presented. At the leading edge of non-invasive brain-based technologies is real-time fMRI (rtfMRI) neurofeedback, which is a powerful tool to better understand the complexity of human brain–behavior relationships. rtfMRI, alone or when combined with other techniques and tools such as EEG and cognitive therapy, could be used to alter neural plasticity and learned behavior to optimize and/or restore healthy cognition and eating behavior. Other promising non-invasive neuromodulation approaches being explored are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS). Converging evidence points at the value of these non-invasive neuromodulation strategies to study basic mechanisms underlying eating behavior and to treat its disorders. Both of these approaches will be compared in light of recent work in this field, while addressing technical and practical questions. The third part of this review will be dedicated to invasive neuromodulation strategies, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS). In combination with neuroimaging approaches, these techniques are promising experimental tools to unravel the intricate relationships between homeostatic and hedonic brain circuits. Their potential as additional therapeutic tools to combat pharmacorefractory morbid obesity or acute eating disorders will be discussed, in terms of technical challenges, applicability and ethics. In a general discussion, we will put the brain at the core of fundamental research, prevention and therapy in the context of obesity and eating disorders. First, we will discuss the possibility to identify new biological markers of brain functions. Second, we will highlight the potential of neuroimaging and neuromodulation in individualized medicine. Third, we will introduce the ethical questions that are concomitant to the emergence of new neuromodulation therapies.
... The hedonic component of appetite is mediated by central reward mechanisms and has the ability to override homeostatic satiety mechanisms . The enjoyment associated with eating is attributed to activation of the dopamine mediated reward pathway in the limbic region of the brain (Wang et al., 2009;DiLeone et al., 2012). The endocannabinoid and opioid systems are also involved in central appetite control, relating to food palatability, and interacting with mesolimbic reward pathway and reinforcing the motivation for food seeking . ...
Article
Full-text available
The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behaviour. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognised to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilisation of this effective and inexpensive class of drug.
Article
Full-text available
Research on psychological dimensions of obesity has evolved considerably in recent years. This chapter aims at underlying the main psychological aspects, such as discrimination and stigma, psychopathological complications, correlations between obesity and personality disorders, eating disorders (particularly Binge Eating Disorders), mood disorders, and stress-anxiety. A brief overview about the connection between obesity and addiction is also provided. Then quality of life and self-esteem in obesity are discussed. The second part of the chapter aims at describing the main psychological rehabilitation protocols for obesity, according to the most evaluated approaches such as cognitive-behavioral, interpersonal, systemic-strategic ones. Particularly, attention is dedicated to the transtheoretical model stages of change (TTM SOC). Some promising treatments are the mindfulness approach as described by Kabat-Zinn and the EMDR-based techniques. Finally, a section is dedicated to the promotion of collaborative rehabilitation protocols with in-patient and out-patient settings using telemonitoring for the continuity of care (the TECNOB project), discussing the psychological components crucial in technology-based remote weight-loss interventions. In conclusion, future directions for research and practice in clinical psychology for obesity rehabilitation are discussed. © 2013 Springer-Verlag Berlin Heidelberg. All rights are reserved.
Article
Full-text available
Since the discovery of the double helix, the study of brain function, in terms of both physiology and behavioral traits, has resulted in a plethora of research linking these activities to the genetic basis of neurotransmitter function. Knowledge about how genes are expressed, as well as their potential impairment due to polygenic inheritance, can shed light on predispositions to addiction and self-destructive behaviors. Genetic information derived from scientific explorations of genetic traits may have important links to understanding the basis for feelings of well-being and potentially the phenomena associated with human happiness. While non-genetic oriented research of social, political, and biological studies have addressed the impact of social and institutional environments on mass political attitudes and behaviors, there is a paucity of solid research on the interrelation and influence of genetic and environmental factors on these parameters. The separate fields of psychology and molecular biology are subject to inherent limitations that may only be resolved through collaboration across disciplines. Certainly areas relating to spirituality ("Genospirituality") and political science are just two that are beginning to emerge as fruitful grounds for identification of specific polymorphic gene associations and may pave the way to advance a new science of human nature. We address the issue of "Nature vs. Nurture" as it relates to questions regarding the definition of happiness, its causes, and its promotion. These questions are central to understanding human nature and are emerging as an important target of research, especially in the area of nutrigenomics. The present commentary attempts to identify key "vector influences" that link genes, the brain, nutrition, and social behavior to a most desired, but misunderstood, and potentially fragile experience known as "happiness." Specifically, we propose that successful changes in body composition/body mass index (BMI)/percentage of body fat will increase not only positive self-image, but overall wellness that produces a state of happiness. We provide preliminary evidence that utilization of a customized dopaminergic agonist LG839 DNA directed nutraceutical, significantly increased happiness in obese subjects. We detail genotypes that may play a role in determining happiness, based on current knowledge.
Article
Background: There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. Methods: Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. Results: We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. Conclusions: Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction.
Article
Glucagon-like peptide-1 (GLP-1) affects appetite, supposedly mediated via the central nervous system (CNS). We investigate if modulation of CNS responses to palatable food consumption may be a mechanism by which GLP-1 contributes to the central regulation of feeding. Using functional-MRI, we determined effects of endogenous GLP-1 and treatment with the GLP-1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP-1 receptor antagonist exendin9-39 (blocking actions of endogenous GLP-1), and during placebo infusion. Study 2 was a randomised, cross-over intervention study in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10-days and 12-weeks. Compared to lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P=0.04). In lean individuals, blockade of endogenous GLP-1 effects inhibited activation in bilateral insula (P≤0.03). Treatment in T2DM with liraglutide, vs. insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P≤0.03), but these effect ceased to be significant after 12-weeks. Our findings in healthy lean individuals indicate that endogenous GLP-1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed.
Article
Different parts of lotus (Nelumbo nucifera Gaertn.) including the seeds, rhizomes, leaves, and flowers, are used for medicinal purposes with health promoting and illness preventing benefits. The presence of active chemicals such as alkaloids, phenolic acids, flavonoids, and terpenoids (particularly alkaloids) may account for this plant’s pharmacological effects. In this review, we provide a comprehensive overview and summarize up-to-date research on the biosynthesis, pharmacokinetics, and bioactivity of lotus alkaloids as well as their safety. Moreover, the potential uses of lotus alkaloids in the food, pharmaceutical, and cosmetic sectors are explored. Current evidence shows that alkaloids, mainly consisting of aporphines, 1-benzylisoquinolines, and bisbenzylisoquinolines, are present in different parts of lotus. The bioavailability of these alkaloids is relatively low in vivo but can be enhanced by technological modification using nanoliposomes, liposomes, microcapsules, and emulsions. Available data highlights their therapeutic and preventive effects on obesity, diabetes, neurodegeneration, cancer, cardiovascular disease, etc. Additionally, industrial applications of lotus alkaloids include their use as food, medical, and cosmetic ingredients in tea, other beverages, and healthcare products; as lipid-lowering, anticancer, and antipsychotic drugs; and in facial masks, toothpastes, and shower gels. However, their clinical efficacy and safety remains unclear; hence, larger and longer human trials are needed to achieve their safe and effective use with minimal side effects.
Article
This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
The increasing prevalence of obesity in developed nations has far-reaching implications for medical toxicology. The management of obese patients is complicated by comorbid illnesses, changes in cardiovascular and respiratory physiology, alterations in pharmacokinetics, and a lack of studies to identify appropriate dosing for current therapeutics and antidotes. In this review article, we examine obesity-associated physiologic and pharmacokinetic changes that may increase the vulnerability of obese patients to overdose. Further research is needed to characterize the relationship between drug toxicity and obesity.
Article
Background: Obesity has been associated with various health disorders, including psychological alterations. Cocoa consumption and weight management may produce a beneficial effect on these problems. Objective: The purpose of this study was to investigate the effect of cocoa extract supplementation as part of an energy-restricted diet on psychological status and peripheral dopaminergic activity in overweight or obese middle-aged subjects. Methods: In a 4-wk, double-blind, randomized, placebo-controlled parallel nutritional intervention, 22 men and 25 women [mean ± SD age: 57 ± 5 y; body mass index (kg/m(2)): 30.6 ± 2.3] were studied. After a 1-wk run-in period, volunteers consumed 15% energy-restricted diets; one-half of the volunteers were randomly assigned to receive ready-to-eat meals supplemented with 1.4 g cocoa extract/d (645 mg total polyphenols/d), whereas the rest of the volunteers received the same meals without cocoa supplementation. Plasma monoamines [dopamine, dopac, and homovanillic acid (HVA)], monoamine oxidase (MAO), and psychological status (anxiety and depressive symptoms) were analyzed in fasting participants at baseline and endpoint. Data were analyzed over time, and regression and correlation analyses were conducted to determine the relation between variables. Results: Depressive symptoms decreased in both groups after the intervention (control: -9.4%, P < 0.001; cocoa: -6.3%, P = 0.008), but anxiety symptoms did not. The increase in plasma HVA was 11.5% greater in the cocoa group than in the control group (P = 0.016), but plasma dopamine, dopac, and MAO changes did not differ between groups. A negative relation between changes in depressive symptoms and changes in plasma HVA was observed in the cocoa group (β = -0.39, P = 0.029). Moreover, the change in plasma dopamine was positively associated with the change in methyl-catechin-O-glucoronide in the cocoa-supplemented group (r = 0.69, P = 0.019). Conclusion: The intake of cocoa extract by participants consuming a 15% energy-restricted diet contributed to an increase in plasma HVA concentrations. This change was associated with a reduction in depressive symptoms, suggesting a potential effect of cocoa extract intake on this relation. The present results are secondary analyses of a clinical trial that was registered at www.clinicaltrials.gov as NCT01596309.
Article
Full-text available
Roux-en-Y gastric bypass (RYGB) surgery is a very effective bariatric procedure to achieve significant and sustained weight loss, yet little is known about the procedure's impact on the brain. This study examined the effects of RYGB on the brain's response to the anticipation of highly palatable versus regular food. High fat diet-induced obese rats underwent RYGB or sham operation and were then tested for conditioned place preference (CPP) for the bacon-paired chamber, relative to the chow-paired chamber. After CPP, animals were placed in either chamber without the food stimulus, and brain-glucose metabolism (BGluM) was measured using positron emission tomography (μPET). Bacon CPP was only observed in RYGB rats that had stable weight loss following surgery. BGluM assessment revealed that RYGB selectively activated regions of the right and midline cerebellum (Lob 8) involved in subjective processes related to reward or expectation. Also, bacon anticipation led to significant activation in the medial parabrachial nuclei (important in gustatory processing) and dorsomedial tegmental area (key to reward, motivation, cognition and addiction) in RYGB rats; and activation in the retrosplenial cortex (default mode network), and the primary visual cortex in control rats. RYGB alters brain activity in areas involved in reward expectation and sensory (taste) processing when anticipating a palatable fatty food. Thus, RYGB may lead to changes in brain activity in regions that process reward and taste-related behaviors. Specific cerebellar regions with altered metabolism following RYGB may help identify novel therapeutic targets for treatment of obesity.
Article
Full-text available
The physiological mechanisms controlling reproduction are closely linked to energy balance. In the recent years, accumulating evidence suggests that prolactin regulates metabolic functions, besides regulating breast development and stimulating milk formation. Hyperprolactinemia is associated with obesity and treatment with dopamine agonists results in weight loss. We discuss the integrated effects of prolactin in the metabolic control and reproductive function, the role of prolactin in the pathogenesis of obesity. The present review also describes the effects of treatment with cabergoline on body weight and cardiovascular risk markers.
Article
Full-text available
Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners like diethylpropion(DEP), phentermine(PHEN) and bupropion(BUP) whose effects are mediated through serotonin, norepinephrine and dopaminergic pathways. The nucleus accumbens shell(NAc-shell) receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc-shell responses to short-term treatments of DEP, PHEN and BUP. These compounds caused a transient decrease in weight and food-intake while increasing locomotion, stereotypy and insomnia and evoked a large inhibitory imbalance in NAc-shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials(LFPs) showed that all three drugs modulated beta, theta and delta oscillations. These oscillations do not reflect an aversive-malaise brain state as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric(and intraNAc-shell) infusions of dopamine antagonists SCH23390(D1-receptor) or raclopride(D2-receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP's oscillations and partially restored the imbalance in NAc-shell activity. These data revealed that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc-shell depend on to various extents on dopaminergic activation thus point to an important role for D1/D2-like receptors(in the NAc-shell) in the mechanism of action for these anorexic compounds. Copyright © 2015, Journal of Neurophysiology.
Article
Full-text available
Eating disorders appear to be caused by a complex interaction between environmental and genetic factors, and compulsive eating in response to adverse circumstances characterizes many eating disorders. We compared compulsion-like eating in the form of conditioned suppression of palatable food-seeking in adverse situations in stressed C57BL/6J and DBA/2J mice, two well-characterized inbred strains, to determine the influence of gene-environment interplay on this behavioral phenotype. Moreover, we tested the hypothesis that low accumbal D2 receptor (R) availability is a genetic risk factor of food compulsion-like behavior and that environmental conditions that induce compulsive eating alter D2R expression in the striatum. To this end, we measured D1R and D2R expression in the striatum and D1R, D2R and α 1R levels in the medial prefrontal cortex, respectively, by western blot. Exposure to environmental conditions induces compulsion-like eating behavior, depending on genetic background. This behavioral pattern is linked to decreased availability of accumbal D2R. Moreover, exposure to certain environmental conditions upregulates D2R and downregulates α 1R in the striatum and medial prefrontal cortex, respectively, of compulsive animals. These findings confirm the function of gene-environment interplay in the manifestation of compulsive eating and support the hypothesis that low accumbal D2R availability is a “constitutive” genetic risk factor for compulsion-like eating behavior. Finally, D2R upregulation and α1R downregulation in the striatum and medial prefrontal cortex, respectively, are potential neuroadaptive responses that parallel the shift from motivated to compulsive eating.
Chapter
The increasing prevalence of obesity worldwide and associated morbidity and mortality highlights the need to understand the neurobiological and functional mechanisms underlying eating behaviors. Gender is a relevant factor since women are reported to have higher rates of obesity than men. To tap into the neurobiological underpinnings of eating behavior, we developed a food stimulation paradigm to be used for imaging and showed that the presentation of food that could not be consumed in normal weight subjects was associated with increased metabolic activity in the orbitofrontal cortex, which is a brain region involved with conditioning, salience attribution, and motivation. Women had greater activation in the anterior prefrontal and the orbitofrontal cortex than men during food stimulation. Using the same food stimulation paradigm, we found blunted activation of brain regions involved with inhibitory control in women when compared with men, which suggests a possible neurobiological mechanism for the gender differences in this behavior. Understanding the mechanism(s) contributing to gender differences in overeating behaviors may provide a scientific basis for pharmacological and behavioral approaches to its prevention and treatment.
Article
Public and professional acceptance that use of drugs and alcohol could lead to physical and psychiatric disease states, that is, substance use disorders, required enormous clinical and research efforts. Now, some feel that this hard earned status is threatened by discussions suggesting that gambling, sex, and food may result in similar outcomes.1,2 However, the manner by which research was used to establish the addicting characteristics of drugs and alcohol must be the gold standard against which further considerations are made. In terms of the question of gambling, much of this work has been accomplished with studies demonstrating striking similarities between gambling and exogenous addictions. Even more valuable lessons have been learned regarding the processing of odds, assessing risk, and decision-making deficits evidenced in both behavioral and neuroimaging studies of compulsive gamblers and patients with substance use disorders.3 Through all of the debate and as a result of systemic study, we have learned that addiction is an acquired, chronic relapsing disorder that begins with some experimentation and pleasurable responses, and for subgroups of individuals is followed by preoccupation, escalation, tolerance, denial, a series of medical, psychologic, and social consequences that relate directly to the continued use, and what has been referred to as a “fatal attraction” between the substance (or activity, eg, gambling) and the patient. Obviously, the process resulting in addiction is not fulfilled in all or even most users.
Article
Full-text available
Aging produces cellular, molecular, and behavioral changes affecting many areas of the brain. The dopamine (DA) system is known to be vulnerable to the effects of aging, which regulate behavioral functions such as locomotor activity, body weight, and reward and cognition. In particular, age-related DA D2 receptor (D2R) changes have been of particular interest given its relationship with addiction and other rewarding behavioral properties. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.
Article
This study explores the long-term effects of exposure to a maternal Western diet (WD) vs. standard diet (SD) in the Yucatan minipig, on the adult progeny at lean status ( n = 32), and then overweight status. We investigated eating behavior, cognitive abilities, brain basal glucose metabolism, dopamine transporter availability, microbiota activity, blood lipids, and glucose tolerance. Although both groups demonstrated similar cognitive abilities in a holeboard test, WD pigs expressed a higher stress level than did SD pigs (immobility, P < 0.05) and lower performance in an alley maze ( P = 0.06). WD pigs demonstrated lower dopamine transporter binding potential in the hippocampus and parahippocampal cortex ( P < 0.05 for both), as well as a trend in putamen ( P = 0.07), associated with lower basal brain activity in the prefrontal cortex and nucleus accumbens ( P < 0.05) compared with lean SD pigs. Lean WD pigs demonstrated a lower glucose tolerance than did SD animals (higher glucose peak, P < 0.05) and a tendency to a higher incremental area under the curve of insulin from 0 to 30 minutes after intravenous glucose injection ( P < 0.1). Both groups developed glucose intolerance with overweight, but WD animals were less impacted than SD animals. These results demonstrate that maternal diet shaped the offspring's brain functions and cognitive responses long term, even after being fed a balanced diet from weaning, but behavioral effects were only revealed in WD pigs under anxiogenic situation; however, WD animals seemed to cope better with the obesogenic diet from a metabolic standpoint.-Gautier, Y., Luneau, I., Coquery, N., Meurice, P., Malbert, C.-H., Guerin, S., Kemp, B., Bolhuis, J. E., Clouard, C., Le Huërou-Luron, I., Blat, S., Val-Laillet, D. Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.
Article
Full-text available
Food addiction (FA) is characterized by behavioral and neurochemical changes linked to loss of food intake control. Gut microbiota may influence appetite and food intake via endocrine and neural routes. The gut microbiota is known to impact homeostatic energy mechanisms, but its role in regulating the reward system is less certain. We show that the administration of Bacteroides uniformis CECT 7771 ( B. uniformis ) in a rat FA model impacts on the brain reward response, ameliorating binge eating and decreasing anxiety-like behavior. These effects are mediated, at least in part, by changes in the levels of dopamine, serotonin, and noradrenaline in the nucleus accumbens and in the expression of dopamine D1 and D2 receptors in the prefrontal cortex and intestine. B. uniformis reverses the fasting-induced microbiota changes and increases the abundance of species linked to healthy metabolotypes. Our data indicate that microbiota-based interventions might help to control compulsive overeating by modulating the reward response.
Article
Highly palatable foods and substance of abuse have intersecting neurobiological, metabolic and behavioral effects relevant for understanding vulnerability to conditions related to food (e.g., obesity, binge eating disorder) and drug (e.g., substance use disorder) misuse. Here, we review data from animal models, clinical populations and epidemiological evidence in behavioral, genetic, pathophysiologic and therapeutic domains. Results suggest that consumption of highly palatable food and drugs of abuse both impact and conversely are regulated by metabolic hormones and metabolic status. Palatable foods high in fat and/or sugar can elicit adaptation in brain reward and withdrawal circuitry akin to substances of abuse. Intake of or withdrawal from palatable food can impact behavioral sensitivity to drugs of abuse and vice versa. A robust literature suggests common substrates and roles for negative reinforcement, negative affect, negative urgency, and impulse control deficits, with both highly palatable foods and substances of abuse. Candidate genetic risk loci shared by obesity and alcohol use disorders have been identified in molecules classically associated with both metabolic and motivational functions. Finally, certain drugs may have overlapping therapeutic potential to treat obesity, diabetes, binge-related eating disorders and substance use disorders. Taken together, data are consistent with the hypotheses that compulsive food and substance use share overlapping, interacting substrates at neurobiological and metabolic levels and that motivated behavior associated with feeding or substance use might constitute vulnerability factors for one another. This article is part of the special issue on ‘Vulnerabilities to Substance Abuse’.
Article
Several behavioral disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and aggressive behaviors are linked with sugar intake and obesity. The reason(s) for this association has been unclear. Here we present a hypothesis supporting a role for fructose, a component of sugar and high fructose corn syrup (HFCS), and uric acid (a fructose metabolite), in increasing the risk for these behavioral disorders. Recent studies have shown that the reason fructose intake is strongly associated with development of metabolic syndrome is that fructose intake activates an evolutionary-based survival pathway that stimulates foraging behavior and the storage of energy as fat. While modest intake may aid animals that would like to store fat as a protective response from food shortage or starvation, we propose that high intake of sugar and HFCS causes a hyperactive foraging response that stimulates craving, impulsivity, risk taking and aggression that increases the risk for ADHD, bipolar disease and aggressive behavior. High glycemic carbohydrates and salty foods may also contribute as they can be converted to fructose in the body. Some studies suggest uric acid produced during fructose metabolism may mediate some of these effects. Chronic stimulation of the pathway could lead to desensitization of hedonic responses and induce depression. In conclusion, a hyperactive foraging response driven by high glycemic carbohydrates and sugars may contribute to affective disorders.
Article
Objectives: Inbred mouse strains differ in the pharmacology mediating sugar and fat intake and conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice are differentially sensitive to dopamine (DA) D1, opioid and muscarinic receptor antagonism of sucrose, saccharin or fat intake, and to DA, opioid, muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonism of acquisition of sucrose-CFP. DA D1, opioid and NMDA receptor antagonists differentially alter fat (Intralipid)-CFP in BALB/c and SWR mice. The present study examined whether naltrexone, SCH23390 or MK-801 altered acquisition and expression of Intralipid-CFP in C57BL/6 mice. Methods: In acquisition, groups of male food-restricted C57BL/6 mice received vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 μg/kg) before 10 training sessions in which mice alternately consumed two novel-flavored 5% (CS+) and 0.5% (CS-) Intralipid solutions. Six two-bottle CS choice tests followed with both flavors mixed in 0.5% Intralipid without injections. In expression, C57BL/6 mice underwent the 10 training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 μg/kg). Results: Fat-CFP acquisition in C57BL/6 mice was significantly though marginally reduced following naltrexone, SCH23390 and MK-801. Fat-CFP expression was similarly reduced by naltrexone, SCH23390 and MK-801 in C57BL/6 mice. Discussion: C57BL/6 mice were more sensitive to DA D1, opioid and NMDA antagonists in the expression of fat-CFP relative to sugar-CFP, but were less sensitive to DA D1 and NMDA antagonists in the acquisition of fat-CFP relative to sugar-CFP.
Article
Hordenine, a natural constituent of germinated barley, is a biased agonist of the dopamine D2 receptor. This pilot study investigated the biokinetics of hordenine and its metabolites in four volunteers consuming beer equal to 0.075 mg hordenine/kg body weight. A new UHPLC–ESI–MS/MS method determined maximum plasma concentrations of 12.0–17.3 nM free hordenine after 0–60 min. Hordenine phase-II metabolism was first dominated by sulfation, but later by glucuronidation. The elimination half-lives in plasma were 52.7–66.4 min for free hordenine and about 60/80 min longer for hordenine sulfate and -glucoronide. Urinary excretion peaked 2–3.5 hours after consumption and accumulated to 3.78 µmol within 24 hours corresponding to 9.9% of the ingested dose. The observed hordenine levels in plasma seem too low to provoke direct interaction with the dopamine D2 receptor related to food reward, but synergistic or additive effects with alcohol or N-methyltyramine may occur.
Article
Dopamine D2 receptors (D2Rs) mediate many of the actions of dopamine in the striatum, ranging from movement to the effortful pursuit of reward. Yet despite significant advances in linking D2Rs to striatal functions with pharmacological and genetic strategies in animals, how dopamine orchestrates its myriad actions on different cell populations —each expressing D2Rs— remains unclear. Furthermore, brain imaging and genetic studies in humans have consistently associated striatal D2R alterations with various neurological and neuropsychiatric disorders, but how and which D2Rs are involved in each case is poorly understood. Therefore, a critical first step is to engage in a refined and systematic investigation of the impact of D2R function on specific striatal cells, circuits, and behaviors. Here, I will review recent efforts, primarily in animal models, aimed at unlocking the complex and heterogeneous roles of D2Rs in striatum.
Article
Purpose Glucagon-like peptide 1 (GLP-1) is an incretin hormone that appears to play a major role in the control of food intake. The aim of this investigation was to evaluate and quantify the association of circulating GLP-1 concentration with ad libitum total calorie and macronutrient intake. Methods One-hundred and fifteen individuals (72 men) aged 35 ± 10 years were admitted for an inpatient study investigating the determinants of energy intake. Ad libitum food intake was assessed during 3 days using a reproducible vending machine paradigm. Fasting plasma GLP-1 concentrations were measured on the morning of the first day and on the morning of the fourth day after ad libitum feeding. Results Plasma GLP-1 concentrations increased by 14% after 3 days of ad libitum food intake. Individuals overate on average 139 ± 45% of weight-maintaining energy needs. Fasting plasma GLP-1 on day 1 was negatively associated with carbohydrate intake (r = − 0.2, p = 0.03) and with daily energy intake from low fat–high simple sugar (r = − 0.22, p = 0.016). Conclusion Higher plasma GLP-1 concentrations prior to ad libitum food intake were associated with lower carbohydrate intake and lower simple sugar ingestion, indicating a possible role of the GLP-1 in the reward pathway regulating simple sugar intake. Trial registration ClinicalTrials.gov identifier: NCT00342732.
Article
Full-text available
PurposeThis study was aimed to examine the structural and construct validity of the Italian version of the Yale Food Addiction Scale in a multisite sample of postgraduate students. Methods Two hundred and fifty-six subjects (78.1% females) aged from 18 to 53 years (mean = 23.93, SD = 4.96) and attending different postgraduate university programs at multiple Italian universities completed the Italian YFAS, the Italian Binge Eating Scale (BES), the Italian Eating Attitudes Test-26 and the Italian Dutch Eating Behavior Questionnaire (DEBQ) online through Qualtrics. ResultsConfirmatory Factor Analysis showed that the single-factor model of the Italian YFAS including all original items had adequate fit indexes (χ2252 = 454.183; p < 0.001; normed χ2 = 1.802; RMSEA = 0.056; 90% CI 0.048–0.076; CFI = 0.761; WRMR = 1.592). However, item analysis revealed that item#25 had zero variance (all subjects were assigned the same score after item dichotomization) and item#24 had a low factor loading, and were thus removed. Furthermore, item#10 and item#11 showed to be almost perfectly correlated (r = 0.998) and were thus parceled. The resulting 19-item single-factor model revealed a better fit to the data (χ2152 = 235.69; p < 0.001; normed χ2 = 1.556; RMSEA = 0.046; 90% CI 0.034–0.058; CFI = 0.858; WRMR = 1.236) and its internal consistency was acceptable (KR-20 = 0.72). Also, a single-factor model including the seven diagnostic symptoms was tested and showed adequate fit values (χ220 = 41.911; p < 0.003; normed χ2 = 2.09; RMSEA = 0.065; 90% CI 0.037–0.093; CFI = 0.946; WRMR = 1.132). Statistically significant and small-to-high correlations were found with all convergent measures, in particular with the BES. Conclusion The Italian 19-item YFAS resulted to be a valid and reliable tool for the assessment of food addiction in postgraduate students. Level of evidenceLevel V, descriptive study.
Article
Full-text available
It has been suggested that a shift in food choices leading to a diet with a lower energy density plays an important role in successful weight loss after Roux-en-Y gastric bypass (RYGB) surgery. A decreased hedonic drive to consume highly palatable foods may explain these changes in eating behavior. Here, we review the literature examining postoperative changes in mechanisms contributing to hedonic drive (food preferences, reinforcing value of food, dopamine signaling, and activity reward-related brain regions). The majority of studies reviewed support that RYGB decrease the hedonic drive to consume highly palatable foods. Still, in order to fully understand the complexity of these changes, we need studies combining sociological and psychological approaches with objective measures of actual food choices examining different measures of hedonic drive.
Article
Full-text available
Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity.
Article
Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D1 receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors. There was no change in D1 receptor density in nucleus accumbens, medial prefrontal cortex or dorsolateral frontal cortex, striatal D2 receptors and dopamine reuptake transporter sites, or μ-opioid receptors in frontal cortex. There were no changes in ligand affinities. The concentrations of monoamines, metabolites and estimates of dopamine (dopamine/dihydroxyphenylacetic acid ratio) and serotonin/5-hydroxyindolacetic acid ratio turnover rates were unchanged in striatum and frontal cortex. However, turnover of dopamine and serotonin in the hypothalamus was increased ~20% and ~15%, respectively. Striatal transmission via D1 receptors is decreased in binge-eating rats while μ-opioid receptor signalling may be increased. These changes are consistent with the attenuation of binge-eating by lisdexamfetamine, which increases catecholaminergic neurotransmission, and nalmefene, a μ-opioid antagonist.
Article
Full-text available
The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.
Article
Full-text available
Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated. Here we report that FoxO1 is highly expressed in DA neurons and mice lacking FoxO1 specifically in the DA neurons (FoxO1 KO(DAT)) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KO(DAT) mice exhibit an increased sucrose preference in concomitance with higher dopamine and norepinephrine levels. Finally, we found that FoxO1 directly targets and negatively regulates tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of the catecholamine synthesis, delineating a mechanism for the KO phenotypes. Collectively, these results suggest that FoxO1 in DA neurons is an important transcriptional factor that directs the coordinated control of energy balance, thermogenesis and glucose homoeostasis.
Chapter
Major depressive disorder (MDD) and cardiovascular disease (CVD) have been evidenced to be interconnected by a bidirectional link since MDD increases the risk of developing CVD and vice versa. However, the biological underpinnings of this relationship are poorly understood up to now. Thus, neuroimaging of shared risk factors of both disorders might shed more light on possible neurobiological implications and help to gain a broader understanding of the mechanisms behind this important clinical connection. Recent neuroimaging studies suggest a predominant involvement of alterations in neural networks of emotion regulation and reward processing in CVD, MDD, and their common risk factors. Moreover, there is evidence that functional and structural brain changes are closely related to inflammatory processes in the development of CVD and MDD. Since these alterations in brain structure and function are yet apparent in subjects at high risk but before the onset of clinically manifest disease and given the observed reversibility of these neural aberrations, neuroimaging findings point to the crucial role of preventive measures in the therapy of both disorders. Especially, therapeutic interventions at an early stage in high-risk populations should be reevaluated in the prevention of both disorders. Future research should focus on the close link between inflammatory and neural processes to provide the neurobiological basis for integrated treatment options for CVD and MDD.
Article
Sensitization is a basic property of the nervous system whereby repeated exposure to a stimulus results in an increase in responding to that stimulus. This increase in responding contributes to difficulty with treatment of drug abuse, as stimuli associated with substance use become signals or triggers for drug craving and relapse. Our work over the past decade has applied the theoretical framework of incentive sensitization to overeating. We have shown, in several studies, that lean adults do not commonly demonstrate behavioral sensitization after repeated exposure to snack food, but a subset of obese adults reliably does. This review will discuss this change in behavioral response to repeated consumption of snack food in obese individuals and apply the theoretical framework of incentive sensitization to drugs of abuse to high fat/high sugar snack foods. We will also show data that suggest that behavioral sensitization to repeated administration of snack food is predictive of weight gain, which may enhance its utility as a diagnostic tool for identifying at-risk individuals for obesity. Finally, we will discuss the future directions of this line of research, including studying the phenomenon in children and adolescents and determining if similar principles can be used to increase motivation to eat healthier food. A combination of reductions in unhealthy food intake and increases and healthy food intake is necessary to reduce obesity rates and improve health.
Article
Full-text available
Introduction Eating Disorders and Obesity are a primary global public health concern. Areas Covered This article aims to trace the neurochemical mechanisms of unwanted eating disorders and target specific loci, within the Brain Reward Cascade (BRC) for therapeutic interventions. Changes due to BRC polymorphisms in functional connectivity and neurotransmission can manifest as overeating, Bulimia Nervosa, and Anorexia Nervosa, and other related eating disorders. Expert opinion Variations in dopamine function within the Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), and Ventral Striatum of individuals result in different outcomes related to maladaptive eating behaviors. The goal is to reduce maladaptive eating behaviors by implementing novel strategies that induce Dopamine Homeostasis within the BRC. Clinicians determine genetic risk severity and identify polymorphic targets for either pharmaceutical or nutraceutical interventions. Precision neuro-nutrient formulations of KB220 (Research ID Code) matched precisely to deficient neurotransmitter systems may promote the long-term development of ‘dopamine homeostasis’ to treat and prevent overeating, Bulimia, and Anorexia Nervosa.
Article
Addiction professionals and the public are recognizing that certain nonsubstance behaviors-such as gambling, Internet use, video-game playing, sex, eating, and shopping-bear resemblance to alcohol and drug dependence. Growing evidence suggests that these behaviors warrant consideration as nonsubstance or "behavioral" addictions and has led to the newly introduced diagnostic category "Substance-Related and Addictive Disorders" in DSM-5. At present, only gambling disorder has been placed in this category, with insufficient data for other proposed behavioral addictions to justify their inclusion. This review summarizes recent advances in our understanding of behavioral addictions, describes treatment considerations, and addresses future directions. Current evidence points to overlaps between behavioral and substance-related addictions in phenomenology, epidemiology, comorbidity, neurobiological mechanisms, genetic contributions, responses to treatments, and prevention efforts. Differences also exist. Recognizing behavioral addictions and developing appropriate diagnostic criteria are important in order to increase awareness of these disorders and to further prevention and treatment strategies.
Article
Full-text available
The National Weight Control Registry (NWCR) is, to the best of our knowledge, the largest study of individuals successful at long-term maintenance of weight loss. Despite extensive histories of overweight, the 629 women and 155 men in the registry lost an average of 30 kg and maintained a required minimum weight loss of 13.6 kg for 5 y. A little over one-half of the sample lost weight through formal programs; the remainder lost weight on their own. Both groups reported having used both diet and exercise to lose weight and nearly 77% of the sample reported that a triggering event had preceded their successful weight loss. Mean (+/-SD) current consumption reported by registry members was 5778 +/- 2200 kJ/d, with 24 +/- 9% of energy from fat, Members also appear to be highly active: they reported expending approximately 11830 kJ/wk through physical activity. Surprisingly, 42% of the sample reported that maintaining their weight loss was less difficult than losing weight. Nearly all registry members indicated that weight loss led to improvements in their level of energy, physical mobility, general mood, self-confidence, and physical health. In summary, the NWCR identified a large sample of individuals who were highly successful at maintaining weight loss. Future prospective studies will determine variables that predict continued maintenance of weight loss.
Article
Full-text available
Activation of the mesolimbic dopamine system is known to trigger relapse in animal models of cocaine-seeking behavior. We found that this "priming" effect was selectively induced by D2-like, and not by D1-like, dopamine receptor agonists in rats. Moreover, D1-like receptor agonists prevented cocaine-seeking behavior induced by cocaine itself, whereas D2-like receptor agonists enhanced this behavior. These results demonstrate an important dissociation between D1- and D2-like receptor processes in cocaine-seeking behavior and support further evaluation of D1-like receptor agonists as a possible pharmacotherapy for cocaine addiction.
Article
Full-text available
Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.
Article
Full-text available
Drugs and food exert their reinforcing effects in part by increasing dopamine (DA) in limbic regions, which has generated interest in understanding how drug abuse/addiction relates to obesity. Here, we integrate findings from positron emission tomography imaging studies on DA's role in drug abuse/addiction and in obesity and propose a common model for these two conditions. Both in abuse/addiction and in obesity, there is an enhanced value of one type of reinforcer (drugs and food, respectively) at the expense of other reinforcers, which is a consequence of conditioned learning and resetting of reward thresholds secondary to repeated stimulation by drugs (abuse/addiction) and by large quantities of palatable food (obesity) in vulnerable individuals (i.e. genetic factors). In this model, during exposure to the reinforcer or to conditioned cues, the expected reward (processed by memory circuits) overactivates the reward and motivation circuits while inhibiting the cognitive control circuit, resulting in an inability to inhibit the drive to consume the drug or food despite attempts to do so. These neuronal circuits, which are modulated by DA, interact with one another so that disruption in one circuit can be buffered by another, which highlights the need of multiprong approaches in the treatment of addiction and obesity.
Article
Full-text available
Trials comparing the effectiveness and safety of weight-loss diets are frequently limited by short follow-up times and high dropout rates. In this 2-year trial, we randomly assigned 322 moderately obese subjects (mean age, 52 years; mean body-mass index [the weight in kilograms divided by the square of the height in meters], 31; male sex, 86%) to one of three diets: low-fat, restricted-calorie; Mediterranean, restricted-calorie; or low-carbohydrate, non-restricted-calorie. The rate of adherence to a study diet was 95.4% at 1 year and 84.6% at 2 years. The Mediterranean-diet group consumed the largest amounts of dietary fiber and had the highest ratio of monounsaturated to saturated fat (P<0.05 for all comparisons among treatment groups). The low-carbohydrate group consumed the smallest amount of carbohydrates and the largest amounts of fat, protein, and cholesterol and had the highest percentage of participants with detectable urinary ketones (P<0.05 for all comparisons among treatment groups). The mean weight loss was 2.9 kg for the low-fat group, 4.4 kg for the Mediterranean-diet group, and 4.7 kg for the low-carbohydrate group (P<0.001 for the interaction between diet group and time); among the 272 participants who completed the intervention, the mean weight losses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively. The relative reduction in the ratio of total cholesterol to high-density lipoprotein cholesterol was 20% in the low-carbohydrate group and 12% in the low-fat group (P=0.01). Among the 36 subjects with diabetes, changes in fasting plasma glucose and insulin levels were more favorable among those assigned to the Mediterranean diet than among those assigned to the low-fat diet (P<0.001 for the interaction among diabetes and Mediterranean diet and time with respect to fasting glucose levels). Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. The more favorable effects on lipids (with the low-carbohydrate diet) and on glycemic control (with the Mediterranean diet) suggest that personal preferences and metabolic considerations might inform individualized tailoring of dietary interventions. (ClinicalTrials.gov number, NCT00160108.)
Article
Full-text available
In vivo microdialysis with HPLC-ED was used to measure dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens of the rat, prior, during, and after 15-min periods of electrical brain stimulation at sites in the ventral tegmental area (VTA) that supported intracranial self-stimulation (ICSS). In the first experiment, both ICSS and yoked stimulation of the VTA evoked significant increases in extracellular concentrations of DA, its metabolites, and 5-HIAA. Comparable results from ICSS and yoked groups were interpreted as evidence that the rewarding properties of VTA stimulation were a causal factor in the elevated DA transmission in the nucleus accumbens, rather than intense operant behavior. Further evidence for this hypothesis came from a second set of data in which changes in extracellular DA levels during the measurement of rate/intensity functions for ICSS were positively correlated. 5-HIAA concentrations also increased during ICSS but these changes were not correlated with either ICSS rate or current intensity, suggesting that changes in serotonin metabolism were unlikely to subserve brain stimulation reward in the VTA. These results add to the growing body of evidence linking changes in extracellular DA in the mesolimbic DA system with both brain stimulation reward and the conditioned and unconditioned rewarding effects of biologically relevant stimuli.
Article
Full-text available
Activation of the mesolimbic dopamine system is known to trigger relapse in animal models of cocaine-seeking behavior. We found that this "priming" effect was selectively induced by D2-like, and not by D1-like, dopamine receptor agonists in rats. Moreover, D1-like receptor agonists prevented cocaine-seeking behavior induced by cocaine itself, whereas D2-like receptor agonists enhanced this behavior. These results demonstrate an important dissociation between D1- and D2-like receptor processes in cocaine-seeking behavior and support further evaluation of D1-like receptor agonists as a possible pharmacotherapy for cocaine addiction.
Article
Full-text available
Considerable evidence indicates that dopaminergic drugs, including drugs that act on D1 receptors, exert their effects by actions on forebrain dopamine terminal regions. Nevertheless, anatomical studies also have demonstrated that there is a high concentration of D1 receptors in the substantia nigra pars reticulata (SNr). The D1 receptors in SNr are located largely on the terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. The present studies were undertaken to determine whether the D1 antagonist SCH 23390 was effective if locally injected into SNr and to compare the results of SNr injections with those obtained from other brain sites. Fixed ratio 5 (FR5) lever pressing and open-field locomotion were used as the behavioral tests because these tasks are sensitive to systemic SCH 23390. Rats received bilateral implantations of guide cannulae into either nucleus accumbens, neostriatum, SNr, or control sites in the cortex or brainstem. Rats in the FR5 study were trained prior to surgery. All rats received one of the following local injections (0.5 microl per side): vehicle, 0.25, 0.5, 1.0, or 2.0 microg SCH 23390. In the FR5 study, the SNr was by far the most potent site for suppression of lever pressing, with an ED50 (dose that produces half maximal response) of 0.33 microg per side. Nucleus accumbens and neostriatum injections were less potent than those in SNr, but more potent than injections into the control regions. With open-field locomotion, the SNr, nucleus accumbens, and neostriatum were approximately equipotent sites, and all three were more potent than the control sites. SNr was a very potent site for suppression of lever pressing and open-field locomotion. These data suggest that D1 antagonists have multiple sites of action, including not only the forebrain dopamine terminal regions but also the SNr. It is possible that blockade of SNr D1 receptors modulates GABA release from striatonigral neurons.
Article
Full-text available
The involvement of dopamine (DA) in conditioned taste aversion (CTA) learning was studied with saccharin or sucrose as the conditioned stimulus (CS) and intraperitoneal lithium as the unconditioned stimulus (US). The dopamine D(1) antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (12.5-50 microg/kg, s.c.), given 5 min after the CS, impaired the acquisition of CTA in a paradigm consisting of three or a single CS-lithium association. SCH 23390 failed to impair CTA acquisition given 45 min after, 30 min before, or right before the CS. (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5a-benzo-(d)-naphtho-(2,1b) azepine (SCH 39166) (12.5-50.0 microg/kg, s.c), a SCH 23390 analog that does not bind to 5HT(2) receptors, also impaired CTA. No significant impairment of CTA was obtained after administration of the specific D(2)/D(3) antagonist raclopride (100 and 300 microg/kg, s.c.). The ability of SCH 23390 to impair CTA learning was confirmed by its ability to reduce the conditional aversive reactions to a gustatory CS (sweet chocolate) as estimated in a taste reactivity paradigm. SCH 39166 impaired CTA also when infused in the nucleus accumbens (NAc) shell 5 min after the CS. No impairment was obtained from the NAc core or from the bed nucleus stria terminalis. The results indicate that D(1) receptor blockade impairs CTA learning by disrupting the formation of a short-term memory trace of the gustatory CS and that endogenous dopamine acting on D(1) receptors in the NAc shell plays a role in short-term memory processes related to associative gustatory learning.
Article
Full-text available
The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.
Article
What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is 'no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the 'taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for 'wanting' incentives, but not for 'liking' them or for learning new 'likes' and 'dislikes'.
Article
Objective: Zonisamide and bupropion have been investigated for weight reduction in obese adults. We conducted a preliminary study comparing the effect on body weight of the combination of these 2 drugs versus zonisamide monotherapy. Method: This was a 12-week, randomized, open-label, parallel-group comparison of 2 active interventions conducted from October 2003 to June 2004. Eighteen obese women (mean [SE] body mass index of 36.8 [1.2] kg/m²) were randomly assigned to receive the combination of zonisamide and bupropion (N = 9) or zonisamide alone (N = 9). All subjects were prescribed a balanced hypocaloric diet (500 kcal/day deficit) and compliance was monitored with self-rated food diaries. Zonisamide therapy was started at 100 mg/day, with a gradual increase to 400 mg/day over 4 weeks for both groups. In addition, the group assigned to combination therapy received bupropion, which was started at 100 mg/day, with an increase to 200 mg/day after 2 weeks. Zonisamide was administered at night and bupropion in the morning. Body weight in kilograms was the primary outcome measure. Results: In an intent-to-treat analysis, carrying the last observation forward for all randomly assigned participants with at least 1 postbaseline assessment, the combination group lost more body weight than the zonisamide group (mean [SE] = 7.2 [1.2] kg [7.5%] vs. 2.9 [0.7] kg [3.1%]; F = 4.7, df = 4,56; p = .003) during the 12-week period. For the subset of 12 patients (combination, N = 7; zonisamide, N = 5) that completed the full 12-week treatment, the mean (SE) weight loss was 8.1 (1.4) kg (8.5%) for the combination group versus 3.0 (0.9) kg (3.3%) for the zonisamide group (F = 4.6, df = 4,40; p =.004). Six subjects in the combination group and 2 in the zonisamide group lost at least 5% of body weight. Conclusion: In this short-term, open-label, preliminary trial, combination treatment of zonisamide and bupropion resulted in more weight loss than treatment with zonisamide alone.
Article
Context: The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention. Objective: To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction. Design, Setting, and Participants: A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002. Intervention: A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40). Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence. Main Outcome Measures: One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report. Results: Assuming no change from baseline for participants who discontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53 %] of 40 participants completed, P=.009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P=.002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P<.001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P=.007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P<.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with self-reported dietary adherence level (r=0.60; P<.001) but not with diet type (r=0.07; P= .40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r=0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P= .48, P= .57, P= .31, respectively). Conclusions: Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group.
Article
Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [35S]GTPγS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or ‘feeding-related’ neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, ‘feeding-related’ neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders.
Article
The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight1, 2. However, in the current ‘obesogenic’ human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions3. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans1, 4, 5. Here we show, using functional magnetic resonance imaging, that peptide YY3–36 (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.
Article
Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised and released from the gastrointestinal tract have been identified. While their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that many of these hormones also physiologically regulate energy balance. Our understanding of how gut hormones signal to the brain has advanced significantly in recent years. Several hormones, including peptide YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent research suggests that gut hormones can be manipulated to regulate energy balance in man and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity pandemic continues unabated, despite public health initiatives and current best therapy. Future gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.
Article
In a long-term longitudinal study of aging in rhesus monkeys, a primary objective has been to determine the effects of aging and caloric restriction (CR) on behavioral and neural parameters. Through the use of automated devices, locomotor activity can be monitored in the home cages of the monkeys. Studies completed thus far indicate a clear age-related decline in activity consistent with such observations in many other species, including humans. However, no consistent effects of CR on activity have been observed. Selected groups of monkeys have also been involved in brain imaging studies, using magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI studies completed thus far reveal a clear age-related decline in the volumes of the basal ganglia, the putamen, and the caudate nucleus, with no change in total brain volume. PET analysis has revealed an age-related decline in the binding potential of dopamine D2 receptors in the same brain regions. These results are consistent with findings in humans. Although additional longitudinal analysis is needed to confirm the present results, it would appear that locomotor activity, volume of the basal ganglia, as well as dopamine D2 receptor binding potential provide reliable, noninvasive biomarkers of aging in rhesus monkeys.
Article
What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is `no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the `taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for `wanting' incentives, but not for `liking' them or for learning new `likes' and `dislikes'.
Article
Background: Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function. Studies in which activity, fitness and cognition are reported in the same individuals could help to resolve this question. Objectives: To assess the effectiveness of physical activity, aimed at improving cardiorespiratory fitness, on cognitive function in older people without known cognitive impairment. Search strategy: We searched MEDLINE, EMBASE, PEDro, SPORTDiscus, PsycINFO, CINAHL, Cochrane Controlled Trials Register (CENTRAL), Dissertation abstracts international and ongoing trials registers on 15 December 2005 with no language restrictions. Selection criteria: All published randomised controlled trials comparing aerobic physical activity programmes with any other intervention or no intervention with participants older than 55 years of age were eligible for inclusion. Data collection and analysis: Eleven RCTs fulfilling the inclusion criteria are included in this review. Two reviewers independently extracted the data from these included studies. Main results: Eight out of 11 studies reported that aerobic exercise interventions resulted in increased cardiorespiratory fitness of the intervention group (an improvement on the maximum oxygen uptake test which is considered to be the single best indicator of the cardiorespiratory system) of approximately 14% and this improvement coincided with improvements in cognitive capacity. The largest effects on cognitive function were found on motor function and auditory attention (effect sizes of 1.17 and 0.50 respectively). Moderate effects were observed for cognitive speed (speed at which information is processed; effect size 0.26) and visual attention (effect size 0.26). Authors' conclusions: There is evidence that aerobic physical activities which improve cardiorespiratory fitness are beneficial for cognitive function in healthy older adults, with effects observed for motor function, cognitive speed, auditory and visual attention. However, the majority of comparisons yielded no significant results. The data are insufficient to show that the improvements in cognitive function which can be attributed to physical exercise are due to improvements in cardiovascular fitness, although the temporal association suggests that this might be the case. Larger studies are still required to confirm whether the aerobic training component is necessary, or whether the same can be achieved with any type of physical exercise. At the same time, it would be informative to understand why some cognitive functions seem to improve with (aerobic) physical exercise while other functions seem to be insensitive to physical exercise. Clinicians and scientists in the field of neuropsychology should seek mutual agreement on a smaller battery of cognitive tests to use, in order to render research on cognition clinically relevant and transparent and heighten the reproducibility of results for future research.
Article
There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.
Article
The aim of this study was to examine the efficacy and safety of topiramate as an adjunct to diet and exercise in drug-naive, obese subjects with type 2 diabetes. Drug-naive individuals with type 2 diabetes, body mass index (BMI) of > or =27 and <50 kg/m(2) and haemoglobin A(1c) (HbA(1c)) of <10.5% were enrolled into the study. All the individuals participated in a non-pharmacologic weight loss program (Pathways to Change((R)); Johnson & Johnson Healthcare Systems, Piscataway, NJ, USA) throughout the trial. After a 6-week placebo run-in, the subjects were randomized to placebo, topiramate 96 mg/day or topiramate 192 mg/day. Subjects were scheduled for 8-week titration and 52-week maintenance phases. The study was ended early; efficacy data were reported for a predefined modified intent-to-treat (MITT) population (n = 229), with 40 weeks of treatment. All the subjects who provided any safety data were included in the safety population (n = 535). Baseline mean weight was 103.7 kg, BMI 36 kg/m(2) and HbA(1c) 6.7% across all treatment groups. By the end of week 40, the placebo, the topiramate 96 mg/day and topiramate 192 mg/day groups lost 2.5, 6.6 and 9.1% of their baseline body weight respectively (p < 0.001 vs. placebo, MITT population using last observation carried forward). The decrease in HbA(1c) was 0.2, 0.6 and 0.7% respectively (p < 0.001 vs. placebo, MITT). Topiramate significantly reduced blood pressure and urinary albumin excretion; a weight-loss-independent HbA(1c) improving effect of topiramate was demonstrated. Adverse events were predominantly related to central nervous system (CNS). Topiramate as an add-on treatment to lifestyle improvements produced significant weight loss and improved glucose homeostasis in obese, drug-naive subjects with type 2 diabetes. These treatment advantages should be balanced against the occurrence of adverse events in the CNS.
Article
Although evidence is accumulating for a protective effect of late life physical activity on the risk of dementia, the findings are inconsistent, especially in men. We examined the association of late life physical activity and the modifying effect of physical function with future risk of dementia in a well-characterized cohort of elderly men participating in the Honolulu-Asia Ageing Study (HAAS). Physical activity by self-report and performance-based physical function was assessed in 2325 men aged 71-92 years without dementia at the baseline exam of the HAAS in 1991 to 1993. Follow-up for incident dementia occurred at repeat examinations conducted in 1994- 1996 and 1997-1999. Analyses were based on Cox proportional hazards models with adjustment for potential confounders, including age, baseline cognitive function, education, and apolipoprotein E genotype. There were 176 incident cases of dementia with a mean follow-up of 6.1 years. Although the incidence of dementia tended to decline with increasing physical activity and function, there was a significant interaction between the latter two factors on dementia risk (P = 0.025). For men with low physical function, high levels of physical activity were associated with half the risk of dementia versus men who were the least active (RH, 0.50; 95% CI, 0.28-0.89). Risk of dementia and Alzheimer’s disease declined significantly with increasing physical activity. Findings persisted after age and risk factor adjustment. Similar associations were absent in men with moderate and high physical function. In elderly men with poor physical function, increasing general physical activity may potentially confer a protective effect or delay the onset for dementia.
Article
The specific binding of [3H]YM-09151-2 was used to investigate the possible differences in age-associated changes in striatal D2 dopamine (DA) receptor properties in genetically obese (fa/fa) Zucker rats and their lean (Fa/?) littermates. The maximal binding sites (Bmax) of D2 DA receptors was found to decline with age in both obese and lean rats; the rate of decline in receptor Bmax was slightly higher in lean than obese rats. However, the Bmax of D2 DA receptor in 6-, 12- and 18-month-old obese rats was significantly lower compared to the age-matched lean rats. These data indicate that obesity decreases the number of striatal D2 DA receptors without affecting the rate at which receptor number decreases with age.
Article
Rats were trained to lever press for intravenous cocaine (1.0 mg/kg/injection) and then switched to bromocriptine (0.3, 1.0, or 3.0 mg/kg/injection) on a FR-1 reinforcement schedule. Bromocriptine sustained responding at all three doses; hourly drug intake increased linearly with log-dose. In a second experiment, animals were trained to respond for cocaine (1.0 mg/kg/injection) or heroin (0.1 mg/kg/injection) reinforcement; drug was available for the first 2 h of each daily session; saline was substituted for cocaine or heroin for 5 subsequent hours. One hour into each saline substitution session, an intravenous injection of saline or bromocriptine (0.0, 0.5, 1.0, or 2.0 mg/kg) was given. Bromocriptine reinstated both cocaine-trained and heroin-trained lever pressing; under these conditions, the drug was most effective in the heroin-trained animals. Reinforcing doses of clonidine (0.0625 and 0.125 mg/kg), methohexital, and nicotine (0.05 and 0.1 mg/kg), and a sub-intoxicating dose of ethanol (2 g/kg) failed to reinstate cocaine-trained responding. These data indicate that bromocriptine has cocaine-like and heroin-like stimulus and reinforcing effects.
Article
The present study provides experimental evidence for the effects of cognitive restraint on sensitivity to internal and external cues of hunger. The design involved four experimental conditions. In each condition the subjects were given either a high calorie or a low calorie early morning drink, and either correctly or incorrectly told its calorie content. The subjects, 10 restrained and 10 nonrestrained normal weight women, then rated their subjective hunger and satiety responses and had a test meal. All subjects reported lower sensations of hunger and higher sensations of fullness after the high calorie drink than the low calorie drink, indicating sensitivity to internal cues. However, the restrained eaters' ratings of hunger were also influenced by the believed content of the drink, indicating sensitivity to external cues. The implications of the results are analysed in terms of current theories of restrained eating and their relevance to further research into pathological eating regulation is discussed.
Article
We have previously shown that endurance training is associated with higher binding of [3H]spiperone to striatal D2 dopamine (DA) receptors of presenescent (21 months old) rats. In the present study we investigated the effects of 6 months of endurance training of young adults on the relationship between steady-state levels of DA and its metabolites in striatum and the affinity and density of striatal D2 DA receptors. The extent of training was confirmed by evaluating the maximal oxygen consumption (VO2 max) in the subjects. D2 DA binding was significantly increased at each of 3 [3H]spiperone concentrations in the young runners. A 'synaptic coupling ratio' calculated as the specific DA binding/DOPAC concentration was significantly increased in runners for the 0.1 and 0.4 nM radioligand concentrations. Across experimental groups levels of DA were highly and positively correlated with specific DA binding at the 0.1, 0.2 and 0.4 nM [3H]spiperone concentrations. Together, these results suggest that exercise can alter the number of DA binding sites and the metabolism of DA in young adult animals.
Article
Pavlovian conditioning was used to teach rats an association between an arbitrary external cue and food. Presentation of the conditioned cue elicited feeding by sated animals. The meal constituted approximately 20 percent of daily intake, and it was compensated for by a reduction of subsequent intake.
Somatosensory evoked potentials (SEPs) to median nerve stimulation have been recorded from parietal and frontal districts in 43 parkinsonians, 17 patients with parkinsonism and 35 healthy controls matched for age and sex. Latency/amplitude characteristics of the parietal P14-N20-P25 and of the frontal P20-N30-P40 wave complexes before and after (10, 20, 30 and 60 min) subcutaneous administration of apomorphine chloride were evaluated in all the 60 patients and in 3 controls. The frontal waves N30 and P40 were either absent or significantly smaller than normal in 31 patients with Parkinson's disease (PD) (72.1%) and in 9 with parkinsonism in baseline records (56.3%). Following apomorphine, the parietal deflections did not significantly vary in amplitude. On the contrary, the frontal complex showed a significant amplitude increase in 27 PD and 8 parkinsonisms (respectively 62.8 and 47.1%); 79.1% of PD and 35.3% of parkinsonisms were improved clinically. Amplitude increase was evident at 10 min after apomorphine, in parallel with clinical improvement, and vanished nearly in coincidence with the end of the clinical effect.
Article
To evaluate the physiological action of striatal dopamine (DA) in exercise, rats were trained to run on a straight treadmill. Extracellular DA and its metabolites, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured by in vivo microdialysis, and striatal tissue tyrosine hydroxylase (TH) activity and monoamine oxidase (MAO) activity were measured using high performance liquid chromatography (HPLC) and spectrophotometer. DA turnover was increased by running, and the increase in DOPAC and HVA was closely related to the speed of running, while the increase in DA had no relationship to the speed. The threshold for the increase in DA, DOPAC, and HVA was between 300 and 660 cm/min. Striatal tissue TH activity was elevated up to 135% of basal values after the rats were trained for 7 days to run at 1800 cm/min. Just after running for 20 min, there was a further increase to 180%. These values became 150% and 90% of basal values at 2 h and 6 h, showing a similar time course as DA detected by microdialysis. MAO-B activity increased up to 160% of basal values after 7 days training but decreased to 130% and 110% just after and 2 h after running, then increased to 145% 6 h after running. MAO-A showed a similar variation as MAO-B. These data suggest that both the synthesis and metabolism of DA have a close relationship with physical exercise and might contribute to adjusting extracellular DA levels within an adequate range in response to exercise intensity.