Non-deprived Rats Research Articles

Relationship between histamine receptors in the brain and diazepam-induced hyperphagia in rats

We investigated whether histaminergic neurons in the brain are involved in diazepam-induced hyperphagia in rats. Pretreatment with intracerebroventricular (ICV) injection of either histamine H 1-receptor antagonist, pyrilamine (10 and 30 μg) or histamine H 2-receptor antagonist, famotidine (3 and 10 μg) did not affect only diazepam (1 mg/kg, subcutaneous, SC)-induced hyperphagia in nondeprived rats, but also spontaneous feeding in food-deprived rats. In addition, pretreatment with ICV injection of histamine H 3-receptor antagonist, thioperamide, and histamine H 3-receptor agonist, (R) alpha methylhistamine, enhanced and inhibited diazepam-induced hyperphagia (1 mg/kg, SC) in nondeprived rats, respectively. However, thioperamide and (R) alpha methylhistamine did not affect spontaneous feeding in food-deprived rats. These findings suggest that histaminergic neurons are not directly involved in diazepam-induced hyperphagia in rats. Furthermore, enhancement or inhibition of diazepam-induced hyperphagia by histamine H 3-receptor antagonist or agonist may occur via histamine H 3-receptors localized in the other neurons in the rat brain.

Nitrous oxide induces feeding in the nondeprived rat that is antagonized by naltrexone

Three experiments investigated a possible effect of nitrous oxide (N 2O) on food intake in nondeprived male hooded rats in independent groups designs. Experiment 1 demonstrated a concentration-related increase in intake with increasing level of nitrous oxide (10–40% N 2O), reaching statistical significance at 20% N 20 when compared to room air controls ( p < 0.05). In experiment 2, pretreatment with 10 and 20 mg/kg of the benzodiazepine antagonist, fiumazenil, failed to significantly attenuate 30% N 2O-induced hyperphagia. In Experiment 3, pretreatment with the opioid antagonist, naltrexone, effectively antagonized 30% N 2O-induced hyperphagia. Pronounced attenuation (to 59% of 30% N 20-induced intake level over a 1 h period) at the lowest dose of naltrexone (0.1 mg/kg, p < 0.01) compared to vehicle level resulted in a shallow dose-response curve across the dose range tested (0.1–10.0 mg/kg). These results suggest that an endogenous opioid mechanism is prominently involved in the N 2O-induced ingestive response.

Effects of maternal and sibling deprivation on basal and stress induced hypothalamic-pituitary-adrenal components in the infant rat

Prolonged maternal deprivation during early infancy increases basal- and stress-induced corticosterone (CORT) levels, but the underlying mechanism is not clear. In general, stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, with secretion and compensatory synthesis of hypothalamic corticotropin-releasing hormone (CRH). In the infant rat, we have demonstrated that maximally tolerated acute cold stress induced a robust elevation of plasma CORT throughout the first 2 postnatal weeks. However CRH messenger RNA (CRH-mRNA) abundance 4 h subsequent to cold stress was enhanced only in rats aged 9 days or older. This suggests a developmental regulation of the CRH component of the HPA-response to this stressor. The present study examined whether increased basal and cold stress-induced CORT levels after 24 h of maternal deprivation were due to enhanced CRH-mRNA abundance in the hypothalamic paraventricular nucleus (PVN). CRH-mRNA abundance, and basal- and cold-induced plasma CORT levels were measured in maternally deprived 6 and 9-day-old pups compared to non-deprived controls. Maternal deprivation increased basal and cold-induced CORT levels on both 6 and 9-day-old rats. CRH-mRNA abundance in the PVN of deprived rats did not differ from that in non-deprived rats. Our results indicate that the enhanced basal and stress-induced plasma CORT observed after 24 h maternal deprivation is not due to increased CRH-mRNA abundance in the PVN.

Intraperitoneal administration of baclofen increases consumption of both solid and liquid diets in rats

It has previously been demonstrated that systemic administration of the GABA B receptor agonist baclofen increases food intake but decreases water intake in rats. In the present study, the effects of baclofen (2–4 mg/kg i.p.) were investigated on food intake in non-deprived rats given access to either pelleted food ( n = 8) or a palatable liquid diet ( n = 8). Baclofen (2–4 mg/kg i.p.) significantly increased the consumption of both the pelleted and the liquid foods. The increased intake of the liquid diet (i) argues against the involvement of non-specific gnawing in the increased consumption of the solid food by baclofen, and (ii) suggests that the inhibition of water intake produced by baclofen is not due to interference with the mechanical aspects of drinking, such as licking on a drinking spout, or the swallowing of liquid.

Resumption of ethanol seeking behaviour in rats

Reexposure to alcohol may induce subjective craving and relapse to drug self-administration in ex-alcoholics. In this study, we proposed a rat model of "first-drink"-induced drug-seeking relapse. Responding was established in Long Evans rats under a fixed-ratio [FR5:S(1)] schedule for oral ethanol. Substitution of water for ethanol solution resulted in extinction of the self-administration. When responding for 8% ethanol and ethanol intake were stable for at least three consecutive 30min sessions, ethanol delivery was discontinued and only three water dipper cup presentations were available upon responding (3[FR5:water]). When the number of active lever presses decreased to a low stable level, responding was considered extinguished. In Experiment 1, subjects under "extinction" were challenged with three 8% ethanol dipper cup presentations. The re-exposure to ethanol was able to significantly reinstate responding in all subjects. Latency to complete the ethanol presentation significantly decreased compared to the value observed during the previous "extinction" session. In Experiment 2, other subjects were tested for extinction and then reexposed to 4, 8 or 16% ethanol. All three concentrations significantly increased active lever presses, but with different patterns of responding. The resumption of responding was linearly correlated to the ethanol concentration but no significant dose-effect relationship was found. In Experiment 3, reexposure to 8% ethanol in nondeprived rats induced a resumption of responding not significantly different from the effect observed in a restricted diet condition. These results demonstrate that ethanol reexposure is able to reinstate ethanol-seeking behaviour in rats with a past history of ethanol self-administration, and that this effect does not depend on a food motivation drive related to the calorific value of ethanol.

Neurones in the median preoptic nucleus projecting to the supraoptic nucleus are sensitive to hemodynamic changes and increase of plasma osmotic pressure in the rat

Water deprivation induces expression of the immediate early gene c-fos in specific brain regions, most likely as a result of the activation of cells that are responsive to changes in osmolality and/or blood volume. We hypothesized that the magnitude of c-fos expression would be a function of both the duration of water deprivation and the time of day at which the deprivation started. This study was designed to examine the pattern of Fos-like immunoreactivity (FLI) following water deprivation in rats under normal light/dark conditions (nLD) and reverse light/dark conditions (rLD). Rats were deprived of water but not food either for 0, 5, 16, 24 or 48 h. As expected, hematocrit ratio (HCT), osmolality (OSM), plasma renin activity (PRA) and weight loss increased as a function of duration of water deprivation. In non-deprived rats (0 h), very little FLI was observed in most brain regions. The number of cells showing FLI increased with duration of water deprivation in the supraoptic nucleus (SON), paraventricular nucleus (PVN), organum vasculosum laminae terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO) in both nLD and rLD conditions. However, the pattern of FLI differed between nLD and rLD conditions. Compared to corresponding nLD groups after 5 or 24-h water deprivation, rLD groups had significantly more FLI in SON and PVN, and higher PRA and HCT. Also, weight loss and FLI in the MnPO were greater after 5 h, and FLI in the SFO was greater after 24 h under rLD compared to nLD conditions. Our findings indicate that the magnitude of c-fos expression, and change in weight and plasma parameters were a function of both the duration of water deprivation and the time of day at which the deprivation started. This may result from ingestion of food early in the deprivation periods during the rLD tests, thus producing greater change in osmolality and blood volume.

Parametric studies of selective D1 or D2 antagonists: effects on appetitive and feeding behaviour.

Dopamine receptor antagonists have long been known to suppress food intake. The main purpose of the present series of experiments was to investigate feeding in rats across several paradigms evaluating the effects of selective dopamine D1 and D2 antagonists. The selective D1 antagonist, SCH 23390, reduced FR8 operant responding for food (0.03mg/kg, s.c.) at a dose lower than that required to reduce food intake in two free-feeding situations (0.1mg/kg, s.c.). The selective D2 antagonist, YM 09151-2, had a biphasic effect on food intake in food-deprived rats, increasing food intake at a low dose (0.01mg/kg, i.p.), but decreasing intake at higher doses in deprived rats (0.1mg/kg, i.p.). A combination of subthreshold doses of SCH 23390 and YM 09151-2 resulted in a significant reduction in food intake. In nondeprived rats eating palatable food and in animals trained on an FR8 schedule of reinforcement, YM09151-2 exerted significant suppressant effects. The results suggest that the operant response is more sensitive to the effects of selective D1 and D2 antagonism than is the consummatory response. The findings also suggest a specific inhibitory role for dopamine D2 (and not D1) receptors on food intake, since selective D1 antagonism did not produce increases in food intake at any of the doses tested. This provides evidence that under some circumstances the effects of D1 and D2 receptor blockade are dissociable.

Ondansetron, a selective 5-HT 3 receptor antagonist, reduces palatable food consumption in the nondeprived rat

This study investigated the effects of ondansetron, a selective 5-HT 3 receptor antagonist, on palatable food consumption in nondeprived male rats, under conditions of familiarity. The results showed that ondansetron (3.0–30 μg/kg, i.p.) significantly reduced food intake at each dose tested. The reduction in food intake was due not to a change in the rate of eating but to a reduction in the time spent eating. This, in turn, was due to a reduction in the mean duration of feeding bouts but not due to a change in the frequency of feeding bouts. Hence, the feeding-suppressant effect of ondansetron resulted from a quite specific alteration in the microstructural characteristics of feeding behaviour. In the 60-min observation period, ondansetron did not affect either locomotor activity or rearing, indicating that it did not have general excitatory or behavioural-suppressant effects. Following ondansetron, animals continued to show a typical decline in feeding over time, indicative of the development of within-meal satiety, but the level of feeding was reduced in such a way as to suggest that ondansetron enhances satiety. As a result, as feeding declined, the level of grooming which typically follows the end of feeding, was increased in ondansetron-treated animals. In a supplementary experiment, ondansetron had no effect on deprivation-induced feeding. Present evidence does not allow these data for a 5-HT 3 receptor antagonist to be easily accommodated into the major current hypothesis dealing with serotonergic control of feeding responses. Therefore, the role of 5-HT 3 receptor-mediated changes in ingestive behaviour requires further investigation.

The selective dopamine uptake inhibitor GBR 12909: Its effects on the microstructure of feeding in rats

Previous experiments have investigated the anorectic effects of mazindol and cocaine, both of which can inhibit dopamine (DA) uptake into presynaptic terminals but do not do so selectively. GBR 12909, however, is an example of a potent and selective inhibitor of DA uptake and therefore, the present study was concerned with investigating its possible effects on feeding behavior in nondeprived rats given access to a sweetened palatable diet. GBR 12909 (5–20 mg/kg, IP) was injected 2 h before a 60 min observation test. It produced a significant reduction in food intake, as a consequence of a reduction in the duration of feeding, without reducing the rate of eating. This anorectic profile is consistent with earlier findings for mazindol and cocaine. The other main behavioral effect of GBR 12909, observed in the present study, was to induce intense sniffing activity, but, unlike cocaine, it did not suppress grooming or induce hyperlocomotion. This selective behavioral effect of GBR 12909 indicates that sniffing can be isolated as one component of a broader array of components typically associated with DA-related stereotyped behavior.

Tegmental pedunculopontine lesions in rats decrease saccharin's rewarding effects but not its memory-improving effect.

The tegmental pedunculopontine nucleus (TPP) of the brainstem has been identified as a critical substrate for both opiate and food reward in nondeprived rats. In this study of rats, TPP lesions blocked saccharin-conditioned place preferences, in both the presence and the absence of water deprivation. TPP lesions also attenuated the unconditioned intake of saccharin and water over several hours after recovery from food and water deprivation. TPP lesions did not block saccharin preferences over water in short-duration tests. The researchers propose that the absence of a lesion effect may reflect previously conditioned discriminations. TPP lesions had no effect on the ability of posttrial presentations of a 3.2% saccharin solution to improve lithium-chloride-conditioned taste aversions. TPP lesions dissociate 2 behavioral processes elicited by saccharin: One mediates unconditioned-reward-conditioned-reinforcing effects, and another mediates the memory-improving effect.

Water deprivation enhances fear conditioning to contextual, but not discrete, conditional stimuli in rats.

Water-deprived and nondeprived rats were fear conditioned with a discrete tone conditional stimulus (CS) and an aversive footshock unconditional stimulus (US). Twenty-four and 48 hr following conditioning, conditional fear to the tone CS and the context cues of the conditioning chamber, respectively, were assessed by measuring freezing behavior. Water deprivation had no effect on baseline responding to either tone or contextual stimuli. Following either 1 or 3 tone-shock pairings, however, water deprivation selectively enhanced conditional freezing to the contextual cues of the training chamber; conditional freezing to the tone was unaffected by water deprivation. These results are consistent with the view that water deprivation affects fear conditioning via an influence on the hippocampus.

Neuroleptics block high- but not low-dose heroin place preferences: further evidence for a two-system model of motivation.

The researchers studied whether 2 separate motivational systems in the brain underlie the rewarding effects of morphine. The brainstem tegmental pedunculopontine nucleus (TPP) is involved in mediating the motivational effects of opiates in nondeprived (drug-naive) rats, whereas dopamine transmission is necessary in mediating the motivational effects of opiates in deprived rats (opiate withdrawal). The results show that heroin's motivational properties obey the same boundary between a nondeprived and a deprived motivational state. Bilateral ibotenic acid lesions of the TPP blocked the acquisition of a place preference for an environment paired with 0.05 mg/kg heroin (a dose that induces no withdrawal aversion) but had no effect on place preference for an environment paired with 0.5 mg/kg heroin (a dose that does induce withdrawal aversion). Dopamine antagonist pretreatment produced the opposite pattern of results.

Meal initiation occurs after experimental induction of transient declines in blood glucose.

Previous studies have shown that a brief rise in plasma insulin followed by a transient fall and rise in blood glucose precede the initiation of feeding in nondeprived rats. In this study, a cholinergic agonist, bethanechol chloride, which is known to induce a brief spike in plasma insulin, was infused intravenously in an attempt to induce transient declines in blood glucose and meal initiation in free-feeding rats. When the blood glucose response to bethanechol chloride administration met the criteria for a transient decline in blood glucose, meal initiation occurred within 20 min in nine out of ten trials. However, if the blood glucose response to bethanechol chloride administration failed to meet the criteria for a transient decline in blood glucose, meal initiation did not occur. The frequency of successful induction of feeding was higher in the late light cycle (80%) compared with the early light cycle (14%) of the photoperiod. These results suggest that cholinergic stimulation can induce feeding only after a brief fall and rise in blood glucose. The blood glucose and behavioral responses to the cholinergic stimulus appear to be strongly dependent on the metabolic state of the animal. These results further strengthen the evidence for a causal relationship between transient declines in blood glucose and meal initiation in free-feeding rats.

Effects of neuropeptide Y on ingestion of flavored solutions in nondeprived rats

Recent evidence suggests that in addition to altering energy balance, neuropeptide Y (NPY) may stimulate ingestive behavior by modifying the orosensory quality of ingested substances. The present experiments investigated the effect of intracerebroventricular administration of NPY (5 μg/5 μl) on ingestion of various flavored solutions in nondeprived rats. Experiment 1 examined the effects of NPY on ingestion of a range of concentrations of saline, sucrose, and saccharin solutions in single-bottle tests. Results indicated that NPY stimulates ingestion of both sucrose and saccharin solutions that are normally palatable. In Experiment 2, palatable sucrose solutions flavored with either orange or black cherry Kool-Aid® for separate training groups were selectively associated with NPY injection during single-bottle training sessions. Subsequent two-bottle preference tests showed a significant shift in preference toward the flavor paired with NPY during training. The results of these experiments extend previous findings by showing that NPY can stimulate ingestion of sweet solutions regardless of caloric value and may potentiate sweet taste preference via an associative mechanism.

Centrally administered μ- and δ-opioid agonists increase operant responding for saccharin

In previous reports, ICV administration of selective μ- or δ-opioid receptor agonists was found to stimulate the intake of saccharin and salt solutions in nondeprived rats. In the present study, we measured the effects of selective μ, δ, and κ-agonists on operant responding for saccharin. The selective μ-agonist [D-Ala 2,N-Me-Phe 4,Gly 5- ol]-enkephalin (DAMGO) and the selective δ-agonist [D-Thr 2]-leucine enkephalin-Thr (DTLET) increased responding, whereas the κ-agonist dynorphin A analog κ ligand (DAKLI) had no significant effect. These results agree with previous studies on saccharin and salt intake and are consistent with the possibility that the effects of opioids on the intake of these fluids are mediated via enhancement of activity in brain reward pathways.

Flavor preference produced by intragastric polycose infusions in rats using a concurrent conditioning procedure

Prior studies demonstrate that nondeprived rats learn to prefer a flavor (the CS+) paired with intragastric (IG) nutrient infusions over another flavor (the CS−) paired with IG water infusions when the flavors are presented on alternate days. The present experiment determined if a nutrient-based preference could be established when both flavors were concurrently available. Adult female rats were fitted with two chronic gastric catheters and were given ad lib access to chow and two flavored solutions (a bitter sucrose octaacetate solution and a sour citric acid solution). Using an automated infusion system, consumption of the CS+ flavor was paired with IG infusions of 32% Polycose, and consumption of the CS− flavor was paired with IG infusions of water. Seven of the eight rats tested developed a strong flavor preference for the CS+ over the CS−; their CS+ preference increased from 53% on day 1 to 95% on day 8. (The remaining animal eventually displayed a 97% CS+ preference after it received one-bottle training with the CS flavors.) During the first several days of training, the rats tended to drink primarily one flavor per day, and consumed primarily one flavor per drinking bout. This provided them with relatively discrete flavor-consequence experiences that presumably facilitated flavor preference conditioning.

Potentiation of metaphit-induced audiogenic seizures by REM sleep deprivation in rats

The possibility that REM sleep deprivation (REMD) induces increased susceptibility of rats to the convulsive effects of metaphit was investigated. Metaphit-induced audiogenic seizures were studied in three groups of animals: 1) caged control; 2) large platform animals; and 3) small platform, REMD animals. After 48 h of confinement to their environments the rats from all three groups were injected with metaphit (10 mg kg −1, IP) and the procedures continued for the next 24 h. Immediately after removal from platforms and at 3-h intervals thereafter all rats were individually subjected to intense sound stimulation. Convulsive responses were recorded and analyzed with respect to incidence, intensity, and duration. The REMD rats were found to be more sensitive to the convulsive effects of metaphit compared to nondeprived rats. This was manifested in significantly shorter latencies to seizures, and significantly higher incidence, severity, and duration of seizures, especially of the most severe seizure component—tonic extensor convulsion. Inducing rats to convulse while they were being REM sleep deprived eliminated the REM sleep rebound observed in REMD rats that did not convulse. The occurrence of spontaneous EEG seizures during the undisturbed recovery period reduced REM sleep rebound. The results demonstrate a reciprocal relation between seizure behavior and REM sleep.

The selective 5-HT 3 receptor antagonist, ondansetron, augments the anorectic effect of d-amphetamine in nondeprived rats

Previous behavioural studies have shown that 5-hydroxytryptamine 3 (5-HT 3) receptor antagonists either block or have no effect on amphetamine-induced effects. The present experiments investigated whether or not the highly selective 5-HT 3 receptor antagonist ondansetron would affect the anorectic effect of a small dose (1 mg/kg) of d-amphetamine. Nondeprived male rats were tested in two feeding paradigms: consumption of a palatable sweetened mash and ingestion of a 3% sucrose solution. Ondansetron (10–100 μg/kg) did not antagonize amphetamine-induced anorexia; instead, in both paradigms consumption was reduced still further when the 5-HT 3 antagonist was given in conjunction with amphetamine. Ondanserton given alone has significant effects on consumption, but the direction of the effect differed according to the paradigm. Sweetened mash intake was significantly increased at 30 and 100 μg/kg, while sucrose ingestion was significantly reduced at 10 and 30 μg/kg ondansetron. It is suggested that ondansetron has two opposing effects on intake, one of which (hyperphagia) can be masked by d-amphetamine, leaving an anorectic effect that augments that of d-amphetamine.

Deprivation alters rats' flavor preferences for carbohydrates and fats

The effects of food deprivation on rats' preferences for the flavors of different macronutrients were investigated. To minimize postingestive influences on flavor preferences, brief test sessions (30 min) and calorically dilute (0.08 kcal/g) solutions or suspensions were used. The findings revealed that whereas nondeprived rats preferred sucrose (2%) to hyrolyzed starch (2% Polycose), food-deprived rats strongly preferred Polycose to sucrose. Deprived rats also acquired a preference for a cue flavor paired with Polycose, while nondeprived rats preferred a sucrose-paired cue flavor. Food deprivation also caused rats to switch their preferences from sucrose to corn starch, and from sucrose to corn oil. Food deprivation did not, howeever, alter the rats' preference for Polycose over corn starch, and it blocked, but did not reverse, their preference for Polycose over corn oil. Taken together, the findings indicate that food deprivation enhances the preference for palatable nonsweet nutrients (Polycose, corn starch, corn oil) over a sweet nutrient (sucrose). This effect was specific to food deprivation; water deprivation did not reverse the rats' preference for sucrose to Polycose.

Striatal regulation of morphine-induced hyperphagia: an anatomical mapping study.

Both systemic and intracranial administration of morphine can result in spontaneous feeding in non-deprived rats. The present investigation was conducted to examine the involvement of the striatum in this phenomenon. Morphine sulfate (0, 0.5, 1.0, 5.0, 10.0, and 20.0 micrograms/0.5 microliters) was microinjected into five discrete striatal subregions in non-deprived rats: the nucleus accumbens, the ventromedial striatum, the ventrolateral striatum, the anterior dorsal striatum, and the posterior dorsal striatum. Feeding, drinking, locomotion, rearing, and food intake were measured over 4 h after infusion. Results indicate that the striatum is a heterogeneous structure with regard to the regulation of opiate-induced feeding behavior and locomotor activity. Morphine infusion into anteroventromedial regions including the nucleus accumbens resulted in a marked hyperphagia that was generally delayed in onset; much smaller increases or no change in feeding occurred after administration into more dorsal, lateral and posterior areas. It is hypothesized that there may exist within the striatum an anatomical gradient that is most sensitive to opiate-induced feeding within the anteroventromedial sector. Since this area has extensive connections with other brain sites sensitive to opiate-induced feeding, it may be a critical part of an opiatergic feeding system within the brain. In addition, a possible role for the anteroventromedial striatum in compulsive feeding and bulimia is discussed.