Insulin receptor activation in the nucleus accumbens reflects nutritive value of a recently ingested meal.

With respect to feeding, insulin is typically thought of as a satiety hormone, acting in the hypothalamus to limit ingestive behavior. However, accumulating evidence suggests that insulin also has the ability to alter dopamine release in the striatum and influence food preferences. With increased access to high calorie foods, Western societies have a high prevalence of obesity, accompanied by insulin insensitivity. Little is known about how insulin is trafficked into the brain following food consumption and whether insulin insensitivity in the periphery is mirrored in the central nervous system. We investigated insulin receptor activation in the ventral striatum of rats receiving water or 16% glucose either orally or intragastrically. We also investigated whether glucose-induced insulin receptor activation was altered in food-restricted (FR) or diet-induced obesity (OB) rat models. Lastly, we examined whether insulin plays a significant role in flavor-nutrient preference learning. Glucose intake stimulated a rapid increase in insulin receptor activity in the ventral striatum of FR and ad libitum (AL) fed rats, but not OB rats. Similarly, both AL and FR, but not OB rats demonstrated significant flavor-nutrient preferences. However AL rats receiving brief inhibition of insulin activity during conditioning failed to acquire a significant flavor-nutrient preference. These findings suggest that impaired insulin receptor activation in the ventral striatum may result in inaccurate valuation of nutritive foods, which could lead to overconsumption of food or the selection of foods that don't accurately meet the body's current physiological needs.

Episodic sucrose intake during food restriction increases synaptic abundance of AMPA receptors in nucleus accumbens and augments intake of sucrose following restoration of ad libitum feeding.

Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for 10 occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-h chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR. Generally, neither a history of sucrose intake nor a terminal bout of sucrose intake affected AMPA receptor abundance in the NAc PSD of AL subjects. Together, these results are consistent with the hypothesis, but the functional contribution of increased synaptic incorporation of AMPA receptors remains to be established.

AMPA receptor subunit GluR1 downstream of D-1 dopamine receptor stimulation in nucleus accumbens shell mediates increased drug reward magnitude in food-restricted rats.

Previous findings suggest that neuroadaptations downstream of D-1 dopamine (DA) receptor stimulation in nucleus accumbens (NAc) are involved in the enhancement of drug reward by chronic food restriction (FR). Given the high co-expression of D-1 and GluR1 AMPA receptors in NAc, and the regulation of GluR1 channel conductance and trafficking by D-1-linked intracellular signaling cascades, the present study examined effects of the D-1 agonist, SKF-82958, on NAc GluR1 phosphorylation, intracranial electrical self-stimulation reward (ICSS), and reversibility of reward effects by a polyamine GluR1 antagonist, 1-NA-spermine, in ad libitum fed (AL) and FR rats. Systemically administered SKF-82958, or brief ingestion of a 10% sucrose solution, increased NAc GluR1 phosphorylation on Ser845, but not Ser831, with a greater effect in FR than AL rats. Microinjection of SKF-82958 in NAc shell produced a reward-potentiating effect that was greater in FR than AL rats, and was reversed by co-injection of 1-NA-spermine. GluR1 abundance in whole cell and synaptosomal fractions of NAc did not differ between feeding groups, and microinjection of AMPA, while affecting ICSS, did not exert greater effects in FR than AL rats. These results suggest a role of NAc GluR1 in the reward-potentiating effect of D-1 DA receptor stimulation and its enhancement by FR. Moreover, GluR1 involvement appears to occur downstream of D-1 DA receptor stimulation rather than reflecting a basal increase in GluR1 expression or function. Based on evidence that phosphorylation of GluR1 on Ser845 primes synaptic strengthening, the present results may reflect a mechanism via which FR normally facilitates reward-related learning to re-align instrumental behavior with environmental contingencies under the pressure of negative energy balance.

Feeding, body weight, and sensitivity to non-ingestive reward stimuli during and after 12-day continuous central infusions of melanocortin receptor ligands.

The brain melanocortin system mediates downstream effects of hypothalamic leptin and insulin signaling. Yet, there have been few studies of chronic intracerebroventricular (i.c.v.) melanocortin receptor (MCR) agonist or antagonist infusion. Although there is evidence of interaction between melanocortin and dopamine (DA) systems, effects of chronic MCR ligand infusion on behavioral sensitivity to non-ingestive reward stimuli have not been investigated. The objective of this study was to investigate effects of chronic i.c.v. infusion of the MCR agonist, MTII, and the MCR antagonist, SHU9119, on food intake, body weight, and sensitivity to rewarding lateral hypothalamic electrical stimulation (LHSS) and the reward-potentiating (i.e., threshold-lowering) effect of D-amphetamine. The MCR antagonist, SHU9119 (0.02 microg/h) produced sustained hyperphagia and weight gain during the 12-day infusion period, followed by compensatory hypophagia and an arrest of body weight gain during the 24-day post-infusion period. At no point during the experiment was sensitivity to LHSS or D-amphetamine (0.25mg/kg, i.p.) altered. The MCR agonist, MTII (0.02 microg/h) produced a brief hypophagia (3 days) followed by a return to control levels of daily intake, but with body weight remaining at a reduced level throughout the 12-day infusion period. This was followed by compensatory hyperphagia and weight gain during the 24-day post-infusion period. There was no change in sensitivity to non-ingestive reward stimuli during the infusion of MTII. However, sensitivity to D-amphetamine was increased during the 24-day post-infusion period. It therefore seems that changes in ingestive behavior that occur during chronic MCR ligand infusion may not affect the response to non-ingestive reward stimuli. However, it is possible that the drive to re-feed and restore body weight following MCR agonist treatment includes neuroadaptations that enhance the incentive effects of drug stimuli.

Effects of chronic ICV leptin infusion on motor-activating effects of D-amphetamine in food-restricted and ad libitum fed rats.

Recently, attention has turned to the possibility that endocrine adiposity hormones, such as leptin, may regulate appetitively motivated behavior by modulating brain dopamine function. By extension, it has been hypothesized that the increased behavioral sensitivity of food-restricted, underweight rats to psychostimulant challenge may be triggered by the accompanying hypoleptinemia. The purpose of the present study was to determine whether two weeks of continuous intracerebroventricular (ICV) infusion of leptin alters the motor-activating effect of D-amphetamine (0.75 mg/kg, IP) in food-restricted rats. Lateral ventricular infusion of leptin, using a regimen that decreases food intake and body weight in ad libitum fed rats (12 microg/day), had no effect on the locomotor response to D-amphetamine in food-restricted rats that were maintained at 80% of prerestriction body weight. This result may indicate that hypoleptinemia is not involved in the induction/maintenance of neuroadaptations that mediate enhanced behavioral sensitivity to psychostimulant challenge. Interestingly, ad libitum fed rats treated with leptin displayed an increased locomotor response to D-amphetamine that was most prominent 3-5 days after termination of the infusion. Body weights and D-amphetamine sensitivity of these subjects returned to control values by 8-10 days postinfusion. The enhanced behavioral sensitivity to D-amphetamine in leptin-treated ad libitum fed rats may be a by-product of adipose depletion and, if so, would further support involvement of a peripheral signal other than hypoleptinemia in the modulation of central sensitivity to psychostimulant challenge.

Anaerobic energy provision does not limit Wingate exercise performance in endurance-trained cyclists.

The aim of this study was to evaluate the effects of severe acute hypoxia on exercise performance and metabolism during 30-s Wingate tests. Five endurance- (E) and five sprint- (S) trained track cyclists from the Spanish National Team performed 30-s Wingate tests in normoxia and hypoxia (inspired O(2) fraction = 0.10). Oxygen deficit was estimated from submaximal cycling economy tests by use of a nonlinear model. E cyclists showed higher maximal O(2) uptake than S (72 +/- 1 and 62 +/- 2 ml x kg(-1) x min(-1), P < 0.05). S cyclists achieved higher peak and mean power output, and 33% larger oxygen deficit than E (P < 0.05). During the Wingate test in normoxia, S relied more on anaerobic energy sources than E (P < 0.05); however, S showed a larger fatigue index in both conditions (P < 0.05). Compared with normoxia, hypoxia lowered O(2) uptake by 16% in E and S (P < 0.05). Peak power output, fatigue index, and exercise femoral vein blood lactate concentration were not altered by hypoxia in any group. Endurance cyclists, unlike S, maintained their mean power output in hypoxia by increasing their anaerobic energy production, as shown by 7% greater oxygen deficit and 11% higher postexercise lactate concentration. In conclusion, performance during 30-s Wingate tests in severe acute hypoxia is maintained or barely reduced owing to the enhancement of the anaerobic energy release. The effect of severe acute hypoxia on supramaximal exercise performance depends on training background.

Effects of the D(3) dopamine receptor antagonist, U99194A, on brain stimulation and d-amphetamine reward, motor activity, and c-fos expression in ad libitum fed and food-restricted rats.

RATIONALE: Previous studies indicate that the D(3) dopamine (DA) receptor is preferentially expressed in limbic forebrain DA terminal areas and may mediate functional effects opposite those of the D(1) and D(2) receptor types. However, the locations of the D(3) receptors that regulate behavior, and the range of behavioral functions regulated, are not clear. OBJECTIVE: The objective of this study was to evaluate behavioral and cellular effects of the preferential D(3) dopamine receptor antagonist, U99194A. METHODS: In experiment 1, the rewarding effect of U99194A (5.0, 10.0 and 20.0 mg/kg, SC) was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) in ad libitum fed rats. To amplify a possibly weak reward signal, testing was also conducted in food-restricted rats. The ability of U99194A to alter the threshold-lowering effect of d-amphetamine was also assessed. In experiment 2, effects of U99194A on horizontal and vertical motor activity were compared in ad libitum fed and food-restricted rats. In experiment 3, effects of a behaviorally active dose of U99194A (5.0 mg/kg) on brain c-fos expression were measured and compared to those produced by d-amphetamine (0.5 mg/kg, IP). In experiment 4, the motor and cellular activating effects of U99194A were challenged with the D(1) dopamine receptor antagonist, SCH-23390 (0.1 mg/kg). RESULTS: U99194A displayed no rewarding efficacy in the LHSS paradigm. U99194A did, however, augment the rewarding effect of d-amphetamine. U99194A also produced a motor activating effect, reversible by SCH-23390, which was greater in food-restricted than ad libitum fed rats. The pattern and intensity of fos-like immunoreactivity (FLI) induced by U99194A was similar to that produced by d-amphetamine and was blocked, in caudate-putamen and nucleus accumbens, by SCH-23390. CONCLUSIONS: These results indicate that U99194A has psychostimulant-like effects on motor activity and striatal c-fos expression that are dependent upon the D(1) DA receptor. However, doses of U99194A that are adequate to stimulate motor activity and c-fos expression in striatal and limbic structures do not possess direct rewarding effects in the LHSS paradigm. Overall, these results seem consistent with the hypothesis that D(3) antagonism enhances D(1)/D(2) mediated signaling with behavioral effects dependent on both the density of D(3) receptors and the prevailing level of DA transmission in particular brain regions.

Rewarding and locomotor-activating effects of direct dopamine receptor agonists are augmented by chronic food restriction in rats.

RATIONALE: Previous studies indicate that chronic food restriction augments the rewarding and motor-activating effects of diverse drugs of abuse. The drugs that have so far proved susceptible to the augmenting effect of food restriction all increase synaptic concentrations of dopamine (DA). It is not known whether behavioral effects of selective, direct DA receptor agonists are also subject to the augmenting effect of food restriction. OBJECTIVES: The first objective of this study was to investigate whether the rewarding and locomotor-activating effects of the D1 agonist, A77636, and the D2 agonist, quinpirole are augmented by chronic food restriction. The second purpose was to investigate whether the augmented rewarding and locomotor-activating effects of d-amphetamine in food-restricted rats are reversed by the D1 antagonist, SCH23390. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. Locomotor-activating effects were measured in terms of the number of midline crossings exhibited by rats in a shuttle apparatus. RESULTS: A77636 (1.0 and 2.5 mg/kg, i.p.) produced a greater threshold-lowering effect in food-restricted than ad libitum fed rats but produced variable effects on locomotor activity with no difference between groups. Quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a marginally greater threshold-lowering effect in food-restricted rats and a dramatic locomotor response that was exclusive to food-restricted rats. The D1 antagonist, SCH23390, at a dose of 0.01 mg/kg (i.p.), had no effect on the lowering of LHSS threshold by amphetamine (0.5 mg/kg, i.p.) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. SCH23390, at a dose of 0.025 mg/kg, had no effect on locomotor activity induced by amphetamine (0.5 mg/kg) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. CONCLUSIONS: These results indicate that the augmentation of reward by food restriction extends to drugs that bypass the DA terminal and act postsynaptically. When taken together with prior immunohistochemical and behavioral findings, these results suggest that food restriction may increase the "enabling" effect of the D1 receptor on DA-mediated behaviors.

Chronic food restriction in rats augments the central rewarding effect of cocaine and the delta1 opioid agonist, DPDPE, but not the delta2 agonist, deltorphin-II.

RATIONALE: Chronic food restriction augments the self-administration and locomotor stimulating effects of opiates, psychostimulants and NMDA antagonists. The extent to which these effects can be attributed to changes in drug pharmacokinetics and bioavailability versus sensitivity of the neuronal circuits that mediate the affected behavioral functions, has not been established. Recent studies point to central adaptive changes insofar as rewarding, locomotor and c-fos-inducing effects of amphetamine and MK-801, injected directly into the lateral ventricle, are greater in food-restricted than ad libitum fed rats. The increased expression of c-fos in nucleus accumbens (NAC) shell, in particular, suggests that food restriction may augment drug reward by modulating dopamine (DA) synaptic function in this area. OBJECTIVES: The first purpose of this study was to investigate whether the rewarding effects of cocaine and the delta1 opioid agonist DPDPE, both of which increase DA synaptic transmission, are augmented by food restriction. The second purpose was to determine whether the delta2 opioid agonist, deltorphin-II, which has been reported to exert DA-independent rewarding effects, is subject to the potentiating effect of food restriction. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. RESULTS: In separate experiments, cocaine (50, 100 and 150 microg, ICV) and DPDPE (10 and 25 microg, ICV) produced greater threshold-lowering effects in food-restricted than ad libitum fed rats. Deltorphin-II (5.0, 10 and 25 microg, ICV) had no effect on reward thresholds, regardless of feeding regimen. CONCLUSIONS: While the reported DA-independence of deltorphin-II rewarding effects seemed to offer a means of testing the hypothesis that DA transmission is the critical modulated variable in food-restricted subjects, rewarding effects of this compound could not be demonstrated in the LHSS paradigm. The present results do, however, confirm and extend prior findings indicating that the enhanced self-administration of abused drugs by food-restricted subjects is due to enhanced sensitivity of a final common pathway for drug reward.

Hypoinsulinemia may mediate the lowering of self-stimulation thresholds by food restriction and streptozotocin-induced diabetes.

7 days beyond cessation of insulin treatment) elevation of threshold in ad libitum fed rats and, more transiently, reversed the threshold-lowering effect of food restriction. Acute insulin treatment (3 mU, 15 min prior) also elevated threshold in food-restricted rats. These results are consistent with the hypothesis that insulin modulates sensitivity of a brain reward system and that hypoinsulinemia may be the common factor in food restriction and diabetes that accounts for the enhancement of perifornical LHSS.

A search for the metabolic signal that sensitizes lateral hypothalamic self-stimulation in food-restricted rats.

Food deprivation and restriction increase the rewarding potency of food, drugs of abuse, and electrical brain stimulation. Based on evidence that the rewarding effects of these stimuli are mediated by the same neuronal circuitry, lateral hypothalamic self-stimulation (LHSS) was used to investigate the involvement of various metabolic signals in the sensitization of reward. In Experiment 1, glucoprivation with 2-deoxy-d-glucose (150 mg/kg, intraperitoneally (i.p.)) and lipoprivation with nicotinic acid (150 mg/kg, subcutaneously (s.c.)), individually and in combination, failed to affect the LHSS threshold in ad lib.-fed rats. These results suggest that signals associated with acute shortage of metabolic substrate do not sensitize reward. Because numerous responses to more prolonged negative energy balance are mediated by neuropeptide Y (NPY), the effect of exogenous neuropeptide Y upon LHSS was investigated in Experiment 2. Intraventricular infusion of orexigenic neuropeptide Y doses (2.0, 5.0, and 12.5 g), in ad lib.-fed rats, had no effect on LHSS threshold. In Experiment 3, other concomitants of prolonged negative energy balance--high circulating levels of free fatty acids (FFA) and beta-hydroxybutyrate (HDB)-were investigated. Nicotinic acid (250 mg/kg, s.c.), which suppressed serum HDB and FFA levels, had no effect on LHSS in food-restricted or ad lib.-fed rats. Mercaptoacetate (68.4 mg/kg, i.p.), which suppressed serum HDB levels and exacerbated the elevation of FFA levels, also had no effect. Thus, the brain reward system, if modulated by these substances, is not affected by transient, though marked, changes in their levels. To investigate the effect of a sustained increase in levels of FFA and HDB, a "ketogenic" diet was employed. Although this diet produced a fourfold increase in serum HDB levels, it had no effect on LHSS thresholds. Moreover, the failure of mercaptoacetate (68.4 mg/kg, i.p.) to decrease LHSS thresholds in these rats supports the conclusion that acute shortage of metabolic substrate does not sensitize reward. Other possible mechanisms of reward sensitization, including sustained decreases in circulating insulin and leptin and increases in corticosterone, are discussed.

Food restriction enhances the central rewarding effect of abused drugs.

Chronic food restriction increases the systemic self-administration and locomotor-stimulating effect of abused drugs. However, it is not clear whether these behavioral changes reflect enhanced rewarding potency or a CNS-based modulatory process. The purpose of this study was to determine whether food restriction specifically increases the rewarding potency of drugs, as indexed by their threshold-lowering effect on lateral hypothalamic self-stimulation, and whether any such effect can be attributed to an enhanced central response rather than changes in drug disposition. When drugs were administered systemically, food restriction potentiated the threshold-lowering effect of amphetamine (0.125, 0.25, and 0.5 mg/kg, i.p.), phencyclidine (1.0, 2.0, and 3.0 mg/kg, i.p.), and dizocilpine (MK-801) (0.0125, 0.05, and 0.1 mg/kg, i.p.) but not nicotine (0.15, 0.3, 0.45 mg/kg, s.c.). When amphetamine (25.0, 50.0, and 100.0 microgram) and MK-801 (5.0, 10.0, and 20.0 microgram) were administered via the intracerebroventricular route, food restriction again potentiated the threshold-lowering effects and increased the locomotor-stimulating effects of both drugs. These results indicate that food restriction increases the sensitivity of neural substrates for rewarding and stimulant effects of drugs. In light of work that attributes rewarding effects of MK-801 to blockade of NMDA receptors on medium spiny neurons in nucleus accumbens, the elements affected by food restriction may lie downstream from the mesoaccumbens dopamine neurons whose terminals are the site of amphetamine-rewarding action. Possible metabolic-endocrine triggers of this effect are discussed, as is the likelihood that mechanisms mediating the modulatory effect of food restriction differ from those mediating sensitization by intermittent drug exposure.

The start-stop procedure: estimation of temporal intervals by human subjects.

In four experiments investigating human timing, subjects produced estimates of sample durations by bracketing their endpoints. On each trial, subjects reproduced a sample duration by pressing a button before the estimated sample duration elapsed (start time) and releasing it after the estimated duration elapsed (stop time). From these responses, middle time (start + stop/2) and spread time (stop - start) were calculated, representing the point of subjective equality and the difference limen, respectively. In all experiments, subjects produced middle times that varied directly with sample duration. In Experiment 2, middle times lengthened when feedback was withheld. Consistent with Weber timing, spread times, as well as the standard deviation of middle times, varied directly with middle time (Experiments 1, 3, and 4). On the basis of an internal clock model of timing (Gibbon & Church, 1990), the data permitted inferences regarding memory processes and response threshold. Correlations between start and stop times and between start and spread times agreed with earlier findings in animals suggesting that the variance of temporal estimates across trials is based in part upon the selection of a single temporal memory sample from a reference memory store and upon one or two threshold samples for initiating and terminating each estimate within a trial.

Internal clock and memory processes in animal timing.

Temporal control of behavior was investigated within the framework of an internal clock model. Pigeons were exposed to signaled fixed-interval 30-s trials mixed with extended unreinforced (baseline) trials. On unreinforced break trials, the signal was interrupted for a period of time after trial onset. In Experiment 1, comparisons between the peak time obtained on baseline and on break trials produced peak time shifts that were longer than those expected if the clock had stopped during the break but shorter than if the clock had reset. In Experiment 2, systematic manipulations of duration and location of breaks produced peak time shifts that were nonlinear functions of break duration and that varied linearly with break location. The obtained peak times were more consistent with a continuous memory decay model than with the stop-retain or the reset hypotheses.