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Sex differences in hedonic and homeostatic aspects of palatable food motivation

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... Nonetheless, these data likely have relevance to sex-differentiated risk for eating pathology because core symptoms (eg, binge eating) occur on a dimensional spectrum 12 and neural disruptions in food-cue and appetite-related processes have been found in eating disorder samples. 99,100 Non-human animal data indicate that female rodents have a greater propensity to overconsume PF, independent of their physiological state (hunger vs satiated) 101,102 and may experience PF as inherently more rewarding than males. 102,103 For example, female rats worked harder to obtain PF than male rats and were also more sensitive to the stimulatory/ palatability effects of an opioid agonist (morphine). ...
... 99,100 Non-human animal data indicate that female rodents have a greater propensity to overconsume PF, independent of their physiological state (hunger vs satiated) 101,102 and may experience PF as inherently more rewarding than males. 102,103 For example, female rats worked harder to obtain PF than male rats and were also more sensitive to the stimulatory/ palatability effects of an opioid agonist (morphine). 102 Compared with male rats, female rats have also been found to show stronger motivation for PF and exhibit greater neural activation of mesocorticolimbic reward circuit regions (eg, nucleus accumbens, medial prefrontal cortex) after PF consumption. ...
... 102,103 For example, female rats worked harder to obtain PF than male rats and were also more sensitive to the stimulatory/ palatability effects of an opioid agonist (morphine). 102 Compared with male rats, female rats have also been found to show stronger motivation for PF and exhibit greater neural activation of mesocorticolimbic reward circuit regions (eg, nucleus accumbens, medial prefrontal cortex) after PF consumption. 103 Although some sex similarities in neural activation in response to PF do occur (eg, increased activation in hypothalamic and amygdala regions; ...
Article
Purpose Eating disorders and their core symptoms (eg, binge eating, body weight/shape concerns) disproportionately affect females, and these sex-differentiated effects become prominent during and after puberty. Although psychosocial influences such as heightened sociocultural pressures for thinness in girls and women contribute to this sex imbalance, biological factors could also play an important role. Methods This narrative review summarizes evidence of biological factors underlying the sex-differentiated prevalence of eating pathology as well as within-sex variability in risk. Findings There are sex differences in the pubertal emergence of genetic effects on eating pathology (adrenarche in males; gonadarche in females), and at least some genetic contributions to eating pathology seem to vary between the sexes. Furthermore, sex steroid hormones (eg, testosterone, estradiol, progesterone) are leading contributors to differential risk for eating pathology in males and females across the life span. Emerging data suggest that between-sex and within-sex variability in risk might occur via hormone-driven modulation (activation/deactivation) of genetic influences and neural responsiveness to food-related cues. Implications There is a biological basis to heightened risk for eating pathology in females, relative to males, as well as unique biological influences within each sex. Findings from this review highlight the importance of studying both sexes and considering sex-specific biological mechanisms that may underlie differential risk for eating pathology
... Accordingly, morphine decreased response rates in male rats during an incremental food-based acquisition procedure, without impairing discrimination accuracy (Paule and McMillan 1984). Other authors reported no effect or increased motivation to eat in rats treated with morphine, as assessed by operant PR schedules of reinforcement (Solinas and Goldberg 2005;Tapia et al. 2019). However, in the latter studies animals were food-deprived prior to operant training, which might account for the discrepancies with the present and prior studies. ...
... In line with the operant behaviour results, the free-feeding experiments showed that substance-naïve female mice ingested more palatable food than substancenaïve male mice. The latter results are consistent with prior free-feeding studies showing that female rats consume more sucrose pellets than male rats (Tapia et al. 2019). Moreover, in the current study, morphine dose-dependently reduced food intake without affecting the percentage of palatable food ingested, which remained approximately 100%. ...
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Rationale Alongside a pathological, excessive, motivation for substances of abuse, substance use disorder (SUD) patients often show a dramatic loss of interest for naturally rewarding activities, such as positive peer social interaction and food intake. Yet, pre-clinical evidence of the latter SUD features remains scarce and inconsistent. Objectives In the current study, we investigated the effect of non-rewarding and rewarding doses of morphine upon social behaviour, motivation for and intake of palatable food, in male and female C57BL/6J mice. Methods First, the rewarding effects of two relatively low morphine doses (1.25 and 2.5 mg/kg) were assessed using a newly established single substance administration/conditioning trial conditioned place preference (CPP) paradigm. Then, morphine (1.25 and 2.5 mg/kg) effects upon social behaviour, motivation for and intake of palatable food were examined by the three-chamber (3-CH), an operant behaviour and a palatable food preference test, respectively. Results Morphine (2.5 mg/kg) induced CPP in both male and female mice, whereas morphine (1.25 mg/kg) induced CPP only in female mice. Both morphine doses (1.25 and 2.5 mg/kg) reduced sociability, motivation for and intake of palatable food in male and female mice, independently of cognitive function or locomotor activity. Conclusions Female mice were more sensitive than male mice to the rewarding effects of morphine. Moreover, both a non-rewarding and a rewarding dose of morphine impaired the interest for naturally rewarding activities, indicating that brain reward systems might be more sensitive to the deleterious than to the rewarding effects of substances of abuse.
... However, female rodents had faster escape times compared to males during the first trials in a one-way foot shock avoidance task that assesses aversive motivation in the context of helplessness behavior (Dalla et al. 2008;Shors et al. 2007). Female rats also outperform males when the total number of presses needed to receive a reward is systematically increased, such as in progressive ratio tasks (Tapia et al. 2019;Anderson et al. 2017;Reichelt et al. 2016;Van Hest et al. 1987). The prior tasks comparing motivation in male and female rats provided only a single reward choice without manipulating effortrelated decision-making, which may be critical for addressing motivational deficits. ...
... Moreover, once lab chow was introduced in training as a choice for the PROG/chow test, food restricted female rats showed similar patterns of behavior to nonfood restricted groups (Fig. 2a-d). This pattern of behavior was unexpected when considering the fact that previous research has demonstrated an increase in food responding that is greater in food restricted rats when provided only a single choice of a food reward (Tapia et al. 2019;Anderson et al. 2017;Reichelt et al. 2016;Van Hest et al. 1987). It is possible that the food restriction used in the current study to increase the performance for the food reward actually served as a chronic stressor to the females, reducing the consumption of palatable foods versus standard foods by female rats. ...
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Rationale Depressed individuals demonstrate debilitating symptoms, including depressed mood, anhedonia, and effort-related deficits. Effort-related decision-making can be measured through providing subjects with a choice between high effort/reward and low effort/reward options, which is a dopamine (DA)–dependent behavior. While previous research has shown sex differences in depression rates, this has not been examined within operant-based effort-related decision-making tasks nor has DA been shown to underlie this behavior in female rats. Objectives The current study investigated sex differences in an effort-related decision-making task prior to and following administration of the DA D2 receptor antagonist haloperidol (HAL). Methods Adult rats were food restricted or fed freely and trained in an effort-related progressive ratio choice task. After stable responding, HAL was administered acutely (0.05–0.2 mg/kg) prior to testing. Results Results indicate a significant effect of sex on training variables, with males having a greater number of lever presses, higher ratios, and longer active lever times. Pretreatment with HAL significantly reduced the same measures in both sexes for the high-valued reward, while increasing chow consumption in the food restricted males. Food restricted rats showed a greater number of total lever presses and achieved higher ratios; however, the effect in male food restricted rats was greatest. Conclusions These data suggest that, although there are sex differences in training, HAL decreases behavior across sexes, demonstrating that the D2 mechanism is similar in both sexes. These findings provide a better understanding of motivational dysfunction in both sexes and potential treatment targets for depression.
... and Comparing data from the last 3 days of testing under signalled vs unsignalled conditions, there was no effect of the houselight signal on lever pressing (data not shown). However, efficiency was significantly lower when the houselight was absent (F 1, 35 < .05). However, there was no effect of 17-OHPC in either sex (data not shown). ...
... When responding for sucrose pellets in a progressive ratio task, they show higher breakpoints than males. 35 Lastly, we also observed a sex difference in the novel object recognition task, where females spent less time than males investigating the novel object. Nonetheless, all rats spent more time investigating the novel object over the familiar object, indicating that object recognition was intact in both sexes. ...
Article
Women with a history of unexplained miscarriage are frequently prescribed the synthetic progestin, 17α‐hydroxyprogesterone caproate (17‐OHPC) during the middle trimester of pregnancy. However, little is known about long‐term behavioral effects of 17‐OHPC. Work in rodents suggests that the developing brain is sensitive to progestins. Neonatal 17‐OHPC impairs adult performance in set‐shifting and delay discounting. The present study tested effects of 17‐OHPC (0.5mg/kg) or vehicle administration from postnatal days 1‐14 on cognitive function in adulthood in rats. Cognitive function was assessed in males and females (n=8‐10/group) by operant responding for sugar pellets, measuring delayed reinforcement or reversal learning. For delayed reinforcement, the rat must wait 15 seconds for pellets after responding on a lever. Delay is signaled by a light or unsignaled. For reversal learning, the rat must respond on the lever under a stimulus light, and then learn to respond on the unlit lever. For delayed reinforcement, rats earned more pellets under signaled vs unsignaled conditions. Likewise, males made more responses and earned more pellets, compared with females. Under signaled conditions, 17‐OHPC‐treated rats earned fewer pellets than controls. For reversal learning, results were similar. Females required more trials than males to respond correctly for the new rule, and 17‐OHPC‐treated rats required more trials than controls. This suggests that 17‐OHPC exposure during development may impair cognitive function. Considering that questions have been raised as to the efficacy of 17‐OHPC to prevent miscarriage, it may be necessary to rethink the use of progestin therapy during pregnancy.
... The current study explored whether PD144418 alters food-reinforced behaviors through manipulation of homeostatic energy balance. Furthermore, while there is knowledge related to sex differences in animal models of feeding behavior [17][18][19][20] and drug self-administration [21][22][23][24] females in examining the effects of σ 1 receptor antagonists in addition to whether a σ 1 receptor antagonist alters motivation to work for palatable food in females. It is important to examine sex differences in regard to PD144418 as not only are there known differences in general feeding behaviors, but males and females also differ with respect to their regulation of energy homeostasis [25]. ...
... However, in male and female rats, 23 -h restriction of food decreased future food consumption, while increasing wheel running [30]. In regard to motivation, female rats are more motivated to consume palatable foods than males, as females show a higher breakpoint under PR schedules of reinforcement [17,18,20,31,32]. Finally, estrous cycle and gonadal hormones can affect operant responding in females; for example, when progesterone levels are low, females significantly increased operant responding for cocaine [33][34][35][36]; on the other hand, estrogen can attenuate motivation for food [33,35,37]. ...
... A more recent study has identified that approximately 40% of female rats tested exhibit an alternate fear behavior in the form of fast paced movements called 'darting'; this was only seen in approximately 10% of male rats tested [17]. There is also evidence of sex differences in the seeking of natural rewards, where it has been reported that female rats consume more sucrose pellets than males and are willing to work harder for them [18]. Dopamine signaling during reward tasks has also been demonstrated to be different between sexes. ...
... In our study, females consistently showed elevated reward-seeking behavior during the reward cue compared to males across the reward pre-training and habituation sessions. These data appear consistent with reward studies showing significant sex differences in response to sucrose, with females willing to work more for sucrose in a progressive ratio paradigm [18], and in response to drugs of abuse, with female rats consistently self-administering drugs more rapidly than males [42]. Estradiol also appears to affect motivation for food (reviewed in [43]). ...
Article
Reward availability and the potential for danger or safety potently regulate emotion. Despite women being more likely than men to develop emotion dysregulation disorders, there are comparatively few studies investigating fear, safety and reward regulation in females. Here, we show that female Long Evans rats did not suppress conditioned freezing in the presence of a safety cue, nor did they extinguish their freezing response, whereas males did both. Females were also more reward responsive during the reward cue until the first footshock exposure, at which point there were no sex differences in reward seeking to the reward cue. Darting analyses suggest females were able to regulate this behavior in response to the safety cue, suggesting they were able to discriminate between fear and safety cues but did not demonstrate this with conditioned suppression of freezing behavior. However, levels of darting in this study were too low to make any definitive conclusions. In summary, females showed a significantly different behavioral profile than males in a task that tested the ability to discriminate among fear, safety and reward cues. This paradigm offers a great opportunity to test for mechanisms that are generating these behavioral sex differences in learned safety and reward seeking.
... Although both male and female WR rats reversed their initial avoidance for HF diet, there was a sex difference in which the reversal of HF diet avoidance occurred with females reversing earlier than males. One potential explanation for this sex difference is that females are more prone to hedonic and binge eating than males [101,102] and their feeding behavior appears to be driven by palatability rather than physiological hunger or metabolic state [103,104]. Both of these factors could act together and exacerbate the development of obesity [56,57], which is more prevalent in females [105]. ...
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Excessive and prolonged intake of highly palatable, high fat (HF) foods contributes to the pathogenesis of obesity, metabolic syndrome, and cognitive impairment. Exercise can restore energy homeostasis and suppress HF diet preference in rats. However, it is unclear if exercise confers similar protection against the detrimental outcomes associated with a chronic HF diet preference and feeding in both sexes. We used our wheel running (WR) and two-diet choice (chow vs. HF) paradigm to investigate the efficacy of exercise in reversing HF diet-associated metabolic and cognitive dysregulation in rats, hypothesizing that beneficial effects of exercise would be more pronounced in males. All WR rats showed HF diet avoidance upon running initiation, and males, but not females, had a prolonged reduction in HF diet preference. Moreover, exercise only improved glucose tolerance and insulin profile in males. Compared to sedentary controls, all WR rats improved learning to escape on the Barnes maze. Only WR females increased errors made during subsequent reversal learning trials, indicating a sex-dependent effect of exercise on behavioral flexibility. Taken together, our results suggest that exercise is more effective at attenuating HF-associated metabolic deficits in males, and highlights the importance of developing sex-specific treatment interventions for obesity and cognitive dysfunction.
... Specialized assays are often used to measure the contribution of motivational vs hedonic processes to food intake in male vs female rats. For example, individual differences in the hedonic processing ("liking") of food is typically inferred from measuring orofacial reactions to food (Grill and Norgren, 1978;Doyle et al., 1993;Ho and Berridge, 2013), whereas differences in motivation for a food ("wanting") can be measured using tasks that require the animal to exert high amounts of physical effort (as in a progressive ratio [PR] task) or endure pain (typically foot shock) to earn the food reward (Oswald et al., 2011;Tapia et al., 2019). Although informative, these assays are limited by the fact that only 1 index (motivation or hedonia) can be measured at a time. ...
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Background: The prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared to male rats. Methods: Here, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (α) of 3 types of palatable food (low fat, high fat and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we next examined the role of orexin function in sex differences of economic demand for palatable foods. Results: The novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, in female rats we observed more orexin-expressing neurons and cFos expression (measure of recent neural activation) in these neurons compared to male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low and high-cost intake for palatable food in both male and female rats. Conclusions: These findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.
... Such findings are in line with the possibility that palatable food is more rewarding for females. Indeed, palatable food induces a more robust conditioned place preference in females than in males [73], and females work harder to obtain palatable food while on a progressive ratio schedule of reinforcement [ [71,[74][75][76], but see [69]]. Thus, our results support the bulk of the available pre-clinical literature showing that females are more motivated to self-administer palatable food compared with males. ...
Article
Previous research in our lab has established a causal role for chronic stress exposure in subsequent increases in relapse-like behaviors in male rats with a history of palatable food self-administration. Given that many of the neurobehavioral consequences of stress are sex dependent, we aimed to determine whether sex differences exist with regard to the effects of chronic stress on relapse. Additionally, because high trait anxiety confers vulnerability to stress-related disorders, we examined whether individual differences in trait anxiety were related to differences in relapse-like behavior after chronic stress exposure. Following elevated plus maze testing for classification into high- or low-anxiety phenotypes, male and female rats responded for highly palatable food pellets. During subsequent extinction training, stress was manipulated (0 or 90 min restraint/day for 7 days). Rats were then tested for cue- and pellet priming-induced reinstatement of palatable food seeking. Results showed that female rats displayed higher levels of responding during cue-induced reinstatement tests compared to males, and that a history of chronic stress caused an attenuation of cue-induced reinstatement in female, but not male, rats. Regarding pellet priming-induced reinstatement, there was a three-way interaction such that neither stress history nor anxiety phenotype was related to reinstatement in females, but a history of stress in males caused increased and decreased responding in low- and high-anxiety rats, respectively. These results suggest that biological sex and trait anxiety level may help to explain differences in vulnerability to relapse among individuals exposed to chronic stress. Such information may be useful in designing more personalized and effective treatments for obesity and eating disorders.
... 24 Homeostatik ve hedonik olarak lezzetli besinleri tüketmeye yönelik motivasyonda cinsiyet farklılıklarının incelendiği çalışmada, dişi ratların erkeklere kıyasla şeker ve yağ içeriği yüksek lezzetli besinleri tüketmeye yönelik bir motivasyon sergiledikleri, yani lezzetli besinleri tüketmeye yönelik hedonik açlığın dişi ratlarda daha yüksek olduğu belirtilmektedir. 25 Bu çalışmaya yaş ortalamaları 37,95±12,30 yıl olan 315 erişkin birey katılmıştır. Bireylerin 18-27 yaş, 28-38 yaş, 39-48 yaş ve ≥49 yaş gruplarındaki hedonik açlık durumları incelendiğinde; BGÖ ölçeği toplam puanı giderek azalmaktadır. ...
... One of the studies testing the taste preference for glucose or saccharine solutions demonstrated that female rats were more attracted to sweetness in oral solutions than males [25]. Similar results have been reported in other conditions with food [26]. However, in contrast to bitterness, results related to sweetness and sex seem to be more difficult to extrapolate from this model to human behavior. ...
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Palatability is a recognized driver of medicine acceptability in pediatrics but deemed less relevant in older populations due to sensory decline. Preliminary findings from an observational study implicated palatability problems with one Alzheimer's medicine. Among 1517 observer reports combining multiple measures on medicines uses in patients aged over 64, we focused on two original formulations of memantine (Ebixa ® , tablets (n = 25) and oral solution (n = 60)). Evaluations were scored with an acceptability reference framework (CAST), the rodent Brief Access Taste Aversion (BATA) model tested aversiveness. Focusing on women treated with Ebixa ® (n = 54), the oral formulation subgroup was classified as "negatively accepted", while the coated tablet was associated with the "positively accepted" cluster. In men, both formulations belonged to the "positively accepted" profile. Using BATA, the original oral solution was categorized as highly aversive/untolerated while solutions of excipients only were well tolerated. Furthermore, the number of licks was significantly lower in female than in male rats. These results revealed that medicine palatability remains important for acceptability in older populations. Moreover, converging results from humans and animal models highlighted that palatability profiles can significantly vary between the sexes. These drivers should be closely considered during drug development to enhance acceptability in this population.
Article
Palatable taste can stimulate appetite in the absence of hunger, and individual differences in hedonic eating may be critical to overeating. Women are more prone to obesity and binge eating than men, which warrants comparisons of hedonic versus physiological consumption and the underlying neural substrates in both sexes. The current study examined palatable (high-sugar) food consumption in male and female rats under physiological hunger and satiety, and the role of the neuropeptide orexin/hypocretin (ORX). Across multiple tests, females consistently consumed similar amounts of palatable food regardless of whether they were sated or hungry prior to testing. In contrast, males typically adjusted their consumption according to their hunger/satiety state. This difference was specific to palatable food consumption, as both sexes ate standard chow according to their hunger state. ORX is important in food motivation and reward behaviors. Thus, to begin to determine the neuronal mechanisms of hedonic eating, we examined activation and signaling of ORX neurons. We systematically characterized Fos induction patterns of ORX neurons across the entire rostrocaudal extent of the lateral hypothalamus and found that they were activated by food and by fasting in both sexes. Then, we showed that systemic blockade of ORX receptor 1 signaling with SB-334867 decreased palatable food consumption in hungry and sated rats of both sexes. These results demonstrate sex differences in hedonic eating; increased susceptibility in females to overeat palatable food regardless of hunger state, and that ORX is a critical neuropeptide mechanism of hedonic eating in both sexes.
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The influences of four different cooking methods-pan, ohmic, vacuum and sous vide-were studied with regard to the microstructural, sensorial and physicochemical characteristics of pork meat. The end point temperature to all cooking methods was 70 °C. Pan cooking resulted in a softer meat with higher overall liking by the consumers, and ohmic cooking produced firmer (p < .05) meats and myofibrils, with higher alignment compared to the pan-cooked meat as well as a golden colour. Sous vide-cooked meats were perceived as insipid, while vacuum-cooked meats showed loss of structure and were perceived as drier (p < .01) and paler (p < .01). No statistically significant differences were found for cooking loss and water-holding capacity (p > .05). The results suggest that consumers preferred pan-cooking, as they described these samples as juicy, tender and tasty. Ohmic-cooked meat, which required shorter cooking times, showed similar characteristics to pan-cooked meat and could be used as alternative to pan cooking in the catering industry.
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The brain plays a key role in the controls of energy intake and expenditure and many genes associated with obesity are expressed in the central nervous system. Technological and conceptual advances in both basic and clinical neurosciences have expanded the traditional view of homeostatic regulation of body weight by mainly the hypothalamus to include hedonic controls of appetite by cortical and subcortical brain areas processing external sensory information, reward, cognition, and executive functions. Thus, hedonic controls interact with homeostatic controls to regulate body weight in a flexible and adaptive manner that takes environmental conditions into account. This new conceptual framework has several important implications for the treatment of obesity. Because much of this interactive neural processing is outside awareness, cognitive restraint in a world of plenty is made difficult and prevention and treatment of obesity should be more rationally directed to the complex and often redundant mechanisms underlying this interaction.
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Obsessive-compulsive disorder (OCD) gradually emerges and reaches clinical significance during early adulthood. Whether a predisposition for OCD manifests as binge eating disorder earlier during adolescence is proposed. To further characterize how OCD-like behaviors increase across maturation and to determine whether an OCD-like predisposition increases the likelihood of binge eating during adolescence. Male and female Sprague-Dawley rats were injected with the tricyclic antidepressant clomipramine (CMI, 15 mg/kg) or saline vehicle twice daily between postnatal days 9-15. Both groups were tested for perseverative (spontaneous alternation) and anxiety-like (elevated plus maze; marble burying) behaviors during juvenility (day 28), adolescence (day 60), and adulthood (day 90). Both motivations to eat sucrose pellets and binge eating on fat were investigated. Sex- and age-dependent increases in anxiety-like and perseverative behavior were observed in CMI subjects. Differences in consummatory behaviors emerged during late adolescence, while no significant differences in alternation or anxiety-like behaviors were detected between CMI and vehicle animals until adulthood. Adolescent CMI females consumed more sucrose pellets in 30 min relative to vehicle females, whereas adolescent CMI males consumed approximately half as much as vehicle males. Sucrose consumption did not differ between groups in adulthood. Adolescent CMI rats demonstrated more fat bingeing than vehicles, independent of sex. OCD-like behaviors are emerging during adolescence, but sucrose consumption and fat bingeing in CMI-treated animals significantly precedes the appearance of anxiety and perseveration. This OCD-like phenotype emerges fully during adulthood, suggesting that eating may likely serve as a coping strategy in these animals.
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This article reviews current research and cross-disciplinary perspectives on the neuroscience of food reward in animals and humans, examines the scientific hypothesis of food addiction, discusses methodological and terminology challenges, and identifies knowledge gaps and future research needs. Topics addressed herein include the role of reward and hedonic aspects in the regulation of food intake, neuroanatomy and neurobiology of the reward system in animals and humans, responsivity of the brain reward system to palatable foods and drugs, translation of craving versus addiction, and cognitive control of food reward. The content is based on a workshop held in 2013 by the North American Branch of the International Life Sciences Institute. © The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute.
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Opioids are important in reward processes leading to addictive behavior such as self-administration of opioids and other drugs of abuse including nicotine and alcohol. Opioids are also involved in a broadly distributed neural network that regulates eating behavior, affecting both homeostatic and hedonic mechanisms. In this sense, opioids are particularly implicated in the modulation of highly palatable foods, and opioid antagonists attenuate both addictive drug taking and appetite for palatable food. Thus, craving for palatable food could be considered as a form of opioid-related addiction. There are three main families of opioid receptors (μ, κ, and δ) of which μ-receptors are most strongly implicated in reward. Administration of selective μ-agonists into the NAcc of rodents induces feeding even in satiated animals, while administration of μ-antagonists reduces food intake. Pharmacological studies also suggest a role for κ- and δ-opioid receptors. Preliminary data from transgenic knockout models suggest that mice lacking some of these receptors are resistant to high-fat diet-induced obesity. Copyright © 2012 S. Karger GmbH, Freiburg.
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In mammals, males consume more food, which is considered a masculinized behavior, but the underlying mechanism of this sex-specific feeding behavior is unknown. In mice, neonatal testosterone (NT) is critical to masculinize the developing brain, leading to sex differences in reproductive physiology. The proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) are critical to suppress energy intake and POMC innervation of hypothalamic feeding circuits develops to a large extent neonatally. We hypothesized that NT programs the masculinization of energy intake by programming POMC neurons. We tested this hypothesis by comparing control females and control males (CMs) with female mice neonatally androgenized with testosterone (NTFs). We show that increased food intake in CMs is associated with reduced POMC expression and decreased intensity of neuronal projections from POMC neurons within the ARC compared with control females. We found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT). NTFs also exhibit hyperleptinemia and a decreased ability of leptin to up-regulate POMC, suppress food intake, and prevent adipose tissue accumulation, independent of signal transducer and activator of transcription 3. However, this leptin resistance is specific to NTFs, is not a consequence of masculinization, and is reproduced by neonatal exposure to estrogen but not DHT. Thus, NT programs a sexual differentiation of POMC neurons in female mice via DHT but also predisposes to leptin resistance and obesity in an estrogen-dependent manner.
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Motivation for food depends on several variables including food palatability, the homeostatic state of the organism, and the nature of the behavior required to obtain the reward. However, few studies to date have tried to evaluate motivation for food considering all these variables at the same time. Since dopamine and opioids have been deeply involved in the regulation of feeding, it is of interest to investigate their role considering all the mentioned variables. In this study, we evaluated the involvement of dopamine and endogenous opioids on food consumption and food motivation using behavioral paradigms that differ in the motor requirement to gain access to the reward, when food palatability and homeostatic state were taken into account. Pellets differentiated on palatability were offered to sated and restricted rats in consummatory tests and in different behavioral paradigms measuring motivational state, but requiring different motor outputs (runway and an operant progressive ratio 3 task). Peripheral injections of naloxone or flupenthixol were administered when these tasks were learned and stable. Naloxone decreased food intake when pellets were palatable, while flupenthixol was without any effect. When considering motivation, naloxone decreased performances in both the runway and progressive ratio tests while flupenthixol was only effective in the progressive ratio test. Impairing the opioid neurotransmission diminishes motivation to obtain food, possibly through a decrease in the perceived palatability of the food reward. The dopaminergic system appears to be more involved in the modulation of motivation to obtain food in a cost/benefit-related manner.
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Various aspects of feeding behavior (eg consumption, motivation and anticipation) are regulated by homeostatic and hedonic systems, and are modulated by dopaminergic and opioid brain systems. Here, we have studied the modulation of these aspects of feeding behavior by opioid and dopaminergic neurotransmission while taking into account food palatability and homeostatic state. Foods that varied in palatability were presented to either food sated or food restricted rats following injections of different doses of naloxone, an opioid receptor antagonist, or flupenthixol, a dopaminergic receptor antagonist, in behavioral paradigms that measured different aspects of feeding. Naloxone decreased food intake in a dose-dependent manner in sated rats given access to palatable food, without modifying food intake in food restricted rats. Flupenthixol did not have any effect on food intake. With regard to motivation, which was tested in a straight alley, naloxone increased the latency to reach the food only in sated rats presented with palatable food. Flupenthixol did not modify the latency of any group. Conditioned locomotor activity to repeated food presentation, a measure of anticipation, is expressed only in food restricted rats. Naloxone did not modify anticipatory activity, whereas flupenthixol decreased it only in food restricted rats presented with palatable food. These results reinforce the idea that the opioid system regulates feeding through the modulation of the perceived palatability of food. The dopaminergic system seems to be more important for the regulation of anticipatory activity related to motivationally relevant stimuli.
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The authors investigated the role of food incentive properties and homeostatic state on the motivational, anticipatory, and consummatory aspects of feeding. Behavioral tests were carried out on food-sated and food-restricted rats that were presented with 2 kinds of food differing in their palatability level. Both food-sated and food-restricted rats consumed large quantities and were highly motivated when presented with very palatable food. In contrast, only food-restricted rats developed anticipatory responses, regardless of the kind of food presented. These data suggest that food incentive properties play a key role in the control of consummatory and motivational components of feeding but seem less involved in the regulation of anticipatory behavior.
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Previous work indicates that female rats initiate cocaine use sooner than male rats and reach significantly higher break points (BPs) for a single injection of cocaine under a progressive ratio (PR) schedule compared to male rats. The present study extends previous work examining sex differences to the acquisition of methamphetamine (METH) (0.02 mg/kg) and maintenance of METH-maintained responding under a PR schedule. An automated priming procedure that has previously been shown to be sensitive to sex differences was used for the acquisition of drug self-administration. A PR schedule that has been shown to be sensitive in detecting sex differences in maintenance levels of cocaine-reinforced responding was used for the maintenance phase of the experiment. A greater percentage of female rats met the acquisition criterion for METH (0.02 mg/kg) self-administration compared to male rats (55.6% versus 11.1%, respectively), and they did so at a significantly faster rate. Under stable fixed-ratio 1 (FR1) conditions (after acquisition and 5 days before the PR schedule) female rats responded for significantly more METH (0.02 mg/kg) infusions compared to males. Dose-response curves obtained under the PR schedule during maintenance indicated that female rats self-administered significantly more METH infusions compared to male rats. These data suggest that female rats are more vulnerable to the acquisition of METH self-administration, and they are more motivated to self-administer METH compared to male rats under a PR schedule during the maintenance phase.
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Objective Several efforts are underway to model binge eating in animals in order to advance neurobiological models of risk. However, knowledge of sex differences in these models is currently lacking. The goal of the present study was to examine sex differences in binge eating phenotypes using a well-established rodent model (i.e., the binge eating resistant/binge eating prone model). Method Thirty male and 30 female adult Sprague-Dawley rats were exposed to feeding tests consisting of intermittent access to palatable food (PF). Rats were then categorized as binge eating prone (BEP) based on the amount and consistency of PF consumption across tests. ResultsAcross multiple methods for BEP classification, rates of BEP phenotypes were two to six times higher in female than male rats. DiscussionFindings provide support for sex differences in rodent models of binge eating and highlight the promise of the BER/BEP model for understanding neurobiological mechanisms underlying sex differences in risk. (c) 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013; 46:729-736)
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Opioid modulation of ingestion includes general opioid antagonism of deprivation-induced water intake and intake of sucrose and saccharin solutions. Previous studies using selective subtype antagonists indicated that opioid effects upon deprivation-induced water intake occured through the mu2 receptor and that opioid effects upon sucrose intake occured kappa and mu2 receptors. The present study compared the effects of intracerebroventricular administration of opioid receptor subtype antagonists upon intakes of saccharin solution and a maltose dextrin (MD) solution to determine which receptor subtypes were involved in modulation of ingestion of different preferred tastants. Significant reductions in saccharin intake (1 h) occured following naltrexone (20–50 μg: 66%) and naltrindole (delta, 20 μg: 75%), whereas [d-Ala2, Leu5, Cys6]-enkephalin (DALCE, delta1, 40 μg: 45%) had transient (5 min) effects. Neither beta-funaltrexamine (B-FNA, mu), naloxanazine (mu1, nor nor-binaltorphamine (Nor-BNI, kappa) significantly altered saccharin intake. Significant reductions in MD intake (1 h) occured following naltrexone (5–50 μg: 69%) and B-FNA (1–20 μg: 38%). MD intake was not reduced by naltrindole, DALCE, naloxanazine and Nor-BNI. Peak antagonist effects were delayed (20–25 min) to reflect interference with the maintenance, rather than the initiation of saccharin or MD intake. Comparisons of opioid antagonist effects across intake situations revealed that naltrexone had consistently low ID40 values for saccharin (29 nmol), MD (25 nmol), sucrose (6 nmol) and deprivation (38 nmol) intake. Despite its significant effects relative to naloxanazine, B-FNA had significantly higher ID40 values for saccharin (800 nmol), MD (763 nmol) and sucrose (508 nmol) relative to deprivation (99 nmol) intake, suggesting that mu2 receptors may be mediating maintenance of intake rather than taste effects. Nor-BNI had low40 values intake of sucrose (4 nmol), but not for saccharin (168 nmol), MD (153 nmol) and deprivation (176 nmol), suggesting that kappa receptors may mediate ingestion of sweet-tasting stimuli. That delta (naltrindole:ID40 = 60nmol), but not delta1, (DALCE:ID40 = 288nmol) antagonist consistently reduce saccharin intake suggests a role for the delta2 receptor subtype in the modulation of hedonic orosensory signals.
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Preferences and cravings for sweet high-fat foods observed among obese and bulimic patients may involve the endogenous opioid peptide system. The opioid antagonist naloxone, opioid agonist butorphanol, and saline placebo were administered by intravenous infusion to 14 female binge eaters and 12 normal-weight controls. Eight of the binge eaters were obese. During infusion, the subjects tasted 20 sugar/fat mixtures and were allowed to select and consume snack foods of varying sugar and fat content. Naloxone reduced taste preferences relative to baseline in both binge eaters and controls. Total caloric intake from snacks was significantly reduced by naloxone in binge eaters but not in controls. This reduction was most pronounced for sweet high-fat foods such as cookies or chololate. No consistent effects on taste preferences or food intakes were observed with butorphanol. Endogenous opioid peptides may be involved in mediating taste responses and preferences for palatable foods, notably those rich in sugar and fat.
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What brain reward systems mediate motivational ‘wanting’ and hedonic ‘liking’ for food rewards? And what roles do those systems play in eating disorders? This article surveys recent findings regarding brain mechanisms of hedonic ‘liking’, such as the existence of cubic-millimeter hedonic hotspots in nucleus accumbens and ventral pallidum for opioid amplification of sensory pleasure. It also considers brain ‘wanting’ or incentive salience systems important to appetite, such as mesolimbic dopamine systems and opioid motivation circuits that extend beyond the hedonic hotspots. Finally, it considers some potential ways in which ‘wanting’ and ‘liking’ might relate to eating disorders.
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Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through activation of the μ opioid receptor; however, an increasing number of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examined, or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.
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Previous research has demonstrated that administration of μ-opioid receptor agonists into the nucleus accumbens increases high-fat diet consumption in sated rats and has shown a role of basolateral amygdala (BLA) activity in mediating this response. The present experiments were conducted to examine the role of BLA opioid transmission in mediating high-fat feeding driven by either intra-accumbens opioid activation or 24-h home cage food deprivation. Injection of the μ-opioid agonist, d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) into the nucleus accumbens (0.25μg/0.5μl/side) increased consumption of a high-fat diet, and this effect was attenuated by pre-treatment with the opioid antagonist, naltrexone (5μg/0.25μl/side) administered into the BLA. In contrast, intra-BLA naltrexone administration had no influence on the increase in high-fat intake following 24-h food deprivation. These findings suggest that BLA opioid transmission is an important mediator of palatability-driven feeding as modeled by intra-accumbens opioid activation, while BLA opioid transmission has no significant influence on the increase in high-fat feeding driven by short-term negative-energy balance.
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The effects of acute and chronic morphine administration and the interaction with oxytocin and vasopressin on food intake response were investigated at various intervals during a 24-h schedule in rats. Acute morphine (5 mg/kg, IP) produced a generalized hyperphagic effect in both light (0-6 h) and dark (6-24 h) phases, the most marked effects being at 0-1 h, 1-3 h and 6-24 h. Chronic morphine (7 days) in an escalating dose schedule (5-35 mg/kg/day) produced (a) an enhancement of the hyperphagic effect in the light phase and (b) an attenuation of the food intake response during the dark phase. Neither oxytocin nor vasopressin had any significant influence on food intake, per se, after either acute or chronic administrations. However, both OXY and AVP reduced the hyperphagic response to acute morphine throughout the 24-h observation period. Further, on chronic administration, both neurohypophyseal peptides blocked the enhancements of morphine-induced hyperphagia (reverse tolerance) during light phase, whereas only vasopressin was effective in attenuating the reduction of hyperphagia (tolerance) during dark phase. These results are discussed in light of complex opiate-oxytocin/vasopressin interactions in the regulation of food intake.
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Liking and craving for chocolate and related substances were surveyed in a sample of University of Pennsylvania undergraduates (n = 249) and their parents (n = 319). Chocolate was highly liked in all groups, with a stronger liking by females. Chocolate is the most craved food among females, and is craved by almost half of the female sample (in both age groups). Although this craving is related to a sweet craving, it cannot be accounted for as a craving for sweets. About half of the female cravers show a very well defined craving peak for chocolate in the perimenstrual period, beginning from a few days before the onset of menses and extending into the first few days of menses. There is not a significant relation in chocolate craving or liking between parents and their children. The current motivation for chocolate preference seems to be primarily, if not entirely, sensory. Liking for chocolate correlates significantly with liking for sweets and white chocolate. The liking for the sensory properties could originate in innate or acquired liking based on the sweetness, texture and aroma of chocolate, or it could be based in part on interactions between the postingestional effects of chocolate and a person's state (e.g., mood, hormone levels). Based on correlational data, we find little evidence for a relation between addiction to chocolate or the pharmacological (e.g., xanthine-based) effects of chocolate and the liking for chocolate.
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Taste preferences of mature male and female rats for caloric and noncaloric sweet solutions have been found to differ. Although females do not drink more water than males, they consume significantly greater quantities of a slightly sweet 3 percent glucose and a very sweet 0.25 percent saccharin solution. When given a choice, males switch their initial preference for a saccharin solution to a preference for a glucose solution after several days, while females maintain a preference for the saccharin solution. Females also prefer significantly higher concentrations of saccharin than males do.
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It has been suggested that endogenous opiate mechanisms may be involved in the physiological control of food and water intake. Support for this hypothesis has been obtained from studies of the effects of narcotic antagonists which reduce feeding and drinking, but it is also necessary to show that food and water intake can be facilitated by opiate agonists. In the present study the food intake of freely-feeding rats was increased by subcutaneous injections of morphine, a stabilised enkephalin and analogue (RX 783030), and ethylketocyclazocine. Water intake was also increased but this effect was more variable than the increased eating. The increased food intake produced by the putative mu receptor agonists morphine and RX 783030 was blocked by a dose of naloxone which did not affect the facilitation of eating produced by ethylketocyclazocine, which may act at a separate population of receptors known as kappa receptors. These data are consistent with the possibility that opiate receptors are involved in the control of feeding and drinking.
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Patterns of caloric intakes and dietary self-selection of the three macronutrients, protein, fat and carbohydrate were examined in male rats following the administration of morphine sulfate (0.0, 1.0, 10.0 and 20.0 mg/kg, IP). Animals were given access to either ground Purina Chow or one of two dietary self-selection regimes, one with a high-fat ration (7.8 kcal/g) and the other with a fat ration isocaloric to the carbohydrate and protein rations (3.8 kcal/g). Animals received morphine injections at the beginning of a six-hour feeding period and nutrient intakes were measured at 1, 2, 4 and 6 hours postinjection. Similar patterns of macronutrient choice were observed for both animals maintained on the high-fat regime and animals with access to the isocaloric components following morphine injections. As a function of morphine injections, animals on both self-selection regimes increased fat intake while suppressing carbohydrate intake and exhibiting little modifications in protein intake.
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A highly palatable diet (ordinary chow supplemented with 4 highly palatable items changes every day) (HPD) provokes hyperphagia and overweight in the rat. After 17 weeks of such a diet, naltrexone (0.5 or 2.5 mg/kg IP) and opiate antagonist, was injected at the beginning of the dark period, and a food intake test was performed during the 3 following hours. Naltrexone does not modify the energy intake in control rats receiving ordinary chow but suppresses HPD induced hyperphagia. The involvement of the beta-endorphin system in this type of hyperphagia is discussed.
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Naloxone's effects on initiation, maintenance, and maximal response effort to acquire food were examined in rats maintained under different levels of food deprivation. In Experiment 1, naloxone was administered SC to rats responding under an FR 80 (first pellet) FR 3 (subsequent pellets) reinforcement schedule. Naloxone did not increase time to acquire the first pellet. Naloxone's suppression of subsequent intake and lowest effective dose were inversely related to level of deprivation. In Experiment 2, rats responded for food under a Progressive Ratio 2 reinforcement schedule. Breakpoint was lowered only when rats were maintained with free access to food. Decreases in response and running rate were inversely related to deprivation level. Results are consistent with the hypothesis that opioids are involved in the maintenance but not the initiation of feeding.
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The effects of repeated morphine infusions (10 micrograms/0.5 microliter) into the nucleus accumbens on feeding were studied in sated rats. As shown previously, intra-accumbens morphine infusions induced a large increase in food intake. After undergoing repeated morphine treatment, animals consumed significant quantities of food in response to a saline or sham injection, compared to their pre-morphine baseline. This conditioned feeding was present up to 18 days after the final drug infusion. Additionally, repeated morphine administration caused a progressive sensitization of feeding; the final morphine infusion elicited nearly double the amount of food intake as the first. Multiple saline infusions had no behavioral effects. Repeated stimulation of opiate receptors may enhance associative mechanisms such that previously neutral environmental stimuli acquire the ability to elicit feeding. Abnormal activation of this system may be a possible neural substrate for compulsive feeding and bulimia.
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The orexigenic agents morphine, neuropeptide Y (NPY), and norepinephrine (NE) and deprivation have been reported to induce selection of specific macronutrients: fat, carbohydrate (CHO), CHO, and fat, respectively. We utilized analysis of covariance to compensate for the influence of baseline preference on feeding induced by six experimental procedures: morphine, NPY, NE, 24 and 48 h food deprivation, and chronic dietary restriction. Rats received one of two dietary regimens: three macronutrient diets containing CHO, protein, or fat (regimen I) and two nutritionally complete diets that were high CHO or high fat (regimen II). Baseline preference significantly influenced dietary selection after all six experimental procedures studied in regimen I and after NPY, NE, 48 h food deprivation, and chronic dietary restriction in regimen II (covariate P < 0.05). In both dietary regimens, morphine (5 mg/kg) increased consumption of fat, NPY (5 micrograms icv) increased selection of CHO, and consumption of all diets was induced equally after NE injections (20 micrograms icv). After 24 or 48 h food deprivation, animals consumed more fat in regimen I and more CHO diet in regimen II. Restricting food intake by 20% increased fat and protein consumption in regimen I but had no effect in regimen II. Diet selection is affected by prior preference, feeding stimulus, and type of diet choice presented.
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The question of whether opiates stimulate feeding by enhancing taste pleasure was investigated by examining the effect of morphine upon hedonic and aversive reactions to taste (tongue protrusions, gapes, etc.). Rats (n = 12) were given SC injections of morphine (4 mg/kg) or equal volumes of isotonic saline 2 h after the start of their daily light cycle. Food intake was measured in a 2-h test. On days when they were given morphine, rats ate significantly more food than when given saline. Hedonic and aversive taste reactions were elicited by an infusion of sucrose-quinine solution into the mouth and were measured subsequently in a slow-motion video analysis. The same rats that showed an increase in food intake after treatment with morphine showed a significant increase in their positive hedonic responses. Aversive reactions were unchanged by morphine. The results support the hypothesis that morphine enhances feeding by increasing the hedonic palatability of food.
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Previous work has shown that morphine infusion into the ventral striatum results in marked hyperphagia in satiated rats. The present investigation was undertaken to determine the relative involvement of opiate receptor subtypes in this phenomenon. Equimolar doses of the synthetic ligands [D-Ala2,NME-Phe4,Gly-ol5]-enkephalin (DAMGO; 0, 0.025, 0.25, and 2.5 micrograms/0.5 microliter), [D-Pen2,5]-enkephalin (DPEN; 0, 0.031, 0.31, 3.1 and 6.2 micrograms/0.5 microliter) and U50,488H (0, 0.0186, 0.186, 1.86 and 3.72 micrograms/0.5 microliters), which are selective for mu, delta and kappa receptors, respectively, were microinfused into three striatal sites: the nucleus accumbens, ventromedial striatum and ventrolateral striatum. Food intake (grams), feeding, drinking, locomotion, rearing and grooming were measured. After injection into all three sites, DAMGO induced a robust, dose-dependent increase in food intake that was blocked by coadministration of naltrexone (5 mg/kg i.p.). DAMGO-induced feeding was delayed in onset and was long lasting. Injections of DPEN were 2 to 3 times less effective in eliciting feeding. DPEN-induced feeding occurred immediately and was short lasting. U50,488H had no effect on food intake. No changes in drinking were noted for any agonist. Spontaneous motor behaviors were also increased by DAMGO and DPEN. These findings demonstrate that mu opiate receptors within the ventral striatum mediate the opiate-induced feeding response.
Article
What are the neural substrates of food reward? Are reward and pleasure identical? Can taste pleasure be assessed in animals? Is reward necessarily conscious? These questions have re-emerged in recent years, and there is now sufficient evidence to prompt re-examination of many preconceptions concerning reward and its relation to brain systems. This paper reviews evidence from many sources regarding both the psychological structure of food reward and the neural systems that mediate it. Special attention is paid to recent evidence from "tasty reactivity" studies of affective reactions to food. I argue that this evidence suggests the following surprising possibilities regarding the functional components and brain substrates of food reward. (1) Reward contains distinguishable psychological or functional components--"liking" (pleasure/palatability) and "wanting" (appetite/incentive motivation). These can be manipulated and measured separately. (2) Liking and wanting have separable neural substrates. Mediation of liking related to food reward involves neurotransmitter systems such as opioid and GABA/benzodiazepine systems, and anatomical structures such as ventral pallidum and brainstem primary gustatory relays. Mediation of wanting related to food reward involves mesotelencephalic dopamine systems, and divisions of nucleus accumbens and amygdala. Both liking and wanting arise from vastly distributed neural systems, but the two systems are separable. (3) Neural processing of food reward is not confined to the limbic forebrain. Aspects of food reward begin to be processed in the brainstem. A neural manipulation can enhance reward or produce aversion but no single lesion or transection is likely abolish all properties of food reward. (4) Both wanting and liking can exist without subjective awareness. Conscious experience can distort or blur the underlying reward process that gave rise to it. Subjective reports may contain false assessments of underlying processes, or even fail at all to register important reward processes. The core processes of liking and wanting that constitute reward are distinct from the subjective report or conscious awareness of those processes.
Article
Ventricular microinjection studies found that whereas mu (beta-funaltrexamine, B-FNA), mu1 (naloxonazine) and kappa (nor-binaltorphamine, Nor-BNI) opioid receptor antagonists, but not delta antagonists, reduce deprivation-induced intake, kappa and mu, but not mu1 or delta antagonists reduce both 2-deoxy-D-glucose (2DG) hyperphagia and sucrose intake. Since opioid agonists stimulate spontaneous food intake in the accumbens, the present study examined whether administration of either naltrexone, B-FNA or Nor-BNI in the accumbens altered intake under deprivation (24 h), glucoprivic (2DG: 500 mg/kg, i.p.) or palatable sucrose (10%) conditions. Naloxonazine's effects in the accumbens were also evaluated for deprivation-induced intake. Deprivation-induced intake was significantly decreased over 4 h by naltrexone (5-20 micrograms, 44%), B-FNA (1-4 micrograms, 55%) and Nor-BNI (4 micrograms, 31%) but not naloxonazine (10 micrograms) in the accumbens. 2DG hyperphagia was significantly decreased by naltrexone (10-20 microgram, 79%), B-FNA (1-4 micrograms, 100%) and NOR-BNI (104 micrograms, 75%) in the accumbens. Sucrose intake was significantly decreased by naltrexone (50 micrograms, 27%) and B-FNA (1-4 micrograms, 37%), but not NOR-BNI in the accumbens. These data suggest that mu receptors, and particularly the mu2 binding site in the accumbens are responsible for the opioid modulation of these forms of intake in this nucleus, and that this control may be acting upon the amount of intake per se.
Article
The effects of 50 mg naltrexone on both pleasantness and intake of 10 common food items were investigated using a double-blind placebo-controlled study with 16 male volunteers. Rated food pleasantness was reduced significantly in the naltrexone condition compared with both controls (placebo and baseline). However, pleasantness ratings were not affected uniformly across foods, with sweetened, fatty, and high-protein foods being most affected. Changes in rated unpleasantness generally mirrored those for pleasantness, but evaluations of saltiness and sweetness were unaffected by naltrexone. Although total intake was reduced in the naltrexone condition, this was not significant compared with placebo. However, fat and protein intakes were significantly less following naltrexone. The effect of naltrexone on intake was also food dependent, but in this case intake of sweet foods was spared relative to other food categories. The apparent discrepancy between liking and intake data with sweet foods could be interpreted in terms of the likely influence of normal eating styles on food selection during a buffet-style meal, and may explain some contradictions in previous studies of this kind. The implications for understanding opioid involvement in food acceptability are discussed.
Article
The striatum is implicated in response selection and performance, the dorsal striatum in sensorimotor control and habit learning, and the ventral striatum in motivation and rewarded behaviors. Ventral striatal lesions produce performance changes on food-reinforced, progressive-ratio (PR) schedules, but the effects of dorsal striatal lesions on this task are not known. In this study, neither medial nor lateral dorsal striatal lesions produced deficits on the main motivational indices of PR performance. In contrast, significant impairments were observed in motoric or "executive" aspects of performance. Motivationally related manipulations of the task (food deprivation and reward magnitude) produced some subtle lesion-specific changes in behavior on these motoric or executive aspects of performance. Findings are discussed in relation to the roles of the dorsal and ventral striatum in reward-related behaviors.
Article
Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.
Article
Rats selectively bred for high intake of a sweet saccharin solution (HiS) consume more ethanol than their low-saccharin intake (LoS) counterparts. The HiS phenotype may be a predictor of abuse of other drugs via other routes of administration. HiS and LoS, male and female rats were tested for acquisition of IV cocaine and heroin self-administration under a fixed-ratio 1 (FR1) schedule, and cocaine-reinforced behavior was examined under a progressive-ratio (PR) schedule. Four groups of rats (HiS males and females and LoS males and females) were trained to self-administer IV cocaine (0.2 mg/kg), and another four groups were trained to self-administer heroin (0.015 mg/kg) using an automated autoshaping procedure. Rats were allowed 30 days to reach a criterion whereby a mean of 100 (cocaine) or 20 (heroin) infusions were self-administered during 6-h sessions over 5 consecutive days. The HiS female rats acquired cocaine self-administration significantly more rapidly than the LoS rats, and females of both phenotypes met the acquisition criteria more rapidly than males. In both HiS and LoS cocaine groups a greater percentage of females (compared with males) met the acquisition criteria within 30 days. The only cocaine group in which 100% met the criterion was the HiS females. The female (compared with male) heroin groups showed a more rapid rate of acquisition, but there was no difference due to saccharin phenotype. In each of the four heroin groups 100% of all rats met the criteria within 30 days. Results of the PR schedule in the HiS females and males and LoS females indicated significantly higher break points in the HiS females (compared with HiS males), but there were no differences in females due to phenotype. Female rats selectively bred for higher saccharin intake show more rapid and successful acquisition of IV self-administration of a low dose of cocaine than those bred for low saccharin intake. Female rats (compared with males) consistently showed accelerated rates of acquisition and maintenance (PR) of cocaine self-administration and acquisition of heroin self-administration.
Article
Male rats display significantly greater analgesic responses following morphine than female rats, with neonatal gonadal manipulations reversing the sex-dependent pattern. The present study assessed whether dose-dependent (0.0005-5 microg, icv) effects of morphine-induced feeding were sensitive to sex-dependent and neonatal gonadectomy manipulations. Sex differences in morphine-induced feeding varied as a function of morphine dose with males showing greater increases at low (0.0005 microg) doses, and females showing greater increases at high (5 microg) doses. Neonatal castration, respectively, enhanced and reduced morphine-induced feeding at very low (0.0005 microg) and low (0.005 microg) doses. In contrast, neonatal testosterone administered to females enhanced morphine-induced feeding at higher (0.5-5 microg) doses. These data indicate that sex and neonatal gonadectomy differences in morphine-induced feeding are dependent upon the dose of morphine employed.
Article
The current studies were designed to evaluate whether incentive motivation for palatable food is altered after manipulations of opioid, GABAergic, and dopaminergic transmission within the nucleus accumbens. A progressive ratio schedule was used to measure lever-pressing for sugar pellets after microinfusion of drugs into the nucleus accumbens in non-food-deprived rats. The mu opioid agonist D-Ala2, NMe-Phe4, Glyo15-enkephalin and the indirect dopamine agonist amphetamine induced a marked increase in break point and correct lever-presses; the GABA(A) agonist muscimol did not affect breakpoint or lever-presses. The data suggest that opioid, dopaminergic, and GABAergic systems within the accumbens differentially modulate food-seeking behavior through mechanisms related to hedonic evaluation of food, incentive salience, and control of motor feeding circuits, respectively.
Article
Gerard Smith was one of the pioneers in the field of neuropeptidergic control of food intake. He established methodology and criteria used to determine whether a neuropeptide acts as an endogenous satiety factor. More recently, he theorized that there are direct and indirect controls of meal size. Direct controls include those that depend upon contact of food with preabsorptive receptors from the tip of the tongue to the end of the small intestine, and indirect controls include those that do not depend upon direct contact of mucosal receptors, such as learning and metabolism. In this review, we consider the evidence that opioids are mediators of reward-related feeding. We address these issues adopting Smith's approach to problem solving, including an evaluation of the opioids as controllers of the meal. We also present a novel concept of "hedonic restriction," resulting in a change in opioid gene expression. Overall, we believe the evidence supporting opioid participation in reward-driven and other types of ingestion is very strong, but much work remains before we understand how opioids contribute to the widely distributed neural network that controls ingestive behavior.
Article
The new lifestyle in the modern world is causing a rapid increase in the prevalence of obesity and associated health problems. Increased availability of palatable and energy dense foods, combined with a lack of physical activity overpower a homeostatic regulatory system that evolved to survive periods of famine rather than preventing obesity. Environmental and lifestyle factors influence energy balance mainly through their impact on cortico-limbic brain structures dealing with reward, cognitive, and social aspects of food intake and voluntary physical activity. To find new behavioral and pharmacological treatments of obesity, it will be important to identify the specific pathways that link these externally driven processes with the homeostatic regulatory system.
Article
Work over the past decade has supported the idea that discrete aspects of appetitive motivation are differentially mediated by separate but interacting neurochemical systems within the nucleus accumbens (Acb). We review herein a series of studies in rats comparing the effects of manipulating Acb amino acid, opioid, acetylcholine, and dopamine systems on tests of free-feeding and food-reinforced operant responding. Results from our laboratory and in the literature support three general conclusions: (1) GABA output neurons localized exclusively within the Acb shell directly influence hypothalamic effector mechanisms for feeding motor patterns, but do not participate in the execution of more complex food-seeking strategies; (2) enkephalinergic neurons distributed throughout the Acb and caudate-putamen mediate the hedonic impact of palatable (high sugar/fat) foods, and these neurons are under modulatory control by striatal cholinergic interneurons; and (3) dopamine transmission in the Acb governs general motoric and arousal processes related to response selection and invigoration, as well as motor learning-related plasticity. These dissociations may reflect the manner in which these neurochemical systems differentially access pallido-thalamo-cortical loops reaching the voluntary motor system (in the case of opioids and dopamine), versus more restricted efferent connections to hypothalamic motor/autonomic control columns (in the case of Acb shell GABA and glutamate systems). Moreover, we hypothesize that while these systems work in tandem to coordinate the anticipatory and consummatory phases of feeding with hypothalamic energy-sensing substrates, the striatal opioid network evolved a specialized capacity to promote overeating of energy-dense foods beyond acute homeostatic needs, to ensure an energy reserve for potential future famine.
Article
A neural network sensitive to leptin and other energy status signals stretching from the hypothalamus to the caudal medulla has been identified as the homeostatic control system for the regulation of food intake and energy balance. While this system is remarkably powerful in defending the lower limits of adiposity, it is weak in curbing appetite in a world of plenty. Another extensive neural system that processes appetitive and rewarding aspects of food intake is mainly interacting with the external world. This non-homeostatic system is constantly attacked by sophisticated signals from the environment, ultimately resulting in increased energy intake in many genetically predisposed individuals. Recent findings suggest a role for accumbens-hypothalamic pathways in the interaction between non-homeostatic and homeostatic factors that control food intake. Identification of the neural pathways that mediate this dominance of cortico-limbic processes over the homeostatic regulatory circuits in the hypothalamus and brainstem will be important for the development of behavioral strategies and pharmacological therapies in the fight against obesity.
Department of Health and Human Services
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The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats
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