Disruption of diurnal feeding patterns of rats by heroin

Adult male rats receiving 5 or 20 mg/kg heroin HCl by single injections (08:00 or 20:00 hr) or in 3 equal injections (8 hr intervals) showed a disruption in the normal diurnal pattern of behavior. Initially, heroin abolished feeding for several hr after the injection, reduced the total daily food consumption in a dose-related manner, due primarily to decreased night-time feeding, and prevented or slowed weight gain. Subsequent heroin injections led to a phase of vigorous feeding following the period of depression. Magnitude and duration of the depression decreased, but the stimulatory phase of feeding became more pronounced as tolerance developed. Total daily food intake and body weight returned towards control levels, but the proportion eaten during daylight hr became elevated. Sporadic feeding occurred on the first withdrawal day with abolition of the stimulatory phase which had followed each heroin injection. Subsequently, the normal diurnal pattern of behavior gradually returned. Close measurement of 24 hr food consumption may be a sensitive and valuable measure of the disruptive effects of narcotic analgesics.     

Zinc tannate salts of heroin,LAAM and hydromorphone attenuate opiate withdrawal syndrome

The effects of long-acting narcotic agonist preparations on the severe withdrawal syndrome following abrupt cessation of daily injections of codeine phosphate were studied in rats. Twelve hours after the last codeine injections, one injection of either a high or low dose of the zinc tannate salt of heroin, levo-alpha-acetylmethadol (LAAM) or hydromorphone in slow-release vehicle (SRV) was administered. Body weight, core temperature and hyperirritability scores (Teiger, 1974) were recorded every 6 h for the next 3 days. With the exception of the group that received the lower dose of heroin zinc tannate, all drug-treated groups lost significantly less weight than the SRV controls. All rats injected with either LAAM or hydromorphone zinc tannate exhibited prolonged marked hyperthermia, but the low, the high dose heroin groups and the SRV groups showed no significant differences in diurnal temperature patterns. Rats treated with the narcotic agonists were generally less irritable, as indicated by lower Teiger scores. These results indicate that a single injection of heroin, LAAM or hydromorphone zinc tannate can ameliorate the characteristic and intense signs of abstinence following withdrawal from codeine.     

Changes occurring in self administration of nicotine by rats over a 28-day period

After rats at reduced body weight had established responding by lever pressing for nicotine injections under a food delivery schedule (FT60 sec) for 1 hr daily sessions for 14 days, the rate of responding was maintained over a second 14-day period even after removal of the schedule. However, the rate was not maintained by rats lever pressing for normal saline without the schedule over the second 14-day period after self administration had been established for nicotine under the schedule. Other rats maintained at reduced body weight were allowed to lever press for nicotine over a 28-day period without the food delivery schedule. Their rate of self administration increased from initially low levels until at the end of the 28-day period the rate had reached that of rats self administering nicotine adjunctive to the food delivery schedule throughout the same period. Without the schedule, rats at reduced body weight self administering normal saline or rats at normal body weight self administering nicotine, continued to lever press only at very low rates throughout the 28-day period. It is suggested that rats maintain self administration of nicotine if the behavior can be established for a critical intake of nicotine over a critical periodof time. The food delivery schedule appears only to hasten the establishment of the behavior but is not essential for self administration of nicotine by rats.     

A study on drug dependence using fast acting drugs]

Physical dependence on narcotics is induced in laboratory animals by intermittent parenteral administration (2 approximately 3 times daily). However, inducing of dependence on pethidine has been unsuccessful using the parenteral method. Recently, it has been reported that physical dependence on pethidine can be induced by continuous infusion methods (5.6). In the present experiment, pethidine was administered to rats (n=5 approximately 6) by ingestion of pethidine-admixed food preparations (0.5 approximately 4.0 mg/g of feed). The results indicated that (a) when rats are allowed free access to two food preparations (0.5 mg/g vs. 1 mg/g of food) for 7 weeks, spontaneous intake ratios of food (1 mg/g of food) gradually increased from 15% to 30% after 3 weeks. (b) Abrupt withdrawal for 48 hr after a 10 day administration period (2 mg/g of food on day 1 approximately 3 and 4 mg/g of food on day 4 approximately 10) resulted in a loss of body weight in the next 24 hr, and the prewithdrawal level of body weight was recovered in 48 hr. (c) The time course of body weight and food intake during the first 24 hr withdrawal period demonstrated the characteristic pattern of abstinence syndrome of pethidine, viz. early onset (12 approximately 13 hr) and rapid recovery (within 48 hr), as compared to morphine withdrawal. (d) Suppression of pethidine abstinence of both a single injection of morphine (10 mg/kg, s.c.) and substitution for morphine-admixed food was also realized. (e) When levallorphan (5 mg/kg, s.c.) was administered to both pethidine and morphine dependence rats, the maximal decrease in body weight was less than that in morphine dependent rats. These data indicate that pethidine possesses about one fifth the dependence liability of morphine and the maximal abstinence syndrome appears within 24 hr after withdrawal. Conclusively, application of a drug-admixed food preparation in drug dependence tests in rats has proven to be a useful method, particularly in the case of pethidine-like drugs which rapidly disappear from the blood.     

Chronic intermittent heroin produces locomotor sensitization and long-lasting enhancement of conditioned reinforcement

In a previous study we showed that chronic intermittent heroin in rats enhanced responding with conditioned reinforcement and reversal learning of a conditioned magazine approach task when tested three days after the heroin treatment. Whether or not this enhanced appetitive learning persists after a protracted withdrawal period remains unknown and constitutes the aim of the present study. Forty-eight male Long Evans rats were each exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, two groups of rats received saline and two groups received heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. This was followed by testing in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another no stimulus. For one saline and one heroin group this testing occurred after 2 days of withdrawal while for the other saline and heroin groups it occurred after 30 days of withdrawal. The results indicate that animals treated with heroin displayed progressively and significantly greater locomotor activity across sessions while animals treated with saline displayed locomotor activity that remained low and stable across sessions. In addition, the heroin groups in each withdrawal condition displayed significantly enhanced responding with conditioned reinforcement compared to their respective saline control groups. These results demonstrate that chronic intermittent heroin enhances appetitive learning for natural reinforcers and motivational processes and that this effect persists even after 30-days of withdrawal.     

Self administration of nicotine with and without a food delivery schedule

Rats have been shown to self administer a range of narcotic drugs using self injection procedures. However, studies of self administration of nicotine have been less successful in inducing rates of self injection comparable to that with narcotics. In this study different methods of self administration of nicotine by naive rats are evaluated. In the three series of experiments reported, rats self injected nicotine or saline through the jugular vein under normal body weight and reduced body weight conditions and also when the inhections were adjunctive to a food delivery schedule. In a fourth series of experiments, oral intake of nicotine by rats under the condition of a food delivery schedule was investigated. The ratesof self injection of nicotine by rats over a continuous 90 hr session were similar to saline injection rates. At reduced body weight the rate of self injection of nicotine was greater than saline. On a fixed interval 60 sec food delivery schedule for two hr day, the rate of self injection of nicotine was significantly greater than the rate of self injection of saline under the same conditions and also signigicantly greater than that for nicotine injections at reduced body weight without the schedule. The oral intake of nicotine under the same conditions was similar to the intake of nicotine by schedule induced injections. Schedule induced self-injections provide a paradigm for testing drug and environmental interactions.     

Testosterone affects food intake and body weight of weanling male rats

The effects of testosterone propionate (TP) on food intake and body weight were investigated using castrated prepubertal male rats. Regardless of dose (1 mg, 0.2 mg or 0.1 mg), daily injections of TP increased body weight gain and food intake during the prepubertal period (from 22 to 40 days to age). Considering previous results, the present observations suggest that in the male rat sensitivity to the effects of gonadal hormones on feeding develops earlier than in females.     

Effects of repeated administration of serotonergic agonists on diet selection and body weight in rats

Food intake, diet selection and body weight gain were examined in three separate experiments in which rats received saline or one of three serotonergic agonists, dexfenfluramine, RU 24969 and fluoxetine. In all experiments, food was available only in the dark period during which time rats were given simultaneous access to two isoenergetic diets which differed in their protein and carbohydrate content. After habituation to this feeding paradigm and intraperitoneal injections, rats were assigned to control or drug group. Saline or a serotonergic agonist was given to the same rat once daily, 15 min prior to feeding, for six consecutive days. All three agonists (1.5 mg/kg for dexfenfluramine and RU 24969; 3 mg/kg for fluoxetine) caused immediate (first two h of feeding) hypophagia which was accounted for by the selective suppression in intake of the high-carbohydrate-low-protein diet. This selective shift in diet choice was sustained upon repeated exposure. Although the effects of these agonists on daily (12-h) feeding was less pronounced, appetite suppression was due entirely to reduced intake of the high-carbohydrate-low-protein diet. Of the three agonists tested, partial tolerance was observed only after dexfenfluramine. Nevertheless, all three agonists caused comparable declines in weight gain. These results suggest that repeated administration of serotonergic agonists has sustained impacts on food intake, diet choice and weight gain.     

A shift to diurnal feeding following chronic administration of theophylline in rats]

Influence of chronic administration of theophylline on feeding behavior in rats was studied in contrast with the saline controls under a 12 hr light-dark cycle. The results obtained were as follows: 1) total amount of food intake per 24 hr was not affected by either chronic administration of theophylline or saline administration; 2) theophyllinized rats, however, ate more food during light time (0900-2100) and less food during the dark (2100-0900); 3) the amount of food intake during the dark in the control group was approximately 80% of total intake, while that in the theophylline group decreased to below 60%; 4) increase in ratios of body weights in the theophylline and the control groups did not differ significantly throughout the entire experimental period. Feeding behavior of the rat is closely correlated with a daily light-dark cycle as was seen in the control group. The feeding circadian pattern disappeared in theophyllinized rats, i.e., the behavioral characteristic of a nocturnal feeder could not be preserved following theophylline administration. The disappearance of the feeding cycle may result from a phase shift of the cycle, which was induced by facilitatory effects of theophylline on food intake during light time.     

The effects of chronic intraperitoneal administration of the GABA B receptor agonist baclofen on food intake in rats

This study was undertaken to examine the effects of repeated administration of the GABA(B) receptor agonist baclofen on food intake in male Wistar rats. In the 1st Experiment, the effects of daily administration of physiological saline and baclofen (2 mg/kg, i.p.) for 27 days were investigated on food intake and body weight in non-deprived rats (n=6 in each group). Baclofen significantly (P<0.05) increased cumulative food intake each day over the treatment period during the 60 min measurement period following administration. Tolerance did not develop to the short-term hyperphagic effect of baclofen over the course of the experiment. In addition, treatment with baclofen did not alter body weight of the animals over the 27 day treatment period when compared with the saline control rats. In the 2nd Experiment, the effects of acute and chronic administration of baclofen (2 mg/kg) were investigated on 24 h food intake in rats. The rats were injected daily for 21 days with either saline (n=6) or baclofen (n=6). Food intake was measured in 30 min time bins for 24 h on treatment Days 1, 12 and 21 following injection. The results showed that while baclofen produced short-term increases in food consumption following injection on treatment Days 1, 12 and 21, the daily (24 h) food intake of the animals was not significantly different from those of control rats. Thus, these data reveal that while chronic administration of baclofen (2 mg/kg) produces short-term increases in feeding without the development of tolerance, daily (24 h) food consumption is not affected. These findings are consistent with the observation that chronic administration of baclofen (2 mg/kg) had no effect on the body weight of these animals.     

Effects of trimethyltin on homecage behavior of rats

Diurnal patterns of feeding, drinking, locomotor activity, and rearing in male Fischer-344 rats were examined for 2 weeks after a single oral dose of trimethyltin chloride (TMT) at 0, 3, 5, or 7 mg/kg. Body weights and feeding and drinking efficiency ratios (ratios of amount of food or water consumed per unit effort) were also determined daily. TMT caused a dose- and time-related drop in body weight; two of five rats in the 7 mg/kg group were killed moribund on 15 days after dosing. Feed consumption fell to 25% of control within 5 days after 7 mg/kg TMT, and to 50% of control for Days 2 and 3 after 5 mg/kg TMT. Water consumption doubled within 2 days after 7 mg/kg TMT and remained elevated for 2 weeks. Feeding efficiency dropped to 40% of control after 7 mg/kg, but drinking efficiency was unchanged. The diurnal patterns of drinking and of rearing were disrupted at all doses of TMT; a normal peak in rearing activity, occurring immediately prior to light onset, was markedly attenuated after all doses on Day 3, and at 5 and 7 mg/kg on Days 5 and 7 post-TMT. These results suggest (1) that the regulation of feed and water intake is severely compromised after a high dose of TMT, and (2) that the rat's cyclical patterns of homecage behavior are sensitive to TMT doses as low as 3 mg/kg.     

Chronopharmacological study of physical dependence on morphine in rats

Relationship between withdrawal time or naloxone injection time and withdrawal signs were examined in morphine-treated rats. Sixty-five rats were treated chronically with morphine-admixed food (1 mg/g food) for 7 days and were divided into 13 groups. The rats of 4 groups were abruptly withdrawn from morphine, and the rats of another 4 groups were given naloxone (3 mg/kg, s.c.) at 20:00 on the 8 th day and 2:00, 8:00 and 14:00 on the 9 th day after the morphine administration, respectively. Withdrawal signs were observed at intervals of 2 hr. After each naloxone injection, abnormal behaviors were observed for 60 min, and body weight was measured for 3 hr at intervals of 15 or 30 min. In the withdrawal test, weight loss at 24 hr after withdrawal in each group was approximately 10%, and there was no difference between each group. However, the body weight of non-treated rats and morphine-treated rats increased during the night period (20:00-8:00) and decreased during the daytime (8:00-20:00). Therefore, body weight reached the minimum at 20:00, and then this time is appropriated for withdrawal. In the naloxone test, withdrawal signs in the night period were more potent than that in the daytime. The withdrawal signs induced by naloxone at 8:00 showed the maximum magnitude. Plasma morphine levels in rats treated with morphine-admixed food were high in the night period and low in the daytime. These results suggest that the magnitude of naloxone-precipitated withdrawal signs depends on the amount of morphine in the plasma.     

Food intake suppression by histidine

Following injection of histidine (as 1-histidine monohydrochloride, 500 mg/kg, IP) rats showed a suppression of total food intake within the first 2 hours of a 12 hour daily feeding period but not if the rats were adapted to a 4 hour daily feeding period. Furthermore, rats adapted to a nocturnal as compared to a diurnal 12 hour feeding period showed a greater response (50% vs. 20% suppression of feeding) to histidine. Overall, within an experiment, food intake suppression correlated with the histidine dose (0, 125, 250, 375 and 500 mg/kg; for mean response r(3) = 0.90, p less than 0.05) although the lowest dose measured to be effective in a cross-over design experiment was 375 mg/kg. No differential effect upon protein or carbohydrate intake was observed in any of the studies. The effects of injections of 250 and 500 mg/kg histidine on food intake were associated with significant elevations of brain histidine and histamine. We conclude that histidine, possibly by changes in brain histidine, influences total food intake but not macronutrient selection.     

Changes in meal patterns and endogenous chemical determinants related to food intake following intra-ventricle III infusion of mazindol

To clarify suppressive effects of mazindol on food intake in rats, changes in body weight, meal patterns as well as 24-hr food intake, and endogenous chemical substances were investigated following the intra-ventricle III infusion of 0.03 mumole mazindol. Experiments were carried out under the condition of a 12: 12 light-dark cycle (light: 0800-2000 hr). Mazindol decreased food intake as well as body weight after a 12 hr starvation. Reduced food consumption was observed during 12 hr following the injection. Weight reduction, however, lasted over all 3-tested days. When food was available ad. lib., mazindol decreased meal size during the 4 hr after injection and prolonged postprandial intermeal interval during the 4 hr period starting 2 hr after the injection. The infusion of mazindol also produced relative hyperglycemia and decreased free fatty acids, which was not accompanied with hyperinsulinemia. These findings, together with other reports, indicates that mazindol, unlike amphetamine and fenfluramine, possesses inhibitory actions on the hypothalamic feeding center.     

Imparied thermal regulation in juvenile rats following perinatal methadone exposure.

Offspring of female rats injected daily with methadone (5 mg/kg) or saline were cross-fostered at birth to form groups exposed to methadone during gestation (G), lactation (L), or gestation and lactation (G-L); controls (C) were exposed only to saline. Rectal temperature, body weight and food consumption were measured from postnatal Days 36-51. Ambient temperature was maintained at 21 degrees C except for Days 42--45, when the temperature was 10 degrees C. Group G rats never differed from controls, but offspring in Groups L and G-L were hypothermic at room temperature; Group G-L rats exhibited a further temperature loss during the cold stress. There were no group differences in food consumption after Day 39, and all groups increased food intake while in the cold. Group differences in body weight were not reliable but Group G-L rats gained less weight than the rest during the experiment, whereas Group L rats gained more. These results indicate that, depending upon treatment schedule, perinatal methadone exposure is associated with hypothermia during the postweaning period. A prolonged withdrawal reaction from methadone may account for the impaired thermal regulation.     

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.     

Long-term effects of high doses of nicotine on feeding behavior and brain nitric oxide synthase activity in female mice

We studied the long-term effects of repeated doses of nicotine, causing dependence, 120 days after its withdrawal on feeding behavior and on brain nitric oxide (NO) formation in female mice. Nicotine dependence was induced by subcutaneous (s.c.) nicotine injection (2 mg/kg, four injections daily) for 14 days. Daily food intake was evaluated for the entire observational period (120 days). Moreover, 30, 60, and 120 days after nicotine withdrawal, we evaluated food intake, nitrite/nitrate levels, and nitric oxide synthase (NOS) activity and expression in the hypothalamus after food deprivation (24 h). In animals in which nicotine dependence was induced (NM), daily food intake was similar to that of controls (M). However, following food deprivation, NM mice showed i) a significant increase in food intake, ii) changes in weight gain and in hypothalamic nitrite/nitrate levels, and iii) enhancement of hypothalamic neuronal NOS (nNOS) activity. Results indicate that high doses of nicotine producing dependence induce long-term changes in feeding behavior consequent to food deprivation associated to alterations in the brain nitrergic system.     

Effects of methylphenidate on food and water consumption at different body weights.

The effects of intraperitoneally administered methylphenidate at 0, 1.5, 3.0, 6.0, and 12.0 mg/kg were studied in two experiments. Experiment 1 determined the effects of methylphenidate on 0.5, 1.0, 2.0, and 24 hr post injection food and water consumption in rats at ad lib feeding body weights. Experiment 2 determined the post injection effects of methylphenidate on 0.5, 1.0 and 2.0 hr food and water and 24 hr water consumption in rats maintained at 80% ad lib feeding body weight due to partial food deprivation. The results of Experiment 1 indicate that when animals are feeding ad lib at normal body weight food and water consumption is decreased for 2 hr following the administration of the lowest 1.5 mg/kg dose of methylphenidate. Methylphenidate in doses as high as 12.0 mg/kg has no effect on 24 hr food and water consumption under these conditions. The results of Experiment 2 indicate that when animals are maintained at reduced body weight due to partial food deprivation, food consumption for 2 hr is significantly decreased by the highest, 12.0 mg/kg, dose of methylphenidate. These effects are observed within the first 30 min post injection when methylphenidate decreases food consumption in a dose dependent manner. Methylphenidate has no effect on water consumption under these conditions. The effects of methylphenidate on ingestive behavior are discussed in terms of previous experiments and the possible differential effects on motor activity at different body weights under different stimulus conditions.     

Prolactin and growth hormone stimulate food intake in ring doves

Ingestive behavior and body weight were measured in male and female ring doves given twice daily subcutaneous injections of ovine prolactin (7 mg/kg/day) or vehicle and in male doves given daily intracerebroventricular (ICV) injections of ovine prolactin at doses ranging from 0.1 to 2.0 micrograms/day. Changes induced by ICV administration of turkey prolactin, turkey growth hormone, ovine growth hormone, human growth hormone, and vehicle were also examined. Subcutaneous injections of ovine prolactin markedly increased food intake and body weight in both sexes. Similar effects occurred in dose-related fashion in male doves given ICV injections of ovine prolactin. The three growth hormone preparations also increased feeding and body weight significantly, but turkey prolactin was ineffective in this regard. Changes in drinking generally paralleled feeding patterns but were less pronounced and may have been secondary to feeding changes. We conclude that feeding in this species is strongly stimulated by some prolactin and growth hormone preparations. However, the physiological mechanisms underlying these effects remain to be clarified.     

Comparison of development of drug dependence in naive and drug dependence-experienced rats]

Phenobarbital, chordiazepoxide, diazepam and/or morphine were repeatedly administered to both male and female rats (N equals 10) for 4 similar to 6 weeks. The drug dose was gradully increased from 5 to 10, 20, 40, 80 and 160 mg/kg once daily (p.o) at seven day intervals. In the case of morphine, the last dose was 40 mg/kg. The drugs were constantly withdrawn for 24 hr at 8 day intervvals. None of the rats were given drugs for 16 days after administration of the last scheduled dose in order to recover their initial weight (Exp. I). Onset of dependence formation, decrease in body weight and food intake, days required to reach the maximum decrease in body weight and duration of withdrawal signs were observed throughout this experiment. The rats (drug dependence-experimented rats) who survived the first stage of this experiment were continuously subjected to re-administration by the same dosage schedule as in Exp. I (seven days of drug administration, 48hr of withdrawal). The re-administered rats showed a more rapid onset of dependence formation and a longer duration of decreas in boy weight during 16 days withdrawal than did the naive rats. It is concluded, that in addition to the decrease in body weight by withdrawal plus duration of the withdrawal signs, the onset of drug dependence formation is also a specific factor.