Chow Intake Research Articles

ZGN-1061, a Novel MetAP2 Inhibitor, and Liraglutide Combine to Improve Glycemic Control and Reduce Body Weight in a Rat Model of Diet-Induced Obesity

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in T2D. This study investigated 5 weeks (weeks) of once-daily SC treatment with a submaximal 0.3 mg/kg dose of 1061, a maximal 0.4 mg/kg dose of liraglutide (lira), 1061+lira, or vehicle (N=10/group) on body weight (BW), food intake/preference, and glycemic control in the Gubra diet-induced obese (DIO) rat model (ad libitum fed chow and highly palatable high-fat, high-sugar [HFHS] diet). Fasting (4 hour) blood glucose (FBG) was collected weekly and a semifasted (16 hour access to 50% of daily energy requirement) OGTT was performed at week 4. At week 5 (day 33), BW changed by +1.7% with vehicle vs. -6.0% with 1061, -9.1% with lira, and -16.9% with 1061+lira (all p<0.001). BW loss occurred earlier with lira (day 1) than 1061 (day 5). Starting at day 6, intake of the HFHS diet was modestly reduced (15-30%) with 1061 vs. vehicle. In contrast, lira and 1061+lira induced rapid and sustained 40-50% and 50-80% reductions in intake of the HFHS diet, respectively, over the first 8-9 days. Cumulative (day 0-35) HFHS diet intake was reduced vs. vehicle by 1061 (13.4%, p=0.07), lira (17.8%, p<0.01), and 1061+lira (38.2%, p<0.001). Cumulative chow intake was increased by 1061 and 1061+lira but not lira alone. There was a modest reduction in FBG (mean week 1-5) with 1061 vs. vehicle (p=0.08), a significant reduction with lira, and 1061+lira produced the largest reduction (both p<0.001) that was significantly lower than either agent alone (both p<0.01). In the OGTT, 1061 reduced the glucose AUC vs. vehicle by 37% (p=0.07), lira by 60% (p<0.001), and 1061+lira by 80% (p<0.001), achieving an AUC that was no different from lean rats. In this DIO rat model, 1061 and lira had complementary effects on reducing BW and normalizing glycemic control. Combination treatment with 1061 and liraglutide may yield greater weight loss and glycemic control than either agent alone in patients with T2D. Disclosure B.F. Burkey: Employee; Self; Zafgen. P.J. Pedersen: None. T.X. Pedersen: Employee; Self; Gubra. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.

The hindbrain is a site of energy balance action for prolactin-releasing peptide: feeding and thermic effects from GPR10 stimulation of the nucleus tractus solitarius/area postrema.

Prolactin-releasing peptide (PrRP) is a neuropeptide that suppresses food intake and increases body temperature when delivered to the forebrain ventricularly or parenchymally. However, PrRP's receptor GPR10 is widely distributed throughout the brain with particularly high levels found in the dorsomedial hindbrain. Thus, we hypothesized that hindbrain-directed PrRP administration would affect energy balance and motivated feeding behavior. To address this hypothesis, a range of behavioral and physiologic variables were measured in Sprague-Dawley rats that received PrRP delivered to the fourth ventricle (4V) or the nucleus of the solitary tract (NTS) at the level of the area postrema (AP). 4V PrRP delivery decreased chow intake and body weight, in part, through decreasing meal size in ad libitum maintained rats tested at dark onset. PrRP inhibited feeding when delivered to the nucleus tractus solitarius (NTS), but not to more ventral hindbrain structures. In addition, 4V as well as direct NTS administration of PrRP increased core temperature. By contrast, 4V PrRP did not reduce ad libitum intake of highly palatable food or the motivation to work for or seek palatable foods. The dorsomedial hindbrain and NTS/AP, in particular, are sites of action in PrRP/GPR10-mediated control of chow intake, core temperature, and body weight.

Oxytocin administration in the basolateral and central nuclei of amygdala moderately suppresses food intake.

Oxytocin (OT) at acting central nuclei decreases meal size and reduces intake of palatable sweet solutions. It remains largely unclear as to which brain sites mediate OT's effect on palatability versus energy or the combination of those aspects of consumption. Here, we expanded the search for sites that mediate anorexigenic properties of OT by focusing on two subdivisions of the amygdala, its central (CNA) and basolateral (BLA) nuclei. We injected OT directly into the BLA or CNA in rats and assessed intake of standard chow induced by energy deprivation and intake of sweet solutions in nondeprived animals. We examined whether these effects are reversible by OT receptor (OTr) antagonism and whether OT presence in BLA or CNA induces taste aversion. We also determined the effect of energy deprivation and exposure to sweet saccharin on BLA and CNA expression of OTr mRNA. OT administration in BLA at 0.3 μg and in CNA at 1 μg reduced standard chow intake after deprivation by ~25%. Only administration of OT in BLA was effective in suppressing consumption of sucrose and saccharin solutions. The anorexigenic effects of OT in BLA and CNA were attenuated by OTr antagonist, L-368,899, pretreatment. OT at anorexigenic doses did not promote acquisition of taste aversion. BLA OTr mRNA expression was affected by exposure to palatable saccharin, whereas that of CNA OTr, by energy deprivation. OT in the amygdala moderately decreases food intake. The functional relationship between amygdalar OT and energy intake versus palatability-driven intake depends on the discrete localization of the OTr within this complex structure.

Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement.

The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([d-Lys3]-growth hormone-releasing peptide-6 and JMV-2959) at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the midlight phase, suggesting that pharmacological activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, whereas blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

Chemical composition and hypocholesterolemic effect of milk kefir and water kefir in Wistar rats

ABSTRACT Objective To compare the effects of fermented kefir on the nutritional, physiological, and biochemical parameters of rats. Methods Grains of milk kefir (whole and skimmed) and water kefir (brown sugar) were used. The chemical composition analysis was performed on substrates and fermented beverages. The rats were evaluated for weight gain, body mass index, as well as their food, water, kefir, and calorie intake. We also evaluated their energy efficiency coefficient, weight of organs, in addition to their serum, and hepatic biochemistry. Results Fermentation increased the acid content index owing to degradation of lactose and brown sugar. The animals consumed more kefir, reducing the intake of chow and water. Kefir did not alter body and organ weight, while improving the lipid profile. Conclusion Water kefir with brown sugar was more effective in improving the lipid profile.

Intragastric preloads of l-tryptophan reduce ingestive behavior via oxytocinergic neural mechanisms in male mice

Human and laboratory animal studies suggest that dietary supplementation of a free essential amino acid, l-tryptophan (TRP), reduces food intake. It is unclear whether an acute gastric preload of TRP decreases consumption and whether central mechanisms underlie TRP-driven hypophagia. We examined the effect of TRP administered via intragastric gavage on energy- and palatability-induced feeding in mice. We sought to identify central mechanisms through which TRP suppresses appetite. Effects of TRP on consumption of energy-dense and energy-dilute tastants were established in mice stimulated to eat by energy deprivation or palatability. A conditioned taste aversion (CTA) paradigm was used to assess whether hypophagia is unrelated to sickness. c-Fos immunohistochemistry was employed to detect TRP-induced activation of feeding-related brain sites and of oxytocin (OT) neurons, a crucial component of satiety circuits. Also, expression of OT mRNA was assessed with real-time PCR. The functional importance of OT in mediating TRP-driven hypophagia was substantiated by showing the ability of OT receptor blockade to abolish TRP-induced decrease in feeding. TRP reduced intake of energy-dense standard chow in deprived animals and energy-dense palatable chow in sated mice. Anorexigenic doses of TRP did not cause a CTA. TRP failed to affect intake of palatable yet calorie-dilute or noncaloric solutions (10% sucrose, 4.1% Intralipid or 0.1% saccharin) even for TRP doses that decreased water intake in thirsty mice. Fos analysis revealed that TRP increases activation of several key feeding-related brain areas, especially in the brain stem and hypothalamus. TRP activated hypothalamic OT neurons and increased OT mRNA levels, whereas pretreatment with an OT antagonist abolished TRP-driven hypophagia. We conclude that intragastric TRP decreases food and water intake, and TRP-induced hypophagia is partially mediated via central circuits that encompass OT.

Perinatal testosterone contributes to mid-to-post pubertal sex differences in risk for binge eating in male and female rats.

Exposure to testosterone early in life may contribute to sex differences and pubertal changes in risk for eating pathology (i.e., females > males, after pubertal onset). Specifically, perinatal testosterone permanently alters brain structure/function and drives the masculinization of several sex-differentiated behaviors. However, the effects of perinatal testosterone are often not evident until puberty when increases in gonadal hormones activate the expression of sex typical behavior, including eating behaviors (e.g., chow intake; saccharin preference) in rodents. Despite perinatal testosterone's masculinizing effects on general feeding behavior, it remains unknown if perinatal testosterone exposure contributes to sex differences in pathological eating. The current study addressed this gap by examining whether perinatal testosterone exposure decreases risk for binge eating proneness after pubertal onset in male and female rats. Sprague-Dawley rats (n = 40 oil-treated control females; n = 39 testosterone-treated females; n = 40 oil-treated control males) were followed longitudinally across pre-to-early puberty, mid-to-late puberty, and adulthood. The binge eating prone (BEP)/binge eating resistant (BER) rodent model was used to identify individual differences in binge eating proneness across the dimensional spectrum. As expected, testosterone-treated females and control males showed masculinized (i.e., lower) risk for binge eating as compared to control females, but only after midpuberty. These animal data are significant in suggesting that perinatal testosterone exposure may protect against binge eating and underlie sex differences in binge eating prevalence during and after puberty. (PsycINFO Database Record

The monoamine-oxidase B inhibitor deprenyl increases selection of high-effort activity in rats tested on a progressive ratio/chow feeding choice procedure: Implications for treating motivational dysfunctions

Motivated behaviors often are characterized by a high degree of behavioral activation and work output, and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with depression and other disorders frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks measuring effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of the monoamine oxidase –B (MAO-B) inhibitor deprenyl (selegiline) to enhance selection of high-effort lever pressing in rats tested on a concurrent progressive ratio (PROG)/chow feeding choice task. Deprenyl is widely used as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans, and to induce antidepressant-like effects in traditional rodent models of depression. Systemic administration of deprenyl (1.5–12.0 mg/kg IP) shifted choice behavior, significantly increasing markers of PROG lever pressing at a moderate dose (6.0 mg/kg), and decreasing chow intake at 6.0 and 12.0 mg/kg. Intracranial injections of deprenyl into nucleus accumbens (2.0 and 4.0 μg) also increased PROG lever pressing and decreased chow intake. Microdialysis studies showed that the dose of deprenyl that was effective at increasing PROG lever pressing (6.0 mg/kg) also significantly elevated extracellular dopamine in nucleus accumbens. Thus, similar to the well-known antidepressant bupropion, deprenyl is capable of increasing selection of high-effort PROG lever pressing at doses that increase extracellular dopamine in nucleus accumbens. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.

A cannabinoid receptor antagonist attenuates ghrelin-induced activation of the mesolimbic dopamine system in mice

Ghrelin has been attributed various physiological processes including food intake and reward regulation, through activation of the mesolimbic dopamine system. Reward modulation involves the mesolimbic dopamine system, consisting of the ventral tegmental area (VTA) dopamine neurons targeting nucleus accumbens (NAc), a system that ghrelin activates through VTA-dependent mechanisms. In the first study, we found that systemic intraperitoneal (ip) administration of rimonabant attenuated intracerebroventricular (icv) ghrelin's ability to cause locomotor stimulation and NAc dopamine release in mice. Ghrelin-induced (icv) chow intake was not altered by rimonabant administration (ip). Finally, we showed that bilateral VTA administration of rimonabant blocks the ability of intra-VTA administered ghrelin to increase locomotor activity, but does not affect food intake in mice. Collectively, these data indicate clear dissociation between regulation of food intake and activation of the mesolimbic dopamine system.

GLP-1 action in the mouse bed nucleus of the stria terminalis

Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses.Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine.Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus.

Effects on Hedonic Feeding, Energy Expenditure and Balance of the Non-opioid Peptide DYN-A2-17

The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.

Neuromodulation of orexin neurons reduces diet-induced adiposity

Background/Objectives:Low levels of orexin are associated with obesity and reduced physical activity in humans and animals.Subjects/Methods:Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) selectively activated orexin neurons in mouse lateral hypothalamus (LH) to measure effects on spontaneous physical activity (SPA). DREADD targeting was achieved by stereotaxic injection of AAV vectors into caudal lateral LH of heterozygous orexin-Cre or C57/B6J mice. In one set of studies, excitation of orexin neurons was examined (virus: AAV2-EF1a-DIO-hM3Dq-mCherry), and test sessions began 3-4 h after light cycle onset. In a study examining the inhibition of orexin neurons (virus: AAV2-hSyn-DIO-hM4Di-mCherry), testing began 15 min prior to dark cycle onset. Clozapine n-oxide (CNO; 1 or 5 mg/kg) or saline was injected intraperitoneally and time spent moving in open field chambers was recorded for 2 h. Follow-up studies in separate mouse cohorts quantified SPA in parallel with changes in energy expenditure (EE) and chow intake using indirect calorimetry chambers (SableSystem™). Following acclimation, testing sessions (saline and/or CNO) took place over the course of ~1 week, with injections administered every day. Changes in SPA, EE, chow intake, fecal boli, and body composition (EchoMRI™) were measured. Additional mice cohorts were fed a high-fat diet (HFD) and injected with CNO daily up to 10 days to assess the potential for orexin activation to prevent diet-induced obesity.Results:Activation of orexin resulted in increases in SPA in male and female mice, and was accompanied by increases in energy expenditure without changes in overall chow intake. When orexin activation occurred in the context of high fat diet, weight gain and adiposity were significantly attenuated. SPA was decreased when DREADDs were used to inhibit orexin activity.Conclusion:These results demonstrate that orexin neurons play a critical role in mediating physical activity and suggest a novel therapeutic target for treating obesity.

Betahistine dihydrochloride transdermal delivery via optimized thermosensitive gels: percutaneous absorption evaluation using rat growth as a biomarker.

The aim of this study was to develop and optimize a betahistine dihydrochloride (BH) thermoreversible bioadhesive gel intended for transdermal delivery. The gels were obtained via cold method. A full factorial design was employed to investigate the joint effect of Poloxamer 407 concentration (18 and 20%), adhesive polymer type (Polyvinyl pyrolidone, Hydroxypropyl methylcellulose, and Carbopol 934), and adhesive polymer concentration (0.5 and 1.5%) on gelling temperature, viscosity at 37°C, and adhesion strength. Data collected were analyzed using multiple linear regression. A desirability index approach with relative importance weight was used to choose the most desirable formulation. F4 (20% Poloxamer+1.5% Carbopol) was selected for further characterization. F4 released 96.97% drug in 12h across hairless rat skin. F4 gelation temperature and time were 36 ± 0.35°C, and 6 ± 0.7min, respectively. F4 adhesive force was 8835.68dyne/cm2. F4 was tested for its appetite suppressing effect in a rat model and it was evaluated histopathologically. Rats' chow intake and weight gain was significantly decreased with no signs of inflammation or lipolysis when the optimized BH gel formulation, F4, was compared with untreated animals and animals treated with BH free gel. The results suggest that BH is percutaneously absorbed from the gel base and that the BH gel is tolerable. The desirability index approach with relative importance weight of responses was effective in determination of the optimum formulation. BH is systemically effective and well-tolerated when applied topically in hydrogel-based systems. The Carbopol-Poloxamer gel is a promising modality for transdermal delivery of BH.

Neural Basis of Ventromedial Hypothalamic Oxytocin-Driven Decrease in Appetite

ObjectivesOxytocin (OT) administration in the ventromedial hypothalamic nucleus (VMH) reduces chow intake. The nature of VMH OT’s anorexigenic action remains unclear. Here we provide insight into neural mechanisms underlying VMH OT-driven anorexia by (a) identifying feeding-related brain sites activated by VMH OT injection; (b) measuring VMH OT receptor (OTr) mRNA changes in response to hunger and palatability; and (c) examining how VMH OT affects episodic sweet solution intake in sated and hungry rats. MethodWe established effective doses of VMH OT in deprivation-induced and scheduled feeding and determined whether an OT antagonist blocks the effect. Then, OT (or antagonist) was injected in the VMH of sated rats given episodically sucrose and saccharin solutions. OT was also injected in hungry animals offered simultaneously chow and sugar water. Brain activation after VMH OT was determined by Fos immunoreactivity (IR). OTr expression was established with rtPCR after chow deprivation or saccharin exposure. ResultsVMH OT decreased intake of chow and the effect was reversed by the antagonist, though the antagonist alone was not orexigenic. OT did not affect intakes of energy-dilute saccharin and sucrose solutions in sated or hungry rats. Fos IR was elevated in the VMH and energy balance-related paraventricular and arcuate nuclei, but not reward areas. VMH OTr expression was higher in hungry rats than in sated controls; saccharin intake had no effect. ConclusionOT acting in the VMH decreases intake driven by energy not by palatability, and it stimulates activity of hypothalamic sites controlling energy balance.

P.6.f.005 - Higher emotional eating scores before a nutritional treatment in patients with obesity moderates the development of binge eating disorder

Binge-like eating behavior (BLE) has been characterized as an eating disorder in which subjects have an enhanced intake of food, mainly fats. However, intake of fats and carbohydrates may have differential effects on motivation. Previously it was shown that BLE produces an increase in operant responding for vegetable shortening, but others were unable to replicate the finding using sucrose as the reinforcer. Our aim was to determine if BLE behavior induced with a cafeteria-like diet (CaLD) with several options with fat content would produce an increment in performance. Male Wistar rats were trained under an exponential progressive ratio schedule of sucrose reinforcement; thereafter, the limited access model was used to induce BLE using CaLD options. Finally, subjects were tested for increments in break points (BPs) in the progressive ratio schedule. Rats with intermittent access to CaLD options showed a clear BLE with an escalation in their intake; however they showed compensatory decrements of chow intake that rendered a similar body weight gain to a continuous access group. Although we were unable to observe an increase in BPs after BLE we were able to observe a protection against the decrements of BP previously observed with sugar. Different mechanisms for processing high fat and high carbohydrate reinforcers are variables worth exploring to gain a better understanding of BLE behavior in rodent models.

Oral Ingestion and Intraventricular Injection of Curcumin Attenuates the Effort-Related Effects of the VMAT-2 Inhibitor Tetrabenazine: Implications for Motivational Symptoms of Depression.

Effort-related choice tasks are used for studying depressive motivational symptoms such as anergia/fatigue. These studies investigated the ability of the dietary supplement curcumin to reverse the low-effort bias induced by the monoamine storage blocker tetrabenazine. Tetrabenazine shifted effort-related choice in rats, decreasing high-effort lever pressing but increasing chow intake. The effects of tetrabenazine were reversed by oral ingestion of curcumin (80.0-160.0 mg/kg) and infusions of curcumin into the cerebral ventricles (2.0-8.0 μg). Curcumin attenuates the effort-related effects of tetrabenazine in this model via actions on the brain, suggesting that curcumin may be useful for treating human motivational symptoms.

The Effects of the Monoamine Stabilizer (\u2212)-OSU6162 on Binge-Like Eating and Cue-Controlled Food-Seeking Behavior in Rats

Binge-eating disorder (BED) is characterized by recurring episodes of excessive consumption of palatable food and an increased sensitivity to food cues. Patients with BED display an addiction-like symptomatology and the dopamine system might be a potential treatment target. The clinically safe monoamine stabilizer (−)-OSU6162 (OSU6162) restores dopaminergic dysfunction in long-term alcohol-drinking rats and shows promise as a novel treatment for alcohol use disorder. Here, the effects of OSU6162 on consummatory (binge-like eating) and appetitive (cue-controlled seeking) behavior motivated by chocolate-flavored sucrose pellets were evaluated in non-food-restricted male Lister Hooded rats. OSU6162 significantly reduced binge-like intake of chocolate-flavored sucrose pellets without affecting prior chow intake. Furthermore, OSU6162 significantly reduced the cue-controlled seeking of chocolate-flavored sucrose pellets under a second-order schedule of reinforcement before, but not after, the delivery and ingestion of reward, indicating a selective effect on incentive motivational processes. In contrast, the dopamine D2/D3 receptor antagonist raclopride reduced the seeking of chocolate-flavored sucrose pellets both pre- and post reward ingestion and also reduced responding under simpler schedules of seeking behavior. The D1/5 receptor antagonist SCH23390 had no effect on instrumental behavior under any reinforcement schedule tested. Finally, local administration of OSU6162 into the nucleus accumbens core, but not dorsolateral striatum, selectively reduced cue-controlled sucrose seeking. In conclusion, the present results show that OSU6162 reduces binge-like eating behavior and attenuates the impact of cues on seeking of palatable food. This indicates that OSU6162 might serve as a novel BED medication.

Junk food diet-induced obesity increases D2 receptor autoinhibition in the ventral tegmental area and reduces ethanol drinking.

Similar to drugs of abuse, the hedonic value of food is mediated, at least in part, by the mesostriatal dopamine (DA) system. Prolonged intake of either high calorie diets or drugs of abuse both lead to a blunting of the DA system. Most studies have focused on DAergic alterations in the striatum, but little is known about the effects of high calorie diets on ventral tegmental area (VTA) DA neurons. Since high calorie diets produce addictive-like DAergic adaptations, it is possible these diets may increase addiction susceptibility. However, high calorie diets consistently reduce psychostimulant intake and conditioned place preference in rodents. In contrast, high calorie diets can increase or decrease ethanol drinking, but it is not known how a junk food diet (cafeteria diet) affects ethanol drinking. In the current study, we administered a cafeteria diet consisting of bacon, potato chips, cheesecake, cookies, breakfast cereals, marshmallows, and chocolate candies to male Wistar rats for 3–4 weeks, producing an obese phenotype. Prior cafeteria diet feeding reduced homecage ethanol drinking over 2 weeks of testing, and transiently reduced sucrose and chow intake. Importantly, cafeteria diet had no effect on ethanol metabolism rate or blood ethanol concentrations following 2g/kg ethanol administration. In midbrain slices, we showed that cafeteria diet feeding enhances DA D2 receptor (D2R) autoinhibition in VTA DA neurons. These results show that junk food diet-induced obesity reduces ethanol drinking, and suggest that increased D2R autoinhibition in the VTA may contribute to deficits in DAergic signaling and reward hypofunction observed with obesity.

147 Responsive Neurostimulation for Impulsivity

Abstract INTRODUCTION Impulsivity is one of the most pervasive and disabling features common to many brain disorders. Heightened responsivity in the nucleus accumbens (NAc) during anticipation of rewarding stimuli predisposes to impulsivity. Electrophysiological correlates have been reported during brief windows of anticipation, which have potential to inform a novel therapeutic to deliver a time-sensitive intervention. But no available neuromodulaion therapy is capable of sensing and therapeutically responding to this vulnerable moment. The objectives of our research are: to identify biomarkers of anticipation of highly-reinforcing food reward in mouse NAc, to use these biomarkers to guide responsive neurostimulation (RNS) to suppress binge-like behavior, and to examine the effect of RNS on other behaviors, such as social interaction. METHODS Multielectrode arrays were implanted into the mouse NAc, and were put on a limited high-fat (HF) exposure protocol known to induce binge-like behavior. Power spectral density analyses of NAc local field potentials (LFPs) before HF intake were performed to identify electrophysiological biomarkers. Identical analyses were performed before house chow intake. RNS was triggered whenever potential biomarkers appeared, and reduction in HF intake induced by RNS was examined. RNS was applied during juvenile interaction test to assess behavioral specificity. RESULTS >Increased delta oscillations were observed immediately prior to HF intake after mice developed binge-like behavior, which was not detected immediately prior to chow intake. RNS utilizing delta power as biomarker significantly reduced HF intake. RNS showed no significant effect on juvenile interaction, while continuous deep brain stimulation (DBS) significantly reduced it. CONCLUSION Our findings demonstrate that NAc LFPs carry critical information relevant to reward anticipation, and have the potential to be used as an electrographic biomarker to guide RNS for neuropsychiatric disorders exhibiting impulsivity. Compared to continuous DBS, RNS has the advantage of targeting specific psychiatric symptom while potentially sparing other behaviors.

Opioidergic and dopaminergic modulation of cost/benefit decision-making in Long Evans Rats

Eating disorders are associated with impaired decision-making and dysfunctional reward-related neurochemistry. The present study examined the potential contributions of dopamine and opioid signaling to these processes using two different decision-making tasks. In one task, Long Evans Rats chose between working for a preferred food (high-carbohydrate banana-flavored sucrose pellets) by lever pressing on a progressive-ratio schedule of reinforcement vs. obtaining less preferred laboratory chow that was concurrently available. In a second (effort-free) task, rats chose between the same two reinforcers when they were both available freely. Rats were trained in these tasks before receiving haloperidol (0.00, 0.05, 0.10mg/kg, intraperitoneally (i.p.)) or naloxone (0.0, 1.5, 3.0mg/kg, i.p.). In the first task, haloperidol decreased breakpoint, lever presses, number of reinforcers earned, and increased chow intake, whereas naloxone decreased breakpoint and number of reinforcers earned but had no effect on chow consumption. In the effort-free task, haloperidol reduced intakes of both foods without affecting preference, whereas naloxone selectively reduced the consumption of banana-pellets. The present findings support converging evidence suggesting that DA signaling affects processes more closely related to appetitive motivation, leaving other components of motivation unchanged. By contrast, opioid signaling appears to mediate aspects of hedonic feeding by selectively altering intakes of highly palatable foods. For preferred foods, both appetitive and consummatory aspects of food intake were altered by opioid receptor antagonism. Our findings argue against a general suppression of appetite by either compound, as appetite manipulations have been shown to unselectively alter intakes of both types of food regardless of the task employed.