Effect of intranasal oxytocin on palatable food consumption and c-Fos immunoreactivity in relevant brain areas in rats.

Peripheral and central injections of oxytocin (OT) in laboratory animals decrease eating for energy and palatability, but the hypophagic response is dependent on the administration route. Human studies rely on intranasal (IN) administration of the peptide, the route underutilized in OT animal feeding studies thus far. Therefore, we examined the effect of IN OT on various aspects of food consumption in rats: (a) overnight deprivation-induced standard chow intake, (b) episodic (2-h) consumption of calorie-dense and palatable high-fat high-sugar (HFHS) chow, (c) 2-h episodic intake of palatable and calorie-dilute sucrose and Intralipid solutions, and (d) 2-h sucrose solution intake in rats habituated to ingesting this solution daily for several weeks. Finally, we assessed c-Fos changes in response to the acute IN OT administration in rats habituated to daily sugar consumption. We found that IN 20µg OT decreased deprivation-induced intake of standard chow and HFHS chow in nondeprived rats without affecting water consumption. IN OT also reduced 2-hour episodic fluid consumption of sucrose, but not Intralipid. In the habitual sugar consumption paradigm, acute IN OT diminished sucrose solution intake in animals accustomed to the 2-hour/day sucrose meal regimen. In rats habitually consuming sucrose, IN OT altered c-Fos immunoreactivity in brain areas related to energy homeostasis and reward, including the central nucleus of the amygdala, the hypothalamic paraventricular and the arcuate nuclei. We conclude that IN OT is an effective appetite suppressant for carbohydrate/sugar diets in rats and its effects involve feeding-related brain circuits.

Behavioral plasticity: Role of neuropeptides in shaping feeding responses.

Behavioral plasticity refers to changes occurring due to external influences on an organism, including adaptation, learning, memory and enduring influences from early life experience. There are 2 types of behavioral plasticity: "developmental", which refers to gene/environment interactions affecting a phenotype, and "activational" which refers to innate physiology and can involve structural physiological changes of the body. In this review, we focus on feeding behavior, and studies involving neuropeptides that influence behavioral plasticity - primarily opioids, orexin, neuropeptide Y, and oxytocin. In each section of the review, we include examples of behavioral plasticity as it relates to actions of these neuropeptides. It can be concluded from this review that eating behavior is influenced by a number of external factors, including time of day, type of food available, energy balance state, and stressors. The reviewed work underscores that environmental factors play a critical role in feeding behavior and energy balance, but changes in eating behavior also result from a multitude of non-environmental factors, such that there can be no single mechanism or variable that can explain ingestive behavior.

Chronic Intermittent Sucrose Consumption Facilitates the Ability to Discriminate Opioid Receptor Blockade with Naltrexone in Rats.

The opioid antagonist naltrexone (NTX) decreases intake of preferred diets in rats at very low doses relative to doses needed to decrease intake of "bland" laboratory chow. In the absence of an opioid agonist, NTX is not discriminable using operant techniques. In the current study, we found that rats given intermittent access to a 25% sucrose solution learned to discriminate between various naltrexone doses and saline. None of the rats given only water learned to discriminate between naltrexone and saline. When access to the sucrose solution was discontinued for 14 days, the rats lost the ability to discriminate between NTX and saline. We also studied the changes of c-Fos IR in selected brain regions in rats treated with saline versus NTX that were drinking water or 25% sucrose. An injection of NTX or saline resulted in a significant drug, diet, and interaction effect in various brain regions associated with feeding behavior, particularly the amygdala, accumbens, and hypothalamic sites. Thus, we found that ingestion of a sucrose solution results in the ability of rats to reliably discriminate naltrexone administration. In addition, sucrose and naltrexone altered c-Fos IR in an interactive fashion in brain regions known to be involved in ingestion behavior.

The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms.

The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated α-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.

Oxytocin as a potential pharmacological tool to combat obesity.

The neuropeptide oxytocin (OT) has emerged as an important anorexigen in the regulation of food intake and energy balance. It has been shown that the release of OT and activation of hypothalamic OT neurons coincide with food ingestion. Its effects on feeding have largely been attributed to limiting meal size through interactions in key regulatory brain regions governing the homeostatic control of food intake such as the hypothalamus and hindbrain in addition to key feeding reward areas such as the nucleus accumbens and ventral tegmental area. Furthermore, the magnitude of an anorexigenic response to OT and feeding-related activation of the brain OT circuit are modified by the composition and flavor of a diet, as well as by a social context in which a meal is consumed. OT is particularly effective in reducing consumption of carbohydrates and sweet tastants. Pharmacologic, genetic, and pair-feeding studies indicate that OT-elicited weight loss cannot be fully explained by reductions of food intake and that the overall impact of OT on energy balance is also partly a result of OT-elicited changes in lipolysis, energy expenditure, and glucose regulation. Peripheral administration of OT mimics many of its effects when it is given into the central nervous system, raising the questions of whether and to what extent circulating OT acts through peripheral OT receptors to regulate energy balance. Although OT has been found to elicit weight loss in female mice, recent studies have indicated that sex and estrous cycle may impact oxytocinergic modulation of food intake. Despite the overall promising basic research data, attempts to use OT in the clinical setting to combat obesity and overeating have generated somewhat mixed results. The focus of this mini-review is to briefly summarize the role of OT in feeding and metabolism, address gaps and inconsistencies in our knowledge, and discuss some of the limitations to the potential use of chronic OT that should help guide future research on OT as a tailor-made anti-obesity therapeutic.

Mild Hypophagia and Associated Changes in Feeding-Related Gene Expression and c-Fos Immunoreactivity in Adult Male Rats with Sodium Valproate-Induced Autism.

A core yet understudied symptom of autism is aberrant eating behaviour, including extremely narrow food preferences. Autistic individuals often refuse to eat despite hunger unless preferred food is given. We hypothesised that, apart from aberrant preference, underfeeding stems from abnormal hunger processing. Utilising an adult male VPA rat, a model of autism, we examined intake of 'bland' chow in animals maintained on this diet continuously, eating this food after fasting and after both food and water deprivation. We assessed body weight in adulthood to determine whether lower feeding led to slower growth. Since food intake is highly regulated by brain processes, we looked into the activation (c-Fos immunoreactivity) of central sites controlling appetite in animals subjected to food deprivation vs. fed ad libitum. Expression of genes involved in food intake in the hypothalamus and brain stem, regions responsible for energy balance, was measured in deprived vs. sated animals. We performed our analyses on VPAs and age-matched healthy controls. We found that VPAs ate less of the 'bland' chow when fed ad libitum and after deprivation than controls did. Their body weight increased more slowly than that of controls when maintained on the 'bland' food. While hungry controls had lower c-Fos IR in key feeding-related areas than their ad libitum-fed counterparts, in hungry VPAs c-Fos was unchanged or elevated compared to the fed ones. The lack of changes in expression of feeding-related genes upon deprivation in VPAs was in contrast to several transcripts affected by fasting in healthy controls. We conclude that hunger processing is dysregulated in the VPA rat.

Whey-Adapted versus Natural Cow's Milk Formulation: Distinctive Feeding Responses and Post-Ingestive c-Fos Expression in Laboratory Mice.

The natural 20:80 whey:casein ratio in cow's milk (CM) for adults and infants is adjusted to reflect the 60:40 ratio of human milk, but the feeding and metabolic consequences of this adjustment have been understudied. In adult human subjects, the 60:40 CM differently affects glucose metabolism and hormone release than the 20:80 CM. In laboratory animals, whey-adapted goat's milk is consumed in larger quantities. It is unknown whether whey enhancement of CM would have similar consequences on appetite and whether it would affect feeding-relevant brain regulatory mechanisms. In this set of studies utilizing laboratory mice, we found that the 60:40 CM was consumed more avidly than the 20:80 control formulation by animals motivated to eat by energy deprivation and by palatability (in the absence of hunger) and that this hyperphagia stemmed from prolongation of the meal. Furthermore, in two-bottle choice paradigms, whey-adapted CM was preferred against the natural 20:80 milk. The intake of the whey-adapted CM induced neuronal activation (assessed through analysis of c-Fos expression in neurons) in brain sites promoting satiation, but importantly, this activation was less pronounced than after ingestion of the natural 20:80 whey:casein CM. Activation of hypothalamic neurons synthesizing anorexigenic neuropeptide oxytocin (OT) was also less robust after the 60:40 CM intake than after the 20:80 CM. Pharmacological blockade of the OT receptor in mice led to an increase in the consumption only of the 20:80 CM, thus, of the milk that induced greater activation of OT neurons. We conclude that the whey-adapted CM is overconsumed compared to the natural 20:80 CM and that this overconsumption is associated with weakened responsiveness of central networks involved in satiety signalling, including OT.

Preliminary Exploration of Obesity-Related Eating Behaviour Patterns in a Sample of Saudi Preschoolers Aged 2-6 Years through the Children's Eating Behaviour Questionnaire.

BACKGROUND: The Children's Eating Behaviour Questionnaire (CEBQ) is used with parents to determine the characteristics of eating behaviour of their children and, consequently, children's propensity to become obese. It has been successfully used mainly in Western countries, but not in Saudi Arabia. In this pilot study, we explored the use of the Saudi version of the CEBQ for preschool children aged 2-6 years in Saudi Arabia, and assessed the associations between eating behaviours and children's age, gender and relative weight and parental weight. METHODS: Parents of 200 Saudi preschool children in Riyadh completed the Saudi version of the CEBQ. Factor analyses on all CEBQ items were performed and differences between genders and age groups were examined. Correlations between children's BMI z-scores and eating behaviours were analysed using linear regression. RESULTS: The factor analysis revealed an eight-factor solution similar to the theoretical factor structure, with good internal reliability and acceptable correlations between subscales. Boys scored higher than girls on food responsiveness; no difference between age groups was found. Positive associations between BMI z-scores and 'food approach' subscales, food responsiveness, enjoyment of food and emotional overeating were found, while 'food avoidant' subscales, satiety responsiveness and slowness in eating had inverse relationships with BMI z-scores. Maternal BMI had a positive association with BMI z-scores and food responsiveness. CONCLUSION: The CEBQ is a valid psychometric tool that can be reliably used to assess eating behaviour characteristics in Saudi preschool children.

Neural Basis of Dysregulation of Palatability-Driven Appetite in Autism.

PURPOSE OF REVIEW: In research on autism spectrum disorder (ASD), cognitive, speech- and anxiety-related impairments have been the focus of the majority of studies. One consistently reported ASD symptom that has rarely attracted attention is disordered appetite. The goal of this paper is to assess whether ASD-related dysregulation of food intake impacts consumption of palatable foods, including sugar. RECENT FINDINGS: Aberrant neural processing at the reward system level is at least partially responsible for excessive intake of palatable tastants, including sugar. Impaired oxytocin (OT) signaling likely contributes to the magnitude of this overconsumption. Since intake for reward is generally elevated in individuals with ASD, one strategy to curb sugar overconsumption might utilize presentation of alternative palatable food choices that are more nutritionally adequate than sucrose. Furthermore, OT, which is clinically tested to alleviate other ASD symptoms, might be an effective tool to curb overconsumption of sugar, as well as - likely - of other excessively ingested palatable foods, especially those that have sweet taste.

Effect of combination of peripheral oxytocin and naltrexone at subthreshold doses on food intake, body weight and feeding-related brain gene expression in male rats.

In a recent case report involving a male with hypothalamic obesity, concurrent administration of oxytocin (OT) and an opioid receptor antagonist, naltrexone (NTX), synergistically affected energy balance. Here, by using laboratory rats, we examined whether the reported synergy between OT and NTX in the context of food intake extends beyond that one unique case. We found that intravenous OT+NTX combination, at doses subthreshold for each of the drugs individually, decreased episodic consumption of a 10% sucrose solution in non-deprived animals. Daily administration of OT and NTX just before a scheduled, 2-hour, high-fat high-sugar (HFHS) meal over 24 days, decreased cumulative HFHS diet intake, but without a change in body weight due to compensatory standard chow intake during the remainder of the day. The NTX-OT treatment affected expression of several feeding-related genes in the hypothalamus, brain stem and nucleus accumbens, brain regions essential for the regulation of energy- and reward-driven consumption. We conclude that OT and NTX act synergistically to decrease food consumption in rats and that this transient effect is accompanied by changes in brain processes relevant to feeding.

Adjustment of Whey:Casein Ratio from 20:80 to 60:40 in Milk Formulation Affects Food Intake and Brainstem and Hypothalamic Neuronal Activation and Gene Expression in Laboratory Mice.

Adjustment of protein content in milk formulations modifies protein and energy levels, ensures amino acid intake and affects satiety. The shift from the natural whey:casein ratio of ~20:80 in animal milk is oftentimes done to reflect the 60:40 ratio of human milk. Studies show that 20:80 versus 60:40 whey:casein milks differently affect glucose metabolism and hormone release; these data parallel animal model findings. It is unknown whether the adjustment from the 20:80 to 60:40 ratio affects appetite and brain processes related to food intake. In this set of studies, we focused on the impact of the 20:80 vs. 60:40 whey:casein content in milk on food intake and feeding-related brain processes in the adult organism. By utilising laboratory mice, we found that the 20:80 whey:casein milk formulation was consumed less avidly and was less preferred than the 60:40 formulation in short-term choice and no-choice feeding paradigms. The relative PCR analyses in the hypothalamus and brain stem revealed that the 20:80 whey:casein milk intake upregulated genes involved in early termination of feeding and in an interplay between reward and satiety, such as melanocortin 3 receptor (MC3R), oxytocin (OXT), proopiomelanocortin (POMC) and glucagon-like peptide-1 receptor (GLP1R). The 20:80 versus 60:40 whey:casein formulation intake differently affected brain neuronal activation (assessed through c-Fos, an immediate-early gene product) in the nucleus of the solitary tract, area postrema, ventromedial hypothalamic nucleus and supraoptic nucleus. We conclude that the shift from the 20:80 to 60:40 whey:casein ratio in milk affects short-term feeding and relevant brain processes.

Impact of Gut and Metabolic Hormones on Feeding Reward.

Ingestion of food activates a cascade of endocrine responses (thereby reflecting a contemporaneous feeding status) that include the release of hormones from the gastrointestinal (GI) tract, such as cholecystokinin (CCK), glucagonlike peptide YY (PYY), peptide PP, and oleoylethanolamide, as well as suppression of ghrelin secretion. The pancreas and adipose tissue, on the other hand, release hormones that serve as a measure of the current metabolic state or the long-term energy stores, that is, insulin, leptin, and adiponectin. It is well known and intuitively understandable that these hormones target either directly (by crossing the blood-brain barrier) or indirectly (e.g., via vagal input) the "homeostatic" brainstem-hypothalamic pathways involved in the regulation of appetite. The current article focuses on yet another target of the metabolic and GI hormones that is critical in inducing changes in food intake, namely, the reward system. We discuss the physiological basis of this functional interaction, its importance in the control of appetite, and the impact that disruption of this crosstalk has on energy intake in select physiological and pathophysiological states. We conclude that metabolic and GI hormones have a capacity to strengthen or weaken a response of the reward system to a given food, and thus, they are fundamental in ensuring that feeding reward is plastic and dependent on the energy status of the organism. © 2021 American Physiological Society. Compr Physiol 11:1425-1447, 2021.

Acute Hypophagia and Changes in c-Fos Immunoreactivity in Adolescent Rats Treated with Low Doses of Oxytocin and Naltrexone.

A recent case report has shown that an adjunctive oxytocin + naltrexone (OT + NTX) treatment promoted more robust hypophagia and body weight reduction than OT alone in an adolescent male with hypothalamic obesity after craniopharyngioma resection. Thus far, there has been no basic research in adolescent laboratory animals that would examine whether the benefit of OT + NTX on appetite extends onto adolescent individuals without surgically induced overeating. Thus, here we examined whether low doses of combined OT + NTX acutely affect post-deprivation intake of energy-dense, standard chow; intake of energy-dense and palatable high-fat high-sugar (HFHS) diet; or calorie-dilute, palaTable 10% sucrose solution without deprivation in adolescent male rats. We assessed whether OT + NTX decreases water intake after water deprivation or produces a conditioned taste aversion (CTA). Finally, by using c-Fos immunoreactivity, we determined changes in activity of feeding-related brain areas after OT + NTX. We found that individual subthreshold doses of OT and NTX decreased feeding induced by energy and by palatability. Significant c-Fos changes were noted in the arcuate and dorsomedial hypothalamic nuclei. The hypophagic doses of OT + NTX did not suppress water intake in thirsty rats and did not cause a CTA, which suggests that feeding reduction is not a secondary effect of gastrointestinal discomfort or changes in thirst processing. We conclude that OT + NTX is an effective drug combination to reduce appetite in adolescent male rats.

The role of oxytocin in regulation of appetitive behaviour, body weight and glucose homeostasis.

Obesity and its associated complications have reached epidemic proportions in the USA and also worldwide, highlighting the need for new and more effective treatments. Although the neuropeptide oxytocin (OXT) is well recognised for its peripheral effects on reproductive behaviour, the release of OXT from somatodendrites and axonal terminals within the central nervous system (CNS) is also implicated in the control of energy balance. In this review, we summarise historical data highlighting the effects of exogenous OXT as a short-term regulator of food intake in a context-specific manner and the receptor populations that may mediate these effects. We also describe what is known about the physiological role of endogenous OXT in the control of energy balance and whether serum and brain levels of OXT relate to obesity on a consistent basis across animal models and humans with obesity. We describe recent data on the effectiveness of chronic CNS administration of OXT to decrease food intake and weight gain or to elicit weight loss in diet-induced obese (DIO) and genetically obese mice and rats. Of clinical importance is the finding that chronic central and peripheral OXT treatments both evoke weight loss in obese animal models with impaired leptin signalling at doses that are not associated with visceral illness, tachyphylaxis or adverse cardiovascular effects. Moreover, these results have been largely recapitulated following chronic s.c. or intranasal treatment in DIO non-human primates (rhesus monkeys) and obese humans, respectively. We also identify plausible mechanisms that contribute to the effects of OXT on body weight and glucose homeostasis in rodents, non-human primates and humans. We conclude by describing the ongoing challenges that remain before OXT-based therapeutics can be used as a long-term strategy to treat obesity in humans.

Effects of opioid receptor ligands in rats trained to discriminate 22 from 2 hours of food deprivation suggest a lack of opioid involvement in eating for hunger.

It is well accepted that opioids promote feeding for reward. Some studies suggest a potential involvement in hunger-driven intake, but they suffer from the scarcity of methodologies differentiating between factors that intersect eating for pleasure versus energy. Here, we used a unique food deprivation discrimination paradigm to test a hypothesis that, since opioids appear to control feeding reward, injection of opioid agonists would not produce effects akin to 22 h of food deprivation. We trained rats to discriminate between 22 h and 2 h food deprivation in a two-lever, operant discrimination procedure. We tested whether opioid agonists at orexigenic doses produce discriminative stimulus effects similar to 22 h deprivation. We injected DAMGO, DSLET, or orphanin FQ in the paraventricular hypothalamic nucleus (PVN), a site regulating hunger/satiety, and butorphanol subcutaneously (to produce maximum consumption). We assessed the ability of the opioid antagonist, naltrexone, to reduce the discriminative stimulus effects of 22 h deprivation and of the 22 h deprivation-like discriminative stimulus effects of PVN-injected hunger mediator, neuropeptide Y (NPY). In contrast to PVN NPY, centrally or peripherally injected opioid agonists failed to induce discriminative stimuli similar to those of 22 h deprivation. In line with that, naltrexone did not reduce the hunger discriminative stimuli induced by either 22 h deprivation or NPY administration in 2 h food-restricted subjects, even though doses used therein were sufficient to decrease deprivation-induced feeding in a non-operant setting in animals familiar with consequences of 2 h and 22 h deprivation. We conclude that opioids promote feeding for reward rather than in order to replenish lacking energy.

The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.

SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.

Blunted hyperphagic and c-Fos immunoreactivity responsiveness to an orexigen, butorphanol tartrate, in aged rats.

Administration of the mixed opioid agonist-antagonist butorphanol tartrate (BT) has been shown to robustly increase food intake in rodent models utilizing adult and young animals. BT at orexigenic doses increases c-Fos-immunoreactivity (IR) in brain areas associated with feeding for energy as well as for reward, including the paraventricular nucleus of the hypothalamus, central nucleus of the amygdala and nucleus of the solitary tract. Interestingly, aged rats given standard chow show a diminished feeding response to BT. It is not known, however, whether this weakened orexigenic response in aged animals extends to palatable tastants and whether it is accompanied by changes in brain activation. In the current study, we injected adult (11-12 months) and aged (26-27 months) rats with BT and studied the effect on intake of chow and palatable ingestants (liquid and solid). We found that BT produced only a moderate increase in consumption of bland or palatable chow as well as sweet solutions (both caloric and non-caloric) in aged rats, and that higher BT doses are required to generate such eating in old animals compared to adults. This blunted hyperphagia after BT is accompanied by diminished c-Fos IR in the central and basolateral amygdala, regions that process emotional aspects of behaviors, including food intake. Thus, aged rats exhibit diminished responsiveness to the feeding effects of BT, independent of the type of diet; and it appears to be due, in part, to diminished neural activity in central circuits involved in emotional behavior.

Effect of Oxytocin on Hunger Discrimination.

Centrally and peripherally administered oxytocin (OT) decreases food intake and activation of the endogenous OT systems, which is associated with termination of feeding. Evidence gathered thus far points to OT as a facilitator of early satiation, a peptide that reduces the need for a meal that has already begun. It is not known, however, whether OT can diminish a feeling of hunger, thereby decreasing a perceived need to seek calories. Therefore, in the current project, we first confirmed that intraperitoneal (i.p.) OT at 0.3-1 mg/kg reduces food intake in deprived and non-deprived rats. We then used those OT doses in a unique hunger discrimination protocol. First, rats were trained to discriminate between 22- and 2-h food deprivation (hungry vs. sated state) in a two-lever operant procedure. After rats acquired the discrimination, they were food-restricted for 22 h and given i.p. OT before a generalization test session. OT did not decrease 22-h deprivation-appropriate responding to match that following 2-h food deprivation, thus, it did not reduce the perceived level of hunger. In order to better understand the mechanisms behind this ineffectiveness of OT, we used c-Fos immunohistochemistry to determine whether i.p. OT activates a different subset of feeding-related brain sites under 22- vs. 2-h deprivation. We found that in sated animals, OT induces c-Fos changes in a broader network of hypothalamic and brain stem sites compared to those affected in the hungry state. Finally, by employing qPCR analysis, we asked whether food deprivation vs. sated state have an impact on OT receptor expression in the brain stem, a CNS "entry" region for peripheral OT. Fasted animals had significantly lower OT receptor mRNA levels than their ad libitum-fed counterparts. We conclude that OT does not diminish a feeling of hunger before a start of a meal. Instead OT's anorexigenic properties are manifested once consumption has already begun which is-at least to some extent-driven by changes in brain responsiveness to OT treatment in the hungry vs. fed state. OT should be viewed as a mediator of early satiation rather than as a molecule that diminishes perceived hunger.

Transcriptional changes in response to ketamine ester-analogs SN 35210 and SN 35563 in the rat brain.

BACKGROUND: Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared across four relevant target regions of the rat brain. RESULTS: SN 35563 produced large-scale alteration of gene expression in the Basolateral Amygdala (BLA) and Paraventricular Nucleus of the Thalamus (PVT), in excess of 10x that induced by ketamine and SN 35210. A smaller and quantitatively similar number of gene changes were observed in the Insula (INS) and Nucleus Accumbens (ACB) for all three agents. In the BLA and PVT, SN 35563 caused enrichment for gene pathways related to the function and structure of glutamatergic synapses in respect to: release of neurotransmitter, configuration of postsynaptic AMPA receptors, and the underlying cytoskeletal scaffolding and alignment. CONCLUSION: The analgesic ketamine ester analog SN 35563 induces profound large-scale changes in gene expression in key pain-related brain regions reflecting its unique prolonged pharmacodynamic profile.

Excessive Consumption of Sugar: an Insatiable Drive for Reward.

PURPOSE OF REVIEW: Eating behavior provides energy to ensure proper functioning of the organism. Reward aids in seeking foods that bring energy and pleasant taste, whose consumption is safe. As evidenced by the obesity "epidemic" which largely stems from overeating, reward becomes a detriment when palatable tastants are available in unlimited quantities. This review presents recent evidence on mechanisms underlying palatability-driven excessive consumption of sugar. RECENT FINDINGS: Appetite for sugar is propelled by changes in the morphology and activity of the reward system reminiscent of addiction. Sugar intake also shifts the hunger-satiety continuum, facilitating initiation of consumption in the absence of energy needs and maintenance of feeding despite ingestion of large food loads that endanger homeostasis. Ingestion of excessive amounts of sugar relies on triggering mechanisms that promote addictive-like behaviors, and on overriding neuroendocrine signals that protect internal milieu.