Schedule-induced Polydipsia In Rats Research Articles

Mutual facilitation between activity-based anorexia and schedule-induced polydipsia in rats.

The objective of this study was to evaluate the possible relationship between drinking (licks) in the schedule-induced polydipsia (SIP) phenomenon and running (turns in the wheel) in the activity-based anorexia (ABA) one. Within-subjects counterbalanced experiments were designed with male Wistar rats which underwent both behavioral procedures; half of them performed the ABA procedure first and the other half the SIP procedure first. In Experiment 1, the initial development of ABA facilitated the subsequent acquisition of SIP, whereas the first acquisition of SIP retarded the subsequent development of ABA. Given that SIP exposure implied food restriction, it could be that adaptation to the food regime contributed to lowering ABA manifestation. Thus, Experiment 2 was carried out in exactly the same way as Experiment 1, with the exception that animals which first went through SIP prior to undergoing the ABA procedure had no food restriction. In this case, both ABA and SIP as first experiences facilitated the further development of SIP and ABA, respectively. This suggests that running in ABA may be functionally similar to drinking in SIP; therefore, both behaviors can be thought of as induced by the schedule/regime of intermittent food availability.

Activation of trace amine-associated receptor 1 attenuates schedule-induced polydipsia in rats

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopaminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia.Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1–10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects.In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.

P.1.h.020 - Activation of trace amine-associated receptor 1 reduces schedule-induced polydipsia in rats

P.1.h.020 - Activation of trace amine-associated receptor 1 reduces schedule-induced polydipsia in rats

Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive-Compulsive Disorder.

Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.

A response strategy predicts acquisition of schedule-induced polydipsia in rats.

Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phenotypic learning traits representative of neural circuitry that underlies SIP and hypothesized that rats that are response-learners will be more susceptible in developing compulsive water drinking. Using the Y-maze, the rats were characterized as either place- or response-learners. They were exposed to the SIP protocol for a period of 21days. Subsequent histological staining for FosB/ΔFosB examined neuronal activation associated with SIP in several brain regions. The rats with a preference for a response-learning strategy were more likely to develop SIP than the rats using a place-learning strategy. Furthermore amphetamine sensitization, observed to increase SIP, also shifted learning strategy to a response-learning strategy. No differences were observed in FosB/ΔFosB expression between SIP and non-SIP rats in the dorsolateral striatum (DLS) and CA1 region of the hippocampus. However, SIP rats had greater FosB/ΔFosB expression in prefrontal cortex regions. The rats that develop SIP have a preference for response-learning strategies and increased neuronal activation in frontal cortical regions associated with habit formation and compulsion.

Role of Dopaminergic DAD1 and DAD2 Receptors in the Sensitization of Amphetamine-Suppressed Schedule-Induced Polydipsia in Rats

Effects of dopaminergic D1 (DAD1) and D2 (DAD2) receptors were examined in the sensitization of amphetamine (AMPH)-suppressed schedule-induced polydipsia (SIP). After training under a fixed-interval 60 sec schedule of food presentation in the presence of a water tube, rats received injections of different doses of AMPH 10 min prior to the test. It was found that AMPH at 2.0 mg/kg significantly to reduced licks and water intake during the SIP. The AMPH-suppressed SIP manifested again following 5-days of pretreatment with a sub-threshold dosage of AMPH (1.0 mg/kg) and a period of withdrawal. The role of dopaminergic D1 and D2 receptors was then examined by introducing D1 or D2 antagonist during the 5-days repeated injections of a sub-threshold dosage of AMPH. Results showed that DAD1 antagonist SCH23390 had little effect on the sensitization. However pretreatment with DAD2 antagonist haloperidol (HAL) prevented the sensitization to AMPH in the long-term rather than short-term withdrawal conditions. It is suggested that SIP could be a useful paradigm to study AMPH sensitization in rats and the involvement of dopamine receptors might be different.

Dopaminergic Actions of d-Amphetamine on Schedule-Induced Polydipsia in Rats

Schedule-induced polydipsia in rats was developed by means of a fixed-time 60-s schedule of food presentation. The acute administration of d-amphetamine sulfate (0.1–3.0 mg/kg) produced a dose-dependent decrease in the rate of licking. d-Amphetamine shifted to the left the temporal distribution of adjunctive drinking within interfood intervals. Dopaminergic antagonists SCH23390 ([R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrochloride], 0.001–0.01 mg/kg), eticlopride (0.001–0.03 mg/kg), and flupenthixol (0.03–0.3 mg/kg) also produced dose-dependent decreases in licks per minute but did not alter the temporal distribution of adjunctive behavior. Selective doses of dopaminergic antagonists further suppressed licking rates when combined with d-amphetamine, 1.0 mg/kg, but an antagonism could be observed on the temporal distribution after the administration of SCH23390 (0.01 mg/kg) or flupenthixol (0.1 mg/kg). The dopaminergic agonists SKF38393 ([R(+)-1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-bezazepine hydrochloride]; 1.0–10.0 mg/kg) and quinpirole (0.003–0.03 mg/kg) produced a dose-dependent decrease in the rate of licking, and when combined with d-amphetamine, additive-like suppressive effects were found. These results suggest a dopaminergic selectivity for the effects of d-amphetamine on the temporal distribution of schedule-induced polydipsia.

Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats

Food-deprived Wistar rats were exposed to a fixed-time 60-s food delivery schedule until they developed schedule-induced polydipsia. Every fifth lick was then followed by an electric shock during two, signalled, 5-min periods, which ran concurrently with the food delivery schedule. Shock intensities were adjusted to reduce licking to 60-70% of the unpunished licking rates. The benzodiazepine full agonists, diazepam (0.3-3.0 mg/kg), chlordiazepoxide (0.3-10.0 mg/kg), oxazepam (0.3-3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0-17.0 mg/kg), led to increases in punished responding at intermediate doses and decreases at the highest doses tested. All benzodiazepine agonists brought about dose-dependent decreases in unpunished schedule-induced polydipsia, with doses required to reduce drinking proving higher than doses required to increase punished schedule-induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by flumazenil and the benzodiazepine inverse agonist, RU-34000. Flumazenil effects, however, could reflect actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the rate-increasing effect of 0.3 mg/kg of diazepam, but at 17.0 mg/kg partially blocked such antipunishment effect. Overall, the present results extend the similarities of the effects of benzodiazepine compounds on adjunctive and operant patterns of behaviour by showing similar interactions within the benzodiazepine receptor complex.

Effects of risperidone on the schedule-induced polydipsia in rats

Locomotor activity increase was a bitonic function of acute caffeine IP doses (2.5–40 mg/kg) in rats. When the schedule-induced polydipsic, orally self-administered dose of caffeine was increased over blocks of daily 3 h sessions from 9.3 to 36.5 mg/kg, postsession activity increased monotonically as a function of dose. The rate of tolerance development to the increase in locomotor activity produced by caffeine depended on the route of administration. Tolerance onset occured on the fourth day of chronic IP doses, but remained incomplete after 21 doses. With the highest dose level of oral caffeine self-administration, tolerance developed on day 13, but remained incomplete even after 17 doses. Acute tolerance occurred for each of the IP doses, whereas a linear relation between locomotor activity and serum caffeine concentration was obtained after oral self-administration. There were two- to threefold higher locomotor activity AUCs(4 h) with oral caffeine at three dose levels compared to the activity AUCs(4 h) for IP doses.

The Generation and Maintenance of Schedule-Induced Polydipsia in Normal Male Rats Without Weight Reduction

TODD, J. T., L. A. CUNNINGHAM, A. A. JANES, J. MENDELSON AND E. K. MORRIS. The generation and maintenance of schedule-induced polydipsia in normal male rats without weight reduction. PHYSIOL BEHAV 62(6) 1385–1390, 1997.—Experiment One demonstrated that two normal male Sprague-Dawley rats (∼60 days old) with free access to food and two control rats whose weights were held constant by dietary restriction acquired schedule-induced polydipsia (SIP) in daily 33–35 min sessions of fixed-time 60-s food delivery. Three of the rats showed rapid acquisition of SIP; the fourth acquired SIP more slowly and consumed less per session the other three rats. After a 36–40 day period without sessions, the constant-weight rats showed a 37% decrease in overall consumption due to reduced drinking bout length. The SIP of the free-feeding rats was not affected by the interruption. After 90–100 periodic food delivery sessions, all subjects consumed an average of 11.2–12.2 mL per session compared with 1.8–4.8 mL per session in baseline sessions with massed food presentations. Experiment Two replicated the acquisition phase of Experiment One using two non-weight-reduced rats of the age and size of those typically used in SIP studies (∼30 weeks old). Both acquired SIP, although one showed only a small average increase in consumption per session over baseline (2.8 mL/session under periodic food vs. 0.8 mL following massed-food presentations). Before weight reduction, the stronger drinker consumed ∼8.8 mL per session compared with an average of 0.6 mL per session in baseline. After weight reduction, both exhibited strong SIP (18–19 mL per session in the final five sessions). This study demonstrates that weight reduction is not a necessary condition for the generation and maintenance of SIP in rats.

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 effect of risperidone on schedule-induced polydipsia.

The effects of risperidone on the acquisition of schedule-induced polydipsia in rats were investigated in a chronic dose regime followed by seven days of withdrawal. Risperidone dose-dependently suppressed water intake and number of panel pushes. Drinking efficiency and free water intake in home cages were unchanged. By comparing the effects of risperidone in the present paper with the effects of different-neuroleptics in the same procedure from an earlier study, it appears that the effect of risperidone is intermediary to that of the 'typical' and 'atypical' neuroleptics. It may be concluded that risperidone acts as an atypical neuroleptic compound; however, increasing the dose only two-fold will cause EPS.

Effects of amperozide on schedule-induced polydipsia in rats

Schedule-induced polydipsia occurs when food-deprived rats are exposed to a fixed-interval feeding schedule (FI = 60 s) for 1 h every day. Amperozide, a novel antipsychotic drug with a strong affinity for the 5-HT 2 receptor, was injected i.p. after completion of the requisite training sessions. The experimental rationale is that although the intensity of licking behavior in schedule-induced polydipsia can be taken as an index for anxiety, the drug-induced motor dysfunction should be assessed. In experiment 1, we tested the effect of amperozide on schedule-induced polydipsia at doses of 2, 4, and 8 mg/kg. The data showed that each dose significantly diminished the amount of licking and water intake. The number of presses decreased only at the dose of 8 mg/kg. During five post-treatment daily sessions for 5 days, these three measures returned to normal levels except that the number of pellets earned during the sessions did not significantly change. In addition, the number of presses showed a rebound after the termination of amperozide administration. In experiment 2, in addition to the total water intake, number of licks, pellets earned and presses, we also analyzed the postpellet temporal variation in the number of licks and presses in each schedule-induced polydipsia session. The drug was stopped for one day after each dose of 0.2, 0.4, 0.8 and 1.6 mg/kg of amperozide. The data showed that doses from 0.2 to 0.8 mg/kg did not alter any measure in drug-treated sessions and that the dose of 1.6 mg/kg decreased the number of licks and water intake. Taken together, these data suggest that, at the dose of 1.6–2.0 mg/kg, amperozide can reduce anxiety without causing motor dysfunction.

The effects of amphetamine, phencyclidine, dopaminergic antagonists and atypical neuroleptics on schedule-induced polydipsia (SIP) are distinguishable.

The effects of amphetamine, phencyclidine, dopaminergic blockers and atypical neuroleptics on the acquisition of schedule-induced polydipsia in rats were compared in a chronic dose regime followed by 7 days of withdrawal. All compounds suppressed water intake. However, different mechanisms were responsible. The antidopaminergic compounds inhibited the initiation of drinking, as the temporal pattern of licking was shifted to the right. Phencyclidine inhibited the maintenance of drinking as the number of licks/ml water consumed was increased. The suppressing effect of amphetamine may have been due to the reduction of high rates of licking and/or a competition between licking and locomotor or other amphetamine-induced activities. The number of panel entries were increased by amphetamine and phencyclidine. The typical antidopaminergic compounds decreased the number of panel pushes, whereas the atypical antidopaminergic compounds were without effect on this parameter. In conclusion, it was possible to differentiate between the types of compounds investigated by comparing their effects on water intake, panel pressing, drinking efficiency and the temporal patterns of licking and panel pressing.

Oral cocaine as a reinforcer

Schedule-induced polydipsia in rats was established in daily, 3h sessions with a fixed-interval 1min food schedule, and continued with two fluids available on concurrent fixed-ratio 6 schedules. A 2% ethanol solution was preferred to water, and succeeding drug solutions (0.16mg/ml cocaine, 0.1mg/ml caffeine, 0.01mg/ml nicotine, 0.11mg/ml lidocaine) also were preferred. Except for lidocaine, these drugs are known to function as reinforcers. Drug solution position was alternated daily, with location indicated by a discriminative stimulus (S(D)) light. Subsequent S(D) manipulations indicated that lidocaine and cocaine preferences were attributable to the prior association of the S(D) with ethanol rather than to the pharmacological effects of the currently accessible drug. Furthermore, when concurrent water choices were instituted, animals continued to choose the water source indicated by the S(D). The effectiveness and durability of the S(D) in determining polydipsic choice attests to the importance of the associative history of environmental S(D)s in triggering and maintaining drug seeking and drug taking. A model is outlined which suggests that drug abuse is a special case of a more general set of excessive behaviors induced by current environmental conditions, with choice of behavior remaining under S(D) control determined, in part, by the associative history of the S(D).

Schedule-induced polydipsia in rats with gastric fistulas

We have investigated the development and maintenance of schedule-induced polydipsia (SIP) when ingested water (and food) was allowed to drain from the stomach. Fourteen male Long-Evans rats were prepared with permanent gastric cannulas and, after recovery, their body weight was reduced to 80%. Water intake was measured, with cannulas open or closed, during 42 daily 1-h sessions in which 45-mg food pellets were delivered one per minute. Allowing ingested material to drain from the stomach impaired the development of SIP and reduced the polydipsia in rats in which SIP had already been established. In contrast, opening the gastric fistulas increased drinking in these rats when all the food pellets were provided at once or after water deprivation. The opposite effects of gastric drainage on dehydration and schedule-induced drinking is consistent with the view that SIP is not a fluid-regulating phenomenon. It is not clear, however, how these unexpected findings fit current hypotheses to explain SIP that are based on oral, neural excitatory, or emotional mechanisms.

Selective serotonin re-uptake inhibitors decrease schedule-induced polydipsia in rats: a potential model for obsessive compulsive disorder.

Schedule-induced polydipsia was used to determine the effects of selective serotonin re-uptake inhibitors on adjunctive water consumption. Polydipsia was induced in food deprived rats by exposure to a fixed time feeding schedule (FT = 60 s) for 150 min per day for 22 days. Selected polydipsic rats consumed 3-4 times greater volume of water compared to food deprived control rats. Chronic administration of the selective serotonin re-uptake inhibitors fluoxetine and clomipramine (CMI) at 5 mg/kg per day and fluvoxamine at 10 mg/kg twice a day significantly decreased schedule-induced polydipsia (SIP) on day 15 and throughout the remainder of the study compared to control rats. The noradrenergic re-uptake inhibitor, desipramine (DMI), only decreased SIP behavior on day 1. The neuroleptic, haloperidol (0.03 and 0.1 mg/kg), and the benzodiazepine, diazepam (2.5 mg/kg), failed to alter SIP behavior. Since obsessive-compulsive disorder (OCD) and polydipsic behavior both involve excessive expression of a normal behavior, the polydipsia model may be relevant for the prediction of compounds useful in the treatment of OCD.

Effects of drugs on the temporal distribution of schedule-induced polydipsia in rats

Drinking was induced in food-deprived rats by a fixed-time 1-min schedule of food presentation. With three rats, d-amphetamine (0.25, 0.5, 1.0, and 2.0 mg/kg) led to a dose-related increase in licking early in the interfood intervals, the peak of the temporal distribution of licking being shifted to earlier values. These effects were seen even when d-amphetamine had no effect on overall rates of licking and drinking. With another three rats, however, diazepam (0.5, 1.0, 2.0, and 4.0 mg/kg) did not shift the peak of the temporal distribution of licks in interfood intervals, even at doses that produced small increases in overall rates of licking and drinking. However, diazepam did reduce the peak of the distributions of licks at doses that did not decrease water intake and licks per minute.

Time-response effects of pimozide on operant behavior and schedule-induced polydipsia

Previous research has indicated that the administration of specific doses of pimozide results in the suppression of the acquisition of schedule-induced polydipsia in rats while not affecting operant behavior. The purpose of this study was to determine if these results were due to a specific action of pimozide on schedule-induced polydipsia or if they were due to an insufficient presession time of drug administration. Pimozide at 1.0 mg/kg was administered to three groups of rats at either 30, 60 or 120 minutes presession with control subjects receiving administration of the drug vehicle also at these times. The results of the study were that both operant behavior and the acquisition of schedule-induced polydipsia were affected in a nondifferential and time-dependent manner by pimozide. It was also found that pimozide caused an alteration in the temporal pattern of both schedule-induced polydipsia and operant responding. This latter result appears to have been caused by a disruption in sensorimotor integration due to the dopamine blocking properties of pimozide.

Isolation-rearing retards the acquisition of schedule-induced polydipsia in rats

Rats were reared from weaning either in isolation or in social groups for 10 weeks and were then tested for the acquisition of schedule-induced polydipsia (SIP). Isolation-reared rats were impaired in the development of this behaviour when compared to socially-reared controls. This reduction in drinking was specific to this test situation. Home cage water consumption and drinking in the SIP test chamber without a schedule of food delivery were unaltered and home cage drinking following water deprivation was significantly higher in the isolates. Housing adult rats in isolation did not impair SIP. The locomotor hyperactivity induced by isolation was also specific to rearing conditions. The inverse relationship between water consumption on the last day of testing and plasma corticosterone levels observed in both the socially-reared and socially-housed rats was absent in both the isolation-reared and isolation-housed rats.