Effect of clonidine on consummatory negative contrast and on novelty-induced stress

In Experiments 1 and 1a rats were shifted from 32% to 4% sucrose solutions. The resultant negative contrast effect in consummatory behavior was not alleviated by clonidine (3.12, 6.25, 12.5, 25.0 and 50.0 micrograms/kg). The lower dose of the drug had no effect on behavior, the higher doses reduced consumption in shifted and unshifted rats in a dose dependent fashion. In Experiment 2 clonidine (6.25, 12.5 micrograms/kg) raised plasma glucose levels in a dose dependent fashion when the animals were exposed to a novel environment. These results are at variance with those obtained with chlordiazepoxide (and other anxiolytics in the case of contrast effects) and suggest limits on the degree to which clonidine can be considered to function as an anxiolytic.     

Activation of the immune system in rats with lipopolysaccharide reduces voluntary sucrose intake but not intraoral intake

Traditional intake measures of voluntary consumption of food or fluid from a specific location involve both appetitive and consummatory behaviors. Appetitive behaviors are food finding behaviors displayed by an animal prior to the consumption of the food, whereas consummatory behaviors are the behaviors involved in the actual consumption of the food. Intraoral intake of a fluid can be measured by directly infusing it into the oral cavity of an animal and quantifying the consummatory behaviors. The present study compared the effects of immune activation (lipopolysaccharide, LPS) and toxin (lithium chloride, LiCl)-induced changes on both a traditional intake measure (bottle drinking) and an intraoral intake measure. In Experiment 1, rats were injected intraperitoneally with LPS (200 microg/kg), LiCl (0.15 M, 20 ml/kg) or NaCl vehicle, and voluntary sucrose (0.3 M) intake was monitored for 1 h from a graduated drinking tube. Voluntary intake was again assessed on a second test day, 72 h later under the same conditions. In Experiment 2, a continuous intraoral infusion of sucrose (0.3 M) was given via intraoral cannulae following systemic injections of LPS, LiCl or NaCl vehicle on two different test days, 72 h apart. Rats injected with LiCl displayed reduced sucrose intake on both the voluntary intake measure and the intraoral intake measure relative to controls (P's<.05). The reduced intake observed was of greater magnitude on the second test day of both experiments, consistent with conditioning effects. In contrast, LPS reduced sucrose intake only when assessed with the traditional intake measure. Intraoral sucrose intake remained unchanged relative to controls. The present results provide further evidence that activation of the immune system has adverse effects on the appetitive phase of ingestion, whereas the consummatory aspects are unaffected.     

The effect of systemic administration of baclofen on food intake in rats.

The effects of systemic administration of the GABAB agonist, baclofen was investigated on food intake in non-fasted rats. Baclofen (1.0, 2.0 and 4.0 mg/kg, s.c.) produced a dose-related increase in food intake in a free-feeding paradigm during the first 90 min after administration, with maximum increases occurring at a dose of 2 mg/kg (Experiment 1). Baclofen (0.5 and 1.0 mg/kg, s.c.) also increased food intake in the 40 min post-drug recording period in non-fasted rats, trained to make operant responses for food on a fixed-ratio schedule (Experiment 2). These results demonstrate that systemic administration of baclofen can stimulate ingestive behaviour in satiated rats and suggest a possible role for a GABAB receptor-mediated mechanism in the control of food intake.     

Effect of serotonergic drugs on negative contrast in consummatory behavior

The effect of acute and chronic administration of the 5-HT1A agonist buspirone on successive negative contrast was investigated in Experiments 1-6. Contrast in consummatory behavior was induced by shifting rats from a 32% to a 4% sucrose solution. Experiments 1-5 showed that buspirone (0.125, 0.25, 0.5, 1.0, 2.0, 15.0 mg/kg) was ineffective in alleviating contrast or in facilitating recovery from contrast. The 15 mg/kg dose substantially decreased consummatory responding. Experiment 6 showed that the chronic (24 days) administration of buspirone (0.5, 2.0 mg/kg) also did not alleviate contrast. The chronic, but not the acute administration of the 2.0 mg/kg dose decreased consummatory behavior. In Experiment 7 the 5-HT1A agonist gepirone (2.5, 5.0 and 10.0 mg/kg) was also found to be ineffective in reducing contrast but, at the higher doses, decreased overall sucrose intake. Experiments 8 and 9 found that the 5-HT2 antagonists ketanserin (2.0 and 8.0 mg/kg) and ritanserin (0.63 and 2.5 mg/kg) also did not alleviate contrast. Midazolam (1.0 mg/kg), included as a positive control, eliminated contrast. These data suggest that serotonergic mechanisms are not involved in negative contrast.     

Differential effects of chronic naltrexone treatment on food intake patterns and body weight in rats depend on their food deprivation status

The aim of the present study was to assess the effect of chronic naltrexone treatment on daily patterns of food intake in food-deprived and free-feeding rats. In experiment 1, Wistar male rats had continuous access to food and water, while in experiment 2 they were deprived of food for 12 h/day. Animals in both experiments were studied as follows: a baseline period (7 days), followed by a treatment period (14 days) with either saline or naltrexone at 10 mg/kg/day. Finally, a post-treatment period (7 days) was assessed. Food and water consumption were measured every 2 h after the naltrexone or saline injection for 12 h and once more 12 h later. Experiment 1: Food intake was higher in the naltrexone group 10 h after injection. Total food intake and body weight gain were higher in the naltrexone group than in the saline group in the second week of treatment and in the post-treatment period. Experiment 2: The overeating observed in the saline group in the hours following the 12 h of the food deprivation period was suppressed by naltrexone, though total daily food intake was not affected. Body weight gain was initially reduced by naltrexone, but a rebound effect was observed during the post-treatment period in the naltrexone group. Naltrexone produced a differential effect on food intake and body weight that depended on the rats' food deprivation status. These results could be explained in terms of opioid receptor up-regulation that enhances the rewarding effects of food or by naltrexone-produced changes in palatability.     

Effects of angiotensin II and an angiotensin converting enzyme inhibitor on alcohol intake in P and NP rats.

While it is known that randomly bred normotensive Wistar stock and hypertensive rats alter their alcohol consumption when activity in the renin-angiotensin (R-A) system is modified, the effect of manipulations to the R-A system on alcohol intake in genetically selected alcohol-preferring P and -nonpreferring NP rats has not been assessed. In Experiment 1, nine P rats and 8 NP rats were injected with the saline vehicle and offered limited access to 10% (v/v) alcohol for 40 min each day for 7 days. When intake stabilized both groups were given daily intraperitoneal injections of the angiotensin converting enzyme inhibitor, ceranapril (20 mg/kg) 45 min prior to alcohol access for 11 days. Ceranapril (SQ 29,852) reduced alcohol intake in both the P and NP animals, while saline had no effect. In Experiment 2, these same two groups of P and NP rats were injected with three doses of angiotensin II (ANG II) (100, 200, 400 micrograms/kg) immediately prior to alcohol access. Each dose was tested for 10 consecutive days, with a 14-day period of no drug preceding and following the ANG II treatments. ANG II reduced alcohol intake in the NP rats and produced a dose-dependent reduction in the alcohol consumption of the P rats. These findings indicate that the renin-angiotensin system can modify alcohol consumption in rats selectively bred for high and low alcohol intake.     

The induction of oral ethanol self-administration by contingent ethanol delivery

The necessity of delivering a highly reinforcing stimulus (20% sucrose) contingent upon ethanol consumption in order to induce ethanol self-administration in free-feeding rats was investigated. Rats water deprived for 12-16 h were placed in an environment in which ethanol drinking resulted in the presentation of ethanol. This procedure was successful in inducing and maintaining ethanol self-administration over concentrations of 5-20% (v/v). Compared to a group of rats initially reinforced for drinking ethanol with sucrose presentation, contingent ethanol delivery resulted in greater ethanol self-administration behavior. When 20% ethanol was available the group trained with ethanol had average intake of 0.91 g/kg, whereas the group trained with sucrose had a mean intake of 0.69 g/kg in a 30-min session. The results suggest that ethanol's reinforcing properties are sufficient to establish ethanol self-administration within the context of the inducing environment.     

Enhanced amphetamine anorexia, but not drinking suppression in obese Zucker rats

The effects of d-amphetamine on ad libitum consummatory behavior of genetically obese Zucker rats and their lean littermates were examined in two experiments. In Experiment 1 food intake was measured every two hours for six hours following intraperitoneal injections of 0.0, 0.5, and 1.0 mg/kg of d-amphetamine sulfate. Both lean and obese animals significantly suppressed food intake for the first two hours after injection of 0.5 and 1.0 mg/kg doses. Lean animals displayed no suppression of food intake at four or six hours after injection. In contrast to lean animals, obese rats continued to show a suppression of feeding at four hours after injection of 1.0 mg/kg. Total six-hour food intake of obese animals was significantly suppressed from baseline after 0.5 and 1.0 mg/kg of amphetamine, but only after the 1.0 mg/kg injection with lean animals. Experiment 2 examined the effects of these same doses on both food and water intake of different groups of obese and lean Zucker rats. The enhanced anorexia with the 1.0 mg/kg injection of amphetamine was replicated. Water intake, however, was suppressed only during the first two hours after both the 0.5 and 1.0 mg/kg injection in obese and lean rats. Results of the present experiments are discussed in light of previous studies of the effects of amphetamine on hypothalamically obese animals.     

Sedation and need-free salt intake in rats treated with clonidine

The effect of intraperitoneal injection of clonidine (9-72 microg/kg) on need-free 1.5% NaCl intake and on performance (defined as percent of a complete trial) in the rotarod test, was studied in normovolemic adult male rats. Clonidine (18 and 36 microg/kg) inhibited the 1.5% NaCl intake in a 2-h test at doses that did not alter the performance in the rotarod test. The dose of 36 microg/kg did not inhibit 10% sucrose intake. Only the highest dose (72 microg/kg) of clonidine inhibited the 1.5% NaCl intake and the performance in the rotarod test, and produced signs of sedation. Sedation was determined either by change in posture (immobility or lack of postural tonus) of the animals during the ingestive test or by their performance in the rotarod test. The results suggest that sedation is not a determinant effect on the inhibition of 1.5% NaCl intake induced by clonidine.     

Level of operant training rather than cocaine intake predicts level of reinstatement

Rationale Extended cocaine self-administration has been shown to potentiate reinstatement. This increased vulnerability to relapse could be attributed not only to extended cocaine exposure but also to extended operant training. Objective This study was aimed at determining the influence of different operant training histories on cocaine-induced reinstatement when cocaine intake is kept constant. Materials and methods Cocaine intake and operant training were dissociated by using experimental procedures generating different histories of operant training but almost identical histories of cocaine intake. Rats were first trained to self-administer cocaine at a classical unit dose (250 μg/inf, FR1), then in independent groups, the level of operant response was changed for the next 20 sessions by changing either the unit dose available (83, 250, or 750 μg/inf, Experiment 1) or the fixed ratio required (FR-1, FR-3, or FR-10, Experiment 2). Then, all rats were tested for reinstatement with different priming doses of cocaine (0, 5, 10, and 15 mg/kg; i.p.) at an early and late stage of an extinction period. Results Level of responding during training predicts the level of reinstatement later on, independently of the amount of cocaine consumed. High FR requirement and low unit dose access led to higher level of reinstatement at early and late stage of the extinction period, respectively. Conclusions This study shows that the level of operant responding required to maintain optimal cocaine intake directly influences later levels of reinstatement. This finding suggests that environmental constrains that make drug-taking demanding and effortful may increase the vulnerability to relapse.     

Opiatergic modulation of preparatory and consummatory components of feeding and drinking

We present data here indicating that stimulation of kappa but not mu opiate receptors influences motivational and consummatory aspects of feeding and drinking. To differentiate mu and kappa mechanisms controlling preparatory (appetitive) and consummatory components of ingestive behavior, the effects of morphine (MORPH), compound U50488H (U50) and naloxone (NAL) were studied in rats trained to negotiate a straight runway using food or water as a reinforcer. At doses that increase feeding and drinking in conditions of free access to food and water (i.e., 1-2 mg/kg IP), MORPH affected neither food- nor water-maintained runway performance. Since 1 mg/kg of NAL is also devoid of effects, mu-opiate mechanisms are probably not involved in food- or water-maintained behavior. Pharmacological manipulation of kappa-opiate mechanisms had complex effects. At 5 mg/kg, NAL accelerated satiation, depressing food intake, without affecting running. U50 did not increase food intake, but accelerated running for food, an effect that was antagonized by a high dose of NAL (5 mg/kg). These findings suggest that motivational and consummatory components of food-maintained runway performance are both activated by kappa-opiate mechanisms. NAL also reduced water intake but had minimal influences on running. In contrast, U50 depressed both water intake and runway performance; rather than being antagonized, these effects were slightly enhanced by NAL. The combined antidipsic and diuretic effects of U50 suggest that kappa-opiate mechanisms play a dissipatory role in water balance. However, the similar antidipsic effects of U50 and NAL, and the fact that NAL did not antagonize the antidipsic effects of U50, suggest that U50 may reduce drinking by mechanisms other than kappa-opiate agonism.     

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.     

Effect of pimozide on home cage ethanol drinking in the rat: dependence on drinking session length

A stimulus-fading procedure was used to initiate ethanol drinking in free-feeding Long Evans rats. During daily half-hour drinking sessions in the home cage, a combination of sucrose and ethanol was first presented to the rats; gradually the sucrose concentration was reduced and the ethanol concentration increased until after 7 weeks the rats were drinking 10% ethanol with no sucrose. After stabilization of intake, either pimozide (PIM, 0.25, 0.50 and 1.00 mg/kg) was injected 4 h before drinking sessions or (d)-amphetamine (DEX, 0.25 and 0.50 mg/kg) was injected 15 min before sessions. The 0.50 and 1.00 mg/kg PIM doses and the 0.50 DEX dose significantly reduced intake compared to vehicle injections. In the second part of the experiment, the rats were given 24-h access to 10% ethanol and water in a two-bottle choice procedure. In this condition, 0.50 mg/kg PIM failed to reduce intake compared to vehicle. The critical difference between the two procedures seems to be that with the 30-min sessions, PIM injections were timed to have their maximal effect during testing. With 24-h sessions, decreases in intake produced by PIM could have been compensated for by increases after the drug had worn off. The hypothesis that dopamine is necessary for ethanol reinforcement receives support from the PIM effect on the 30-min sessions. The DEX effect extends the generality of our previous finding that DEX reduces ethanol-reinforced lever pressing in free-feeding rats.     

Effects of clonidine and guanfacine on drinking and ambulation in spontaneously hypertensive rats

Present experiment was undertaken to compare the effects of clonidine and guanfacine on water drinking behavior and ambulatory activity in spontaneously hypertensive rats (SHR). Equipotent hypotensive doses of clonidine and guanfacine, 150 micrograms/kg and 1500 micrograms/kg, respectively, given twice a day at 8:00 and 20:00, produced a triphasic pattern of behavioral changes; initial increase in water drinking and ambulation during the light period, decrease in water intake and ambulation at the beginning of the dark period, and a second increase in water drinking and ambulation at the end of the dark period. Guanfacine treated SHR showed less change in water drinking behavior and ambulation than the clonidine treated SHR.     

Satietin: route of injection, dose response, effect on food and water intake and on running-wheel activity in the rat

Semipurified satietin significantly (p less than 0.05) reduced food intake when injected subcutaneously at 10, 15, 20 mg/kg into 48 hr fasted rats with no indication of a dose response. When infused intracerebroventricularly (ICV) at 12.5, 25 and 50 micrograms/rat (10 microliter vol) into ad lib fed rats at the end of the light period there was no effect on food intake for the first hour but 24 hr food intake was (p less than 0.001) reduced at all doses. The ICV dose response curve was shallow, with similar suppression at both 12.5 and 25 micrograms doses, but a (p less than 0.05) greater suppression with the 50 micrograms dose. An ICV threshold between 6.25 micrograms and 12.5 micrograms appears to exist since no suppression occurred after a dose of 6.25 micrograms. Four consecutive daily ICV infusions of satietin (25 micrograms/rat) in two rats progressively suppressed food intake to low levels, suggesting a cumulative effect. Following termination of satietin treatment daily food intake slowly returned towards normal without evidence of rebound feeding. In other ad lib fed rats, four ICV infusions of semipurified satietin, on days alternated with no infusion, reduced food intake (p less than 0.001), water intake (p less than 0.003) and running wheel activity (p less than 0.001) on the first day of injection but not on subsequent injection days. Suppression of activity approached significance on the second injection day. Highly purified satietin infused ICV produced similar responses. These findings may indicate a general disruption of behavior by satietin, thus, it may not play a physiological role in feeding behavior because of its apparent non-specificity.     

Serotonergic influences on food intake: effect of 5-hydroxytryptophan on parameters of feeding behaviour in deprived and free-feeding rats.

Three experiments were carried out to examine the effect of the serotonin precursor, 5-hydroxytryptophan, upon food intake and the micro-structure of eating in deprived rats, and on the pattern of meal taking in free-feeding animals. The study also investigated the capacity of a peripheral decarboxylase inhibitor (MK-486) to antagonise the effect of 5-HTP in order to identify a central or peripheral mode of action. In deprived rats 5-HTP brought about a dose related inhibition of food intake which was midly antagonised by MK-486. A detailed analysis of the behavioural changes occurring during eating showed that the inhibition of food intake by 5-HTP was reflected in a reduced number of eating bouts and a slower rate of eating. MK-486 did not antagonise the effect of 5-HTP on eating rate. In free-feeding rats whose food comsumption was continuously monitored for 24-hr periods, 5-HTP gave rise to reduction in meal size and a slowing of the intra-meal rate of eating. These findings are in keeping with the effects of other serotonergic manipulations on the patterns of feeding in rats.     

Ethanol intake as a function of concentration during food deprivation and satiation

Ethanol intake and responding of 6 male albino rats were measured at concentrations of 0 (water control) 2, 4, 8, 16, and 32% (W/V) during daily 1-hr sessions in operant conditioning chambers. The rats were run first food deprived (80% of free-feeding weight) and then food satiated (free access to food in home cages). Ethanol intake was greater when the rats were food deprived, but under both food conditions: (1) ethanol intake exceeded that of water at all concentrations, (2) quantity (mg) consumed increased with the concentration, and (3) the highest rate of responding occured at the beginning of the session. In a second experiment, fixed-ratio responding maintained by contingent presentation of 32% (W/V) ethanol exceeded water control responding. This finding strengthened the conclusion that this concentration can serve as a reinforcer for the food-satiated rat.     

Characterization of the enhanced responsiveness to postingestive satiety signals in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated Han/Wistar rats.

Previous studies have shown that under free-feeding conditions, TCDD-treated Han/Wistar (H/W) rats consume less sucrose solution but ingest more saccharin solution than their controls thus implying hyperresponsiveness to postingestive satiety signals. In this study, nutrient preloads were employed to further elucidate this phenomenon. Male H/W rats were given a single high but usually non-lethal intraperitoneal dose (1000 micrograms/kg) of TCDD. Feed intake was stimulated by 24 hr feed deprivation at various time points after TCDD exposure. When TCDD-dosed rats were allowed to drink either a 20% sucrose or a 0.25% saccharin solution and then given access to feed, those that had had sucrose ate only about 50% of the amount consumed by the saccharin group. Although the preloads were similar in control rats, no such difference in subsequent feeding occurred. The sucrose solution also produced a longer-lasting suppression of feed intake in TCDD-treated compared with control rats when infused directly into the stomach. By contrast, TCDD-treated H/W rats failed to exhibit an augmented satiety response to parenterally applied glucose independent of testing time. Oral corn oil reduced feed intake in both control and TCDD-exposed rats, but the inhibition was slightly larger in TCDD-treated animals. TCDD did not markedly affect the responsiveness of H/W rats to the suppression of feeding by CCK-8 or bombesin. It is concluded that gastrointestinal factors appear critical to the exaggerated response of TCDD-treated H/W rats to nutrient energy.     

Evidence for zolpidem-induced hyperphagia, but not anxiolysis, in a successive negative contrast paradigm

Zolpidem is an imidazopyridine which binds to certain benzodiazepine receptor types with varying degrees of affinity. The effect of zolpidem on successive negative contrast was investigated in three experiments. In each experiment, a contrast group was given brief access to 32% sucrose for 10 days, then shifted to 4% sucrose for 2 days; a procedure that elicits anxiety primarily on the second postshift day. One control group was given only 4% sucrose. Experiments 2 and 3 included a 2% sucrose group as an intake rate-dependent control. In Experiment 1, zolpidem (4.0 and 0.5 mg/kg) dose-dependently reduced contrast on the two postshift days. Contrast occurred during the first postshift consummatory burst. Zolpidem prolonged the first postshift burst equally in both shifted and unshifted groups, suggesting a general facilitation of intake masked by a ceiling effect in controls. In Experiment 2, zolpidem's (4.0 mg/kg) anti-contrast action was equivalent to its hyperphagic effect in the 2% control group. Zolpidem prolonged the first postshift burst equally in all three groups, again consistent with general intake facilitation. In Experiment 3, 8.0 mg/kg zolpidem produced an anti-contrast effect not present in 2% controls on both postshift days. This does not appear attributable to anxiolysis, however, as the effect was equivalent during stressful and non-stressful phases of the postshift period, and zolpidem extended the duration of the first postshift burst equally in all three sucrose groups. Thus, unlike benzodiazepines, zolpidem is not anxiolytic in this paradigm.     

Effects of naloxone and its quaternary form on fluid consumption in rats

Three studies were performed on albino rats to determine the effects of naloxone and its quaternary derivative, naloxone methylbromide, on fluid consumption. The doses of the quaternary naloxone were equated with naloxone by molarity and effectiveness in order to facilitate direct comparisons. All rats were deprived of food and water for 12 hr and exposed to a 20% sucrose solution for a 2 hr period. In Experiment 1, a low (0.01 mg/kg) dose of naloxone or an equated dose of quaternary naloxone was given ICV and immediate access allowed to the fluid on four consecutive days. Animals receiving naloxone were not significantly different from controls, and rats receiving quaternary naloxone exhibited seizures, resulting in decreased consumption. In Experiment 2, the low dose of naloxone or the equated dose of quaternary naloxone was given IP for four consecutive days and neither was significantly different from controls. In Experiment 3, animals were given an IP dose of either 1 mg/kg naloxone, a 1 mg/kg or 50 mg/kg dose of quaternary naloxone, or saline and tested for a single 2 hr period. The doses of 1 mg/kg naloxone and 50 mg/kg quaternary naloxone produced significantly less drinking than controls. In all studies, the initial 30 min period produced the most drinking. Suppression of drinking by a dose of 50 mg/kg quaternary naloxone suggested, in contrast to other studies, that it may cross the blood-brain barrier at high doses.