Naloxone antagonism of diazepam-induced feeding in the Syrian hamster

Three experiments investigated the effects of the intragastric administration of the benzodiazepine diazepam on feeding in non-deprived Syrian hamsters ($\text{mesocricetus auratus}$). In the first experiment diazepam (0, 0.5, 1.0, 2.0, and 4.0 mg/kg) produced dose dependant increases in feeding. 4.0 mg/kg of diazepam produced significantly more feeding than the other doses tested and the lowest dose tested (0.5 mg/kg) produced a significant increase in feeding. In the second experiment naloxone (10 mg/kg) partially antagonized the effect of 4 mg/kg of diazepam on feeding. In the third experiment the ability of naloxone (0.1, 1.0, 5.0, 10.0 or 20 mg/kg) to reduce feeding produced by either 4 mg/kg or 2 mg/kg of diazepam was tested. Naloxone partially antagonized the effects of 4 mg/kg of diazepam on feeding in a dose dependant manner. While 2 mg/kg of diazepam produced significantly less feeding than 4 mg/kg, naloxone did not antagonize the effect of 2 mg/kg on feeding. The results suggest that two mechanisms are involved in diazepam-induced feeding in hamsters. The high dose of diazepam may produce increased feeding by activating the endorphin system while the low dose of diazepam produces increased feeding via a naloxone insensitive mechanism.     

The effect of epinephrine on feeding and motion patterns in goldfish Carassius auratus (L.)

The effect of intraperitoneal injections of epinephrine (0.14 and 0.70 mg/kg) on some characteristics of feeding activity (ration and total time of feeding) as well as on motion patterns (time of swimming in group and separately) in juvenile goldfish has been investigated. Two-phase (short-term decrease in the first phase, increase in the second one) feeding response under both doses of epinephrine has been revealed. More pronounced effect of epinephrine at the dose of 0.14 mg/kg on the ration and time of feeding (comparing to the dose of 0.70 mg/kg and Ringer injection) was observed in the second phase. Furthermore, significant decrease of time of "separated" swimming in the first phase under both doses of the hormone is revealed. The hyperglycemic response induced by the injections of epinephrine, with synchronous reduction of the concentration of glycogen in hepatopancreas allows to suggest that glycogen-phosphorylase activating mechanism was underlying the "first-phase" change of feeding reactions of goldfish.     

甘露寡糖对异育银鲫生长性能、免疫及HSP70基因表达的影响

为探讨甘露寡糖(MOS)对异育银鲫生长、免疫、肠道组织结构及抗病力的影响,试验选取360尾异育银鲫[初均重(16.19±0.03)g],随机分成5组、每组3个重复,在日粮中添加不同浓度甘露寡糖(0、60、120、240、480 mg/kg),连续投喂80d,并于第80天时进行嗜水气单胞菌感染,测定异育银鲫生长、免疫、肠道结构等指标及异育银鲫抗嗜水气单胞菌感染的能力。试验结果表明,无论投喂50d,还是80d,甘露寡糖对鱼体的生长指标(特定生长率、增重率、蛋白质效率、饵料系数)均没有显著影响(P>0.05);投喂50d,与对照组比,甘露寡糖能显著提高血清球蛋白浓度(P<0.05);投喂80d后,与对照组比,240、480 mg/kg甘露寡糖组能显著提高碱性磷酸酶活性,甘露寡糖组能显著提高血清球蛋白浓度(P<0.05),480 mg/kg甘露寡糖组能显著提高血清总抗氧化能力,120、240 mg/kg甘露寡糖组能显著提高肠褶皱襞长(P<0.05),对皱襞间质宽、黏膜下层宽没有显著影响(P>0.05),肌层宽随着MOS的添加有增加趋势(P>0.05);嗜水气单胞菌感染后,与对照组比,240、480 mg/kg甘露寡糖组成活率提高了22.6%,免疫保护率达45.4%。日粮中添加甘露寡糖组对鱼体肝脏HSP70基因表达没有显著影响(P>0.05)。因此,添加240、480 mg/kg甘露寡糖能提高鱼体的免疫能力,增强鱼体抗病原菌感染能力。     

Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin

A new antagonist of the peripheral cholecystokinin receptor, L-364,718, was found to block the reductions in food intake and exploratory activity induced by intraperitoneal administration of cholecystokinin octapeptide sulfate. L-364,718 significantly reversed the cholecystokinin-induced reduction in feeding at doses of 10 micrograms/kg - 10 mg/kg i.p. L-364,718 significantly reversed the cholecystokinin-induced reduction in exploratory activity at doses of 500 ng/kg - 10 mg/kg i.p. The time course of antagonist activity of L-364,718 was immediate to 90 minutes after intraperitoneal administration. L-364,718 had no significant effect on food intake or exploratory activity when administered alone, over the dose range of 100 ng/kg-10 mg/kg i.p. This compound appears to be at least one hundred times more potent than proglumide or benzotript as an antagonist of the behavioral effects of peripherally administered cholecystokinin.     

Gametocytocidal and sporontocidal effects of antimalarial drugs on malaria parasites. I. Effect of single and multiple doses of primaquine on Plasmodium cynomolgi

A study was undertaken to determine the gametocytocidal and sporontocidal activity of primaquine against blood-induced Plasmodium cynomolgi infections in seven rhesus monkeys (Macaca mulatta). Infected animals were treated orally with single (1.95 mg/kg primaquine base) or multiple doses of primaquine (0.65 mg/kg/day × 5 primaquine base). The effect of the drug on the sporogonic stages of the parasite was observed in Anopheles maculatus mosquitoes fed at appropriate intervals before and after treatment began. Mosquitoes were also fed on control untreated monkeys on a parallel feeding schedule. The results indicated that primaquine given in the above doses exerted a marked sporontocidal activity within 4 hr after initial medication whereas its gametocytocidal effect first became obvious 2–3 days later. Single doses of primaquine were less effective as compared to multiple doses in the sense that full mosquito infectivity was restored as early as 3 days after single dosage treatment. Primaquine (as base) given in much smaller amounts (0.08 mg/kg/day × 5 or 0.24 mg/kg × 1) acted exclusively as a sporontocidal agent. The sporontocidal action of primaquine was very rapid. Its gametocytocidal effect was less apparent.     

Naloxone reduction of stress-related feeding

The effects of the narcotic antagonist, naloxone, on various types of stress- related feeding in rats were examined. Tail pinch-induced eating of a palatable substance, and 3 hr daytime rat chow intake following acute 2-deoxy-D-glucose (2-DG, 400 mg/kg) administration or 24 hr food deprivation were significantly decreased by low doses (1 mg/kg) of naloxone. Night time food intake was likewise decreased by naloxone (4 mg/kg). In contrast, hyperphagia induced by insulin (10 U/kg) was not decreased by naloxone (0.06–16 mg/kg). These findings suggest that narcotic antagonists should be considered as possible anorexics selective for stress-induced eating, and that endogenous opiates may prove to be another significant factor involved in the control of food intake.     

The role of putative 5-HT1A and 5-HT1B receptors in the control of feeding in rats

8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) and 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H indole succinate (RU 24969), two agonists on the putative serotonin 1A and serotonin 1B receptors, were used for exploring the role of these sites in the inhibitory effect of serotonin (5-HT) on feeding. In free-feeding rats, 2.5-5 mg/kg RU 24969 significantly reduced food intake while doses of 8-OH-DPAT ranging from 0.125 to 0.5 mg/kg increased eating. The effects of the highest doses were associated with hyperlocomotion and hyperreactivity for RU 24969 and a typical motor syndrome (flat body posture and forepaw treading) for 8-OH-DPAT. The motor syndrome caused by 0.5 mg/kg 8-OH-DPAT was much more obvious in food-deprived rats in which food intake was also markedly reduced. RU 24969 1.25 and 5 mg/kg reduced food intake by food-deprived rats and caused hyperlocomotion not different from that in free-feeding animals. Pretreatment with metergoline (2 mg/kg i.p.) prevented the effect of 5 mg/kg RU 24969 on food intake by food-deprived rats but had no effect on the reduction of eating caused by 0.5 mg/kg 8-OH-DPAT. The motor syndrome caused by 8-OH-DPAT was not changed by metergoline but the hyperlocomotion caused by RU 24969 was potentiated. Haloperidol (0.1 mg/kg i.p.) completely blocked the hyperlocomotion but did not change the reduction of food intake caused by RU 24969 in food-deprived rats. It is suggested that the putative serotonin 1B receptors specifically mediate the inhibitory effect of 5-HT on feeding whereas serotonin 1A sites act by enhancing eating only in free-feeding animals.     

Potency of CR 1409, a new proglumide analog, on cholecystokinin-mediated behaviors and receptor binding

Behavioral and receptor binding techniques were employed to evaluate the potency of CR 1409, a new analog of proglumide, as a cholecystokinin antagonist. CR 1409, at doses of 1 mg/kg i.p. in mice, effectively blocked the inhibition of feeding and exploratory behaviors induced by cholecystokinin. In rats, CR 1409 alone, at doses of 1 and 10 mg/kg, did not affect feeding or exploratory behaviors, but at 25 mg/kg alone, CR 1409 reduced food intake and exploratory behaviors, suggesting a mixed agonist-antagonist profile. On these several behavorial parameters, CR 1409 antagonized peripherally administered cholecystokinin with 10–1000 times greater potency than that reported for proglumide (Crawley et al., J. Pharmac. Exp. Ther. 236, 320–330, 1986). In binding to pancreatic cholecystokinin membranes, CR 1409 was more than 100,000-times more potent than that reported for proglumide (Rovati, Scand. J. Gastroenterol. 11, 113–118, 1976). CR 1409 inhabited binding of 125-I-cholecystokinin octapeptide in mouse parcreatic and brain membranes with IC₅₀ values of 13.7 nM and 2.6 μM, respectively, demonstrating its selectivity for peripheral-type CCK receptors.     

Stimulation of pancreatic secretory process in the rat by low-molecular weight proteinase inhibitor

Summary Application of a single dose of a new type of proteinase inhibitor camostate (FOY-305) via orogastric tube was used in rats to study the dose-response relationship of resulting pancreatic stimulation. Doses up to 10 mg/ kg failed to elicit any response, while significant decrease in enzyme content and increase in serum CCK-levels were observed with doses ranging from 25 to 400 mg/kg. A single dose of 100 mg/kg was selected for a time-sequence analysis, which revealed a 60 to 70% depletion of enzyme stores persisting over 6 h and reverting to control levels by 12 h. Peak increases in serum CCK-levels (15-fold above the elevation observed after regular food intake) were found after 30 min and persisted as an 8-to 10-fold elevation for at least 3 h, then declined to control levels by 9 h. This prolonged endogenous hormone release and resulting pancreatic stimulation were also verified in a separate group of animals in which volume, protein, and enzyme output were measured after cannulation of the pancreatic duct. While volume secretion was not altered by feeding a single dose of 100 mg/kg FOY-305, protein and enzyme output increased 2-to 3-fold over a period of 7 h. Fine-structural analysis of the pancreas demonstrated efficient depletion of zymogen granules from acinar cells with all doses between 50 and 400 mg/kg, accompanied by the appearance of membrane material in the acinar lumina at 3 and 6 h. The same transient increase in the number of lysosomal bodies predominantly containing mitochondria with all doses above 50 mg/kg was interpreted as increased organelle turnover due to persisting hormonal stimulation.Supported by a grant from the Deutsche Forschungsgemeinschaft (Ke 113/15-1/2)     

Effects of the alpha 1-adrenergic agonist cirazoline on locomotion and brown adipose tissue thermogenesis in the rat.

Anorexia is induced by injection of alpha 1-adrenergic receptor agonists into the hypothalamic paraventricular nucleus (PVN) in rats. Of the agonists tested to date, cirazoline is the most potent when administered either into the PVN or systemically. The present experiments assess the effects of systemically administered cirazoline, at doses that suppress food intake, on dopamine and norepinephrine systems as evident in locomotion and stereotypy and in the induction of brown adipose tissue (BAT) thermogenesis. In Experiment 1, adult male rats were treated with either vehicle (0) or 0.05, 0.1, 0.2 or 0.4 mg/kg cirazoline (IP) prior to 30 minutes assessment of horizontal and vertical locomotion and stereotypy in Omnitech activity chambers. Horizontal activity and stereotypy were significantly suppressed at 0.05 mg/kg cirazoline but these effects waned at higher cirazoline doses. In Experiment 2, interscapular BAT temperature in adult male rats was monitored for 30 minutes after injection (IP) of either vehicle or 0.4 mg/kg cirazoline. Cirazoline, at 0.4 mg/kg did not influence BAT temperature whereas a positive control treatment (phenylpropanolamine: 40 mg/kg) rapidly increased BAT temperature during a 15 minute period after injection. These results suggest that cirazoline-induced anorexia is not the result of competing motor responses and that this drug, at a dose that produces maximal suppression of feeding, does not alter BAT thermogenesis.     

Thermoregulatory, motor, behavioural, and nociceptive responses of rats to 3 long-acting neuroleptics

We investigated physiological effects of intramuscular injections of the following 3 long-acting neuroleptics commonly used in wildlife management: haloperidol (0.05, 0.1, and 0.5 mg/kg body mass), zuclopenthixol acetate (0.5, 1, and 5 mg/kg), and perphenazine enanthate (1, 3, and 10 mg/kg), in a rat model. Body temperature and cage activity were measured by intra-abdominal telemeters. Nociceptive responses were assessed by challenges to noxious heat and pressure. Haloperidol (0.5 mg/kg) produced a significant nocturnal hypothermia (p < 0.05) and decreased nighttime cage activity and food intake. Zuclopenthixol (5 mg/kg) significantly decreased nighttime body temperature and cage activity and, at 1 mg/kg and 5 mg/kg, significantly decreased food intake 5-17 h after injection (p < 0.05). Perphenazine (10 mg/kg) significantly decreased nighttime body temperature and cage activity and, at all doses, significantly decreased food intake 5-17 h after injection (p < 0.05). Significant analgesic activity was evident in rats given 5 mg/kg zuclopenthixol up to 40 h after injection, and 10 mg/kg perphenazine from 48 to 96 h after injection (p < 0.0001). Zuclopenthixol (5 mg/kg) and perphenazine (10 mg/kg) had significant antihyperalgesic activities at 16 h postinjection and 24-48 h postinjection, respectively (p < 0.0001). Haloperidol had no significant antinociceptive activity at doses tested. Motor function was impaired in rats given 0.5 mg/kg haloperidol, 5 mg/kg zuclopenthixol and 10 mg/kg perphenazine. Effects of long-acting neuroleptics on body temperature, feeding, and activity were short-lasted and should not preclude their use in wildlife. Antinociceptive actions were longer-lasting, but were nonspecific, and we recommend additional analgesics for painful procedures during wildlife management.     

The Effect of O,O-DIMETHYL-O-(2,4,5-Trichlorophenyl) Phosphorothioate (Fe Nc H Lor Phos) On Cholinesterases in the Blue Fox (Alopex Lagopus)

Four blue fox bitches were used in the experiments. Two foxes were given fenchlorphos in the feed, one 100 mg/kg body weight and the other 200 mg/kg daily for 30 days. The maximum inhibition of plasma Cholinesterase was 65 and 69 %, respectively. The corresponding values of the erythrocyte acetylcholinesterase were 43 and 63 %. For the third bitch given 0.4 mg/kg as a single dose i.v. the effect was only measurable as a small transient decrease of the plasma Cholinesterase level. Eighty % of the plasma Cholinesterase of the fourth fox, given 500 mg/kg as a single oral dose, was inhibited on the third day. The erythrocyte acetylcholinesterase activity level only showed a slight decline. This fox vomited during feeding the day after administration. Symptoms as salivation, tremors, diarrhea, pinpoint pupils and respiratory distress were never seen in any of the foxes. It was concluded that fenchlorphos administration in the feed in doses recommended to dogs is well tolerated by healthy foxes as far as Cholinesterase inhibition is concerned.     

Ultrastructural changes in thyrocytes exposed to the antithyroid preparations betazin and diiodotyrosine

Ultrastructure changes in the thyroid gland cells of rats were studied when feeding of bethazine and diiodthyrozine to rats at doses 0.01, 0.1 and 1.0 mg/kg of body's weight for 12 months. The ultrastructure changes in thyrocytes typical both for hyper- and for hypofunction of the gland were revealed.     

Long-term gentamicin ototoxicity in the rat: research on retro-cochlear involvement by study of evoked auditory potentials of the brain stem

Four groups of rats treated with single (50 mg/kg and 200 mg/kg) or multiple (3 X 200 mg/kg and 5 X 200 mg/kg) doses of gentamycin were studied over a 6-month period and compared with a control group. At 50 mg/kg no significant changes were observed. Significant signs of intoxication were observed at 200 mg/kg doses and at multiple doses. A significant lengthening of the latencies with changes in amplitude and a transitional increase in the auditory threshold were observed as early as the end of treatment. This was followed by a phase of amplitude decrease, a rise in auditory threshold and a decrease in latencies which remains unexplained.     

Genotoxic effect of Anovlar 21, an oral contraceptive, on mouse bone marrow

Anovlar 21, a combination drug containing the oestrogen ethinyloestradiol and the progestin norethisterone acetate, was studied for its in vivo genotoxic effect on the bone marrow cells of Swiss albino mice. The chromosomal aberration assay and the micronucleus test were employed for the study. 0.08, 0.4, 0.8, 1.6, 3.2, 4.8, 6.4 and 8.0 mg/kg/day of the drug was orally administered for 15 consecutive days to mice. Bone marrow preparations were made 24 h after the final feeding. The lowest dose, 0.08 mg/kg, represents the human therapeutic range. Marrow preparations of mice fed 0.8 mg/kg/day for 15 days were made at 6, 12, 24, 48 and 96 h, and 1, 2 and 3 weeks and a time-yield analysis was carried out. Statistically significant increases in chromosomal aberrations were observed in animal groups fed doses of greater than or equal to 0.4 mg/kg/day. In the time-response study, the maximum frequency of aberrations was noted at 24 h, thereafter decreasing gradually with increasing time. But the drug did not induce a significant increase in the number of micronuclei in bone marrow erythrocytes at any of the doses or time intervals studied.     

Influence of Feeding Schedule on Chronopharmacological Aspects of Gentamicin in Mice

The effects of the time of day of drug administration on the subchronic toxicity and pharmacokinetics of gentamicin, as well as the role of feeding schedule on circadian rhythms, were investigated in mice. ICR male mice were housed in a light-dark (LD) cycle (12:12) with food and water ad libitum (ALF) or under a time-restricted feeding (TRF) schedule (feeding time: 8 h during the light phase) for 1 day or 14 days before drug administration. The animals were given a single subcutaneous dose of gentamicin 180 mg/kg for the kinetic studies and subcutaneous doses of gentamicin 180 mg/kg/day for 14 days or 220 mg/kg/day for 18 days for the subchronic toxicity studies. A significant dosing-time dependency was shown for mortality and body weight loss, with higher values at midlight and lower ones at the middark (p > 0.05). A significant circadian rhythm was also found for gentamicin kinetics in ALF mice, with the highest clearance at middark and the lowest one at midlight (p > 0.01). The kinetic rhythm of gentamicin coincided well with the toxicity rhythm of the drug. The TRF schedule had a marked influence on the rhythms of gentamicin kinetics and toxicity, showing lowest clearance and higher toxicity at middark. The rhythm of subchronic toxicity of gentamicin seems to be due, at least in part, to the rhythm in kinetics and is strongly influenced by the feeding schedule. Thus, the timing of dosing is an important factor in the kinetics and the subchronic toxicity of gentamicin administration in mice, and the manipulation of feeding schedule can modify the rhythm of the toxicity by changing the rhythm of gentamicin kinetics.     

Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents

Objectives: Obestatin has been initially characterized as a new peptide derived from the ghrelin precursor, which suppresses food intake and inhibits the orexigenic and prokinetic actions of ghrelin when injected peripherally or centrally in lean mice. However, reproducing these data remains controversial. Reasons for the disparity may be the use of different doses, routes, and animal models. We aimed to investigate the effects of peripheral and intracisternal (IC) injection of obestatin on feeding, gastric motility, and blood glucose in rats as well as in diet‐induced obese (DIO) mice. Research Methods and Procedures: Food intake and gastric emptying of a semi‐liquid caloric meal were measured after intraperitoneal (IP) injection of obestatin in rats and DIO mice. Gastric phasic motility and blood glucose were monitored in urethane‐anesthetized rats after IC or intravenous (IV) injection of obestatin. Results: Obestatin injected intraperitoneally at doses ranging from 0.1 to 3 mg/kg influenced neither acute food intake nor gastric emptying in rats. Obestatin injected intravenously at 0.3 or 3 mg/kg and IC at 7.5 or 30 µg/rat modified neither fasted gastric phasic motility nor blood glucose levels, while ghrelin (30 µg/kg, IV) increased and vagotomy suppressed gastric motility, and an oligosomatostatin analog (3 µg/rat, IC) decreased blood glucose. Obestatin, injected intraperitoneally (0.3 mg/kg) in DIO mice, did not alter feeding response to a fast, while urocortin 1 (10 µg/kg, IP) induced a 73.3% inhibition at 2 hours. Discussion: Our data demonstrate that peripheral administration of obestatin did not modify food intake in rats or obese mice or gastric motor function in rats.     

Dihydropyridine neuropeptide Y Y(1) receptor antagonists

Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).     

ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists

ACTH-(1-24) and alpha-MSH, intracerebroventricularly (ICV) injected at the doses of 4 and 10 micrograms/animal, respectively, markedly inhibited spontaneous feeding in adult Sprague-Dawley rats, the effect remaining significant for 6-9 hours. At these same doses, ACTH-(1-24) and alpha-MSH abolished the feeding-stimulatory effect of the kappa opiate receptor agonist pentazocine, intraperitoneally (IP) injected at the dose of 10 mg/kg. The same antagonism was obtained by ICV injection of ACTH-(1-24) into rats IP treated with other kappa opiate agonists, bremazocine and tifluadom, at the doses of 1 and 5 mg/kg, respectively. These data suggest that melanocortin peptides play an inhibitory role in the complex regulation of food intake, and further support and extend the hypothesis of a melanocortin-opioid homeostatic system, its two neuropeptide components usually having opposite, mutually-balancing effects.