Interpellet Interval Research Articles

AgRP neurons coordinate the mitigation of activity-based anorexia.

Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented bodyweight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons have been well characterized in their ability to regulate appetite, yet much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals exhibited a maladaptive inhibitory response to food, independent of basal activity changes. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity, but only during periods of food availability. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.

Excessive habit formation in schedule-induced polydipsia: Microstructural analysis of licking among rat strains and involvement of the orbitofrontal cortex.

Schedule-induced polydipsia (SIP) is an animal model of compulsive drinking that selects for individual differences and varies across rat strains. The aim of this study was to investigate excessive habit formation by analyzing the SIP licking microstructure among rat strains, and to compare the brain areas activated by SIP in different populations. Wistar, Long Evans and Roman High- and Low-Avoidance rat strains were compared using a cluster analysis of 2 main variables, that is, frequency of licking (percentage of interpellet intervals with drinking episodes) and intensity of licking (mean number of licks per interpellet interval), and were found to exhibit high intensity and frequent licking (compulsive drinkers, CD), low intensity but frequent licking (habitual drinkers, HD), and low intensity and low-frequency licking (low drinkers, LD). The Wistar strain showed a higher frequency and intensity of licking, and had the largest group of CD rats when compared with the other strains. Regarding the acquisition of SIP, CD rats showed a higher intensity of licking when compared with the HD and LD rats. Moreover, c-Fos quantification revealed that rats in the CD group showed hyperactivity in the lateral orbitofrontal cortex and basolateral amygdala when compared with the LD group. Analyzing the SIP microstructure could be a valuable tool for understanding the role of excessive habit formation in the development of compulsive drinking and its underpinning neurobiological mechanisms.

Temporal distributions of schedule-induced licks, magazine entries, and lever presses on fixed- and variable-time schedules.

In this article, schedule-induced drinking (SID) refers to increased drinking by hungry rats exposed to intermittent delivery of food pellets. Two major accounts of SID differ in their explanation of why such drinking tends be concentrated soon after pellet delivery. Temporal discrimination theories propose that drinking is a form of displacement activity that occurs when a pellet is least likely. Adventitious reinforcement theories propose that drinking is displaced to early in an interpellet interval (IPI) by magazine-directed behavior that occurs toward the end of an IPI. The main aim of this study was to examine the latter response-competition account by recording distributions of both licking and magazine entries as SID developed when pellets were delivered to different groups either on a fixed-time (FT 30 s) or on a variable-time schedule (VT 30 s), as in Experiment 1. Although VT 30-s schedules produced essentially flat distributions of magazine entries, licking still tended to be concentrated early in an IPI. Furthermore, there was no indication (Experiments 1 and 2) that magazine entry distributions developed ahead of licking distributions. Experiment 3 examined distributions of lever presses instead of licks: Initially high rates of lever pressing declined both with response-independent schedules (FT and VT) and when a minimal response-dependency was introduced (recycling conjunctive schedule), yet this response also tended to be most frequent soon after pellet delivery. Overall, the data were generally consistent with temporal conditioning theories.

Reply to Pellón and Killeen's (2015) commentary on Boakes, Patterson, Kendig, and Harris (2015).

This reply notes the importance of data from variable-time schedules for resolving the issue of whether competition from magazine approach behavior is a major factor responsible for the concentration of schedule-induced drinking early in interpellet intervals. Pellón and Killeen propose that this temporal distribution of schedule-induced drinking reflects the effectiveness of adventitious reinforcement of this behavior over a delay, as detailed in their model. However, there is no evidence to support either of their key assumptions: (a) that schedule-induced behaviors are maintained by adventitious reinforcement ("are operants") and (b) that behaviors vary in their sensitivity to a delay before the subsequent occurrence of a reinforcer.

Responses compete and collaborate, shaping each others' distributions: Commentary on Boakes, Patterson, Kendig, and Harris (2015).

Boakes, Patterson, Kendig, and Harris (2015) showed that schedule-induced drinking (SID), typically concentrated in the first half of the interpellet interval, is not moved there exclusively by competition from magazine entries, and that not all arbitrary responses can be maintained by adventitious reinforcement. They attribute such inferences to Killeen and Pellón (2013) and Patterson and Boakes (2012), and on that basis reject their explanation for the excessive nature of many adjunctive responses as a result of reinforcement. It is a mistaken attribution, as Killeen and Pellón emphasized that reinforcers act on many competing interim and terminal responses. That attribution is a minor oversight on the authors' part; their return to a discredited motivational account is, however, a major blunder. It discards the seminal recent advances in understanding the nature of schedule-induced responses (e.g., those of Patterson and Boakes), and even the positive contributions of their own article: Their data show very strong correlations between magazine entries and drinking, providing much more evidence for response competition than their microanalysis provides against it.

Effects of inter-food interval on the variety effect in an instrumental food-seeking task. Clarifying the role of habituation

Food variety increases consumption and the rate of instrumental behavior that is reinforced by food in humans and animals. The present experiment investigated the relationship between the variety effect and habituation to food by testing the role of the interval between successive food presentations on responding in an operant food-seeking task. Habituation to food was expected at short, but not long, interfood intervals. The effects of variety on food's long-term reinforcing value were also tested. Four groups of rats were trained to lever-press on different random-interval (RI) schedules of reinforcement to earn 45-mg food pellets. Half the rats in each group received an unpredictable mix of grain and sucrose pellets, while the other half consistently received sucrose pellets. Response rate began at a high rate and then decreased within each 30-min session for groups that received short inter-pellet intervals (i.e., RI-3 s and RI-6 s reinforcement schedules) but not in groups that received longer inter-pellet intervals (i.e., RI-12 s and RI-24 s). A variety effect in the form of higher responding in the mix group than the sucrose-only group was also only evident at the shorter intervals. Habituation and variety effects were also most evident with the short intervals when we controlled for the number of reinforcers earned, suggesting that they were not merely due to rapid satiation. The variety effect also appeared quickly when groups trained with longer inter-pellet intervals (RI-12 s and RI-24 s) were transitioned to shorter intervals (RI-3 s and RI-6 s). There was no effect of variety on resistance to extinction or on resistance to the response-suppressing effects of pre-session feeding. The results more clearly link this version of the variety effect to the short-term effect of variety on food habituation.

Interval, blocking, and marking effects during the development of schedule-induced drinking in rats.

Schedule-induced drinking (SID) can occur when food-deprived rats are given access to water while receiving pellets on an intermittent reinforcement schedule. These conditions can increase water intake excessively. The possible role of adventitious reinforcement of postpellet drinking was assessed by testing whether response-reinforcer contiguity, the relative predictiveness of a response, and whether it is marked are important in the development of SID. Rats exposed to a short interpellet interval acquired SID most rapidly, with this acquired drinking response maintained when animals were transferred to a longer interpellet interval, thus indicating an easy-to-hard effect (Experiment 1). Further experiments demonstrated that a stimulus (a brief-flashing house light) occurring prior to pellet delivery could block the acquisition of SID (Experiment 2), while a lick-contingent tone, intended to increase the associability of this response, produced more rapid acquisition of SID (Experiment 3). Analysis of lick distributions revealed that licking became concentrated in the first half of an interpellet interval only after several sessions. Overall, the results indicated that similar factors affect the acquisition of both SID and instrumental conditioning with delayed reinforcement, as is consistent with a superstitious conditioning account of SID development.

The effects of signalled and unsignalled lick-dependent delays on the development of schedule-induced drinking in rats

Food pellets were programmed to be delivered to rats every 60 sec (Fixed Time 60-sec schedule), and the development of schedule-induced drinking was measured in terms of the amount of water consumed and the number of licks per inter-pellet interval. For some rats (masters) 10-sec delays in food delivery were dependent on licks. Yoked-control rats received food at the same time as their masters and independently of their own behaviour. In Experiment 1, in which the delays were signalled by a blackout, the master rats began to drink, but this schedule-induced behaviour then decreased to levels lower than those shown by the yoked controls. When the signalled delays were discontinued, the drinking of the master rats recovered. In Experiment 2, in which the delays were not signalled, the master rats did not develop as much schedule-induced drinking as the yoked controls, and discontinuing the delays led to only small increases in drinking. These results support the view that schedule-induced drinking is subjec...

FOOD‐DEPRIVATION EFFECTS ON PUNISHED SCHEDULE‐INDUCED DRINKING IN RATS

Food-deprived rats (at 80% of their free-feeding weights) were exposed to a fixed-time 60-s schedule of food-pellet presentation and developed schedule-induced drinking. Lick-dependent signaled delays (10 s) to food presentation led to decreased drinking, which recovered when the signaled delays were discontinued. A major effect of this punishment contingency was to increase the proportion of interpellet intervals without any licks. The drinking of yoked control rats, which received food at the same times as those exposed to the signaled delay contingency (masters), was not consistently reduced. When food-deprivation level was changed to 90%, all master and yoked control rats showed decreases in punished or unpunished schedule-induced drinking. When the body weights were reduced to 70%, most master rats increased punished behavior to levels similar to those of unpunished drinking. This effect was not observed for yoked controls. Therefore, body-weight loss increased the resistance of schedule-induced drinking to reductions by punishment. Food-deprivation effects on punished schedule-induced drinking are similar to their effects on food-maintained lever pressing. This dependency of punishment on food-deprivation level supports the view that schedule-induced drinking can be modified by the same variables that affect operant behavior in general.

Food-delay duration and the development of schedule-induced polydipsia in rats

Twelve rats were exposed to a schedule that delivered a food pellet every 60 s (fixed time 60 s). The development of schedule-induced polydipsia was measured in terms of the water consumed and the licks per interpellet interval. Every lick by master rats initiated an unsignalled delay of 2 or 50 s in food delivery. Yoked-control rats received food at the same time as their masters, being unaffected by their own licking. Schedule-induced polydipsia developed in master rats exposed to 2-s delays, but more slowly and to a lesser extent than control animals. The development of polydipsia was prevented in master rats exposed to 50-s delays, however. When these delays were discontinued, polydipsia was obtained by master rats. The finding that the effect of the delays was modulated by their duration supports the view that the development of schedule-induced polydipsia is sensitive to control by its environmental consequences.

The impact of inter-pellet interval and polydipsia on hypoalgesia elicited by non-contingent food delivery

Exposure to non-contingent food delivery has been shown to elicit an increase in nociceptive thresholds in rats. The conditions which elicit analgesia are similar to those that elicit schedule-induced polydipsia. In both instances animals are food-deprived and receive food on an intermittent schedule. Interpellet interval has been found to be an important predictor of schedule-induced polydipsia. Experiment 1 therefore investigated the effect of varying the interval between pellet deliveries on tail flick latencies in rats. The relationship between nociceptive threshold and inter-pellet interval was found to be bitonic in nature given that animals submitted to fixed time schedules of 30 or 60 s, but not 15 or 120 s, exhibited significant increases in tail flick latencies. Experiment 2 examined the effect of providing animals with water during exposure to non-contingent food delivery. Under these conditions animals exhibited polydipsic behaviour, the development of which attenuated the hypoalgesic response to non-contingent food delivery.

Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline.

Experiment 1 showed that the reduction of intake produced by 5 or 10 mg/kg fluoxetine in rats eating either a solid or a liquid meal was partially antagonised by 1 mg/kg of the 5HT1/5HT2 antagonist metergoline but not by 1 mg/kg of the 5HT2 antagonist ketanserin. Experiment 2 examined the meal patterning of rats given 5 mg/kg fluoxetine and 1 mg/kg metergoline. Fluoxetine alone increased the latency to feed, reduced meal size and shifted the inter-pellet interval (IPI) distribution to the right. Metergoline alone had little immediate effect on food intake or other feeding parameters but partially reversed the reduction of food intake produced by fluoxetine. There was a complete reversal of the increased latency to feed and a partial reversal of the depression of meal size. However, the rightward shift of the IPI distribution caused by fluoxetine, which indicated a depression of feeding rate, was more pronounced after combined treatment. We conclude that fluoxetine reduces food intake by enhancing satiety through a serotonergic dependent mechanism but reduces feeding rate through a separate mechanism, whose neurochemical basis remains to be established.

The effects of food schedule adaptation on the ability of naloxone to suppress the aquisition of schedule-induced polydipsia

Naloxone suppressed the acquisition of schedule-induced polydipsia (SIP) in rats given no previous exposure to the feeding schedule. Adaptation to the feeding schedule prior to SIP acquisition attenuated this suppression. Specifically, water consumption, bout probability, licks/bout and maximum lick rates during the interpellet interval (IPI) were significantly increased by adaptation. Although adaptation attenuated the suppressive effects of naloxone on SIP, this attenuation was not complete. Adapted, naloxone-treated subjects displayed both decreased water consumption and bout probability as compared to distilled water-treated controls. Unlike the effects of adaptation on naloxone's suppression of SIP, adaptation completely eliminated naloxone's suppression of feeding. That adapted subjects ate at control levels while still displaying a lower level of SIP suggests that the suppressive effect of naloxone on the acquisition of SIP is not an indirect effect of naloxone on feeding, but rather a direct effect of naloxone on developing SIP. Given that naloxone has a general suppressive effect on drinking (including SIP), what remains to be determined is why naloxone has no effect on established SIP. Possible explanations for this are discussed.

Microstructural analysis of the anorectic action of peripherally administered 5-HT

The anorectic action of systemically administered 5-HT (1, 2 and 4 mg/kg SC) was investigated in food deprived rats using the technique of microstructural analysis; small food pellets were delivered to a food hopper, and the time and occurence of each pellet removal was recorded. Long-survivor analysis of inter-pellet intervals was used to define feeding bouts, and this was then used to compute measures of bout frequency, bout size, bout duration and eating rate. The 5-HT reduced food intake by selectively decreasing bout size and bout duration. No effects of 5-HT were observed on any of the other parameters measured. These effects of 5-HT are robust over a range of bout criteria, and replicable. Methysergide (3 mg/kg IP) attenuated the anorectic action of 5-HT by a significant increase in bout frequency and an attenuation of the effects of 5-HT on bout size, and bout duration. The results are discussed in terms of a possible role for peripheral 5-HT in the control of satiety, and implications for the mode of action of serotonergic anorectic agents such as fenfluramine.

The effects of variations in the interpellet interval on wheel running in the rat

Three rats were given access to a running wheel during spaced food deliveries. As the interpellet interval increased, the overall amount of running increased, the rate of running neither systematically increased nor decreased, and the locus of maximal running occurred later in the interpellet interval. Both the overall amount and the temporal distribution of running exhibited considerable within-schedule changes during successive exposures to the different schedules. These data are discussed in terms of Staddon’s (1977) assignment of behavior into different functional classes, that is, schedule-induced and facultative.

Histamine plays no part in schedule-induced polydipsia in the rat

Twelve Sprague-Dawley male albino rats were tested with or without combined antagonism of peripheral H1 (using 2 mg/kg dexbrompheniramine IP) and H2 (using 32 mg/kg cimetidine IP) receptors for histamine prior to (a) drinking after 2.5 mg/kg histamine SC, (b) drinking after 24-hr water deprivation, and (c) drinking during the acquisition and maintenance of schedule-induced polydipsia (SIP) with a 45 mg Noyes pellet delivered every 90 sec. Such antagonism of histamine receptors abolished drinking elicited by exogenous histamine without inhibiting drinking after water deprivation. Moreover, histaminergic antagonism failed to prevent the acquisition and maintenance of SIP and failed to alter the distribution of contacts with the drinking spout during interpellet intervals. These findings demonstrate no role for endogenous systemic histamine in SIP.

Do random time schedules induce polydipsia in the rat?

The present experiments investigated the role of signals for pellet delivery in the development of polydipsia on random time schedules. In Experiment 1, when an explicit signal or auditory stimulation from pellet dispenser operation was available to the rats, polydipsia developed in all ofthe animals. In Experiment 2, animals receiving signaled pellet deliveries developed poly­ dipsia more quickly than those receiving unsignaled pellet deliveries. Furthermore, behavioral observations suggested that animals showing polydipsia in the unsignaled group may have been able to detect the operation of the pellet dispenser despite our attempt to mask such cues. In Experiment 3, the information value of pellet-dispenser cues was degraded by the operation of an empty pellet dispenser during the interpellet interval. Under these conditions, almost all animals did not develop polydipsia and the data suggest that for the few that did, pellet-dispenser cues were probably not responsible. Thus, the present findings suggest two conclusions: (1) In studies reporting polydipsia on random schedules, the animals may have been inadvertently provid­ ed with cues for pellet availability, and (2) although Pavlovian conditioning may be an impor­ tant modulator of adjunctive behavior, other factors must also be considered.

A reevaluation of the CS− hypothesis for schedule-induced polydipsia under intermittent schedules of pellet delivery

Lashley and Rosellini (1980) have recently suggested that schedule-induced polydipsia (SIP) is determined by the occurrence of absolute periods within schedules of periodic food delivery which are associated with a low probability of food delivery, that is, CS− periods. To assess this hypothesis, SIP was examined in the present experiments under three schedules—fixed time, variable time, and random time (RT)—which differed in probability of occurrence and/or duration (Experiment 1), and under a range of RT schedules in which the CS− period was systematically varied by changing the interpellet interval (Experiment 2). In both experiments, the level and temporal distribution of SIP did not seem to be related to the absolute period associated with the absence of food. Instead, SIP was more systematically related to the average length of the interpellet interval and, therefore, to the average period associated with no food. It was suggested that drinking under intermittent schedules of pellet delivery, that is, SIP, is determined by an average CS− period and not by an absolute period associated with the unavailability of food.

Schedule-induced polydipsia in the cotton rat (Sigmodon hispidus)

Two of three wild-caught cotton rats developed schedule-induced polydipsia on fixed-time (FT) food schedules in which both level of deprivation and length of the interpellet interval were varied systematically. One cotton rat first developed polydipsia on an FT 2-min schedule at 80% body weight; the other cotton rat did not develop polydipsia until placed on an FT 3-min schedule and body weight was reduced to 70%. These data indicate the importance of systematic variation of relevant variables before concluding that a given species does not display schedule-induced polydipsia. The adaptive significance of adjunctive behaviors is discussed.

Control of drinking-bout magnitude in schedule-induced polydipsia by interpellet-interval duration

Schedule-induced polydipsia (SIP) is a function of interpellet-interval (IPI) durations: intermediate (40-180-sec) IPIs are most effective in producing SIP, while longer and shorter IPIs are increasingly less effective. In order to determine whether each IPI exerts its influence on SIP by regulating drinking during that IPI itself or during the immediately succeeding IPI, rats were presented with systematic sequences of IPI durations during individual sessions of SIP testing. It was found that a very brief (20-sec) IPI tended to reduce the duration of drinking during the ongoing IPI, but that a very long (4-min) IPI reduced the probability that any drinking would occur during subsequent IPIs. It was suggested that the motivation to drink is reduced following long IPIs, while feeding, or behaviors anticipatory to feeding, compete with drinking when IPI lengths are very short.