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PubMed1992

Radioprotection by caffeine pre- and post-treatment in the bone marrow chromosomes of mice given whole-body gamma-irradiation.

The effect of caffeine given as pre- and post-treatment in mice exposed to whole-body gamma-irradiation (1.5 Gy 60Co gamma-rays) was studied. The pre-treatment was either acute or chronic. The acute dose (5 mg/kg and 15 mg/kg body weight) was in the form of an injection given intraperitoneally, 30 min before irradiation. The chronic administration was in the form of caffeine solution (4.208 x 10(-3) M and 7.72 x 10(-4) M) contained in the drinking water that mice had had ad libitum access to instead of plain drinking water for 5 weeks prior to radiation exposure. The acute pre-treatment with caffeine reduced the radiation-induced frequency of chromosomal aberrations discernibly, whereas the chronic pre-treatment afforded a much more significant degree of radioprotection. The caffeine post-treatment (5 mg/kg and 15 mg body weight) was given in the form of an intraperitoneal injection to the mice immediately following whole-body gamma-irradiation. It is noted that both post-treatment concentrations of caffeine also significantly reduced the frequency of chromosomal aberrations induced by gamma-rays. These data are briefly discussed in terms of possible mechanistic considerations.

Animals↗
PubMed1992

Effects of acute and subchronic administration of propranolol on the social behaviour of mice; an ethopharmacological study.

The effects of dl-propranolol on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (1.5 and 6 mg/kg) and after administration for 10-13 days in the drinking fluid at 12.4 mg/l (1.9 mg/kg daily) and 24.9 mg/l (4.6 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive and a less aversive situation, an unfamiliar neutral cage and the animals' home cage. The behaviour of each mouse also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after the injection. In the light-dark box, propranolol, after acute administration, increased the number of transitions between the light and dark compartments and increased scanning in the light area but propranolol had no significant effect after subchronic administration. In the home cage, propranolol significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, propranolol, after acute administration, increased digging of the sawdust and decreased exploratory activity at both dose levels, while at the largest dose it also increased social investigation. In the neutral cage, propranolol, given by subchronic administration, increased aggressive behaviour as well as social investigation and digging of the sawdust at both dose levels, while reducing non-social exploratory activity. The largest dose of propranolol also increased investigation of the substrate. These results indicate that propranolol increased reactivity to normal environmental and social stimuli, in addition to its anxiolytic profile of behavioural effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1992

Intracerebral actions of the 5-HT1A agonists, 8-OH-DPAT and buspirone and of the 5-HT1A partial agonist/antagonist, NAN-190, on female sexual behavior.

Proestrous rats were infused intracerebrally with 50-1000 ng 8-OH-DPAT, 500 or 2000 ng buspirone or 125-500 ng NAN-190. For each drug, bilateral infusions into the mediobasal hypothalamus inhibited female lordosis behavior and proceptivity and initiated resistive behavior. The effects of the drugs were evident within 5-20 min of infusion and generally lasted for 1-2 hr. The effective sites for 5-HT1A-mediated inhibition of sexual behavior were most concentrated in the ventromedial nucleus of the hypothalamus. Cannulae sites anterior, posterior or dorsal to the ventromedial nucleus or clearly within the IIIrd ventricle were less effective at disrupting lordosis behavior. The inhibition of sexual behavior, following 8-OH-DPAT occurred in a dose-dependent manner and appeared to include the loss of motivation of the female to mate. Buspirone produced similar, but quantitatively smaller, effects on lordosis behavior. NAN-190 slightly, but significantly, suppressed lordosis behavior after either intracerebral or intraperitoneal injection and substantially increased resistive behavior. These results suggest that the inhibition of lordosis behavior, following treatment with 5-HT1A agonists, include an action within the ventromedial nucleus. Moreover, 5-HT1A receptors in this area appear to play a functionally important role in the modulation of the female's "willingness" to mate.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Effects of acute and subchronic administration of ritanserin on the social behaviour of mice.

The effects of ritanserin on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (0.1, 0.3 and 0.6 mg/kg) and after administration for 12-15 days in the drinking fluid at 1.6 mg/l (0.32 mg/kg daily) and 3.1 mg/l (0.7 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive situation, an unfamiliar neutral cage, and in a familiar situation, the animal's home cage. Behaviour also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after injection. In the home cage, ritanserin significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, acutely administered ritanserin increased social investigation and reduced non-social activity at all dose levels. Effects were maximal at 0.3 mg/kg, and at this dose it also increased aggression. In the neutral cage after subchronic administration, ritanserin at both dose levels increased aggression, digging and investigation of the substrate and occurrence of the social act, "attend", while reducing the time spent in non-social exploration. Ritanserin did not affect behaviour in the light-dark box. The significance of these findings relative to the anxiolytic and antidepressant effects of ritanserin is discussed.

Administration, Oral↗
PubMed1993

Effects of quinpirole on the behaviour shown by mice in the light-dark box and during social interactions.

Quinpirole (0.25, 0.5 and 1.0 mg/kg) was administered by intraperitoneal injection to pair-housed adult DBA/2 mice. Controls received injections of physiological saline. Effects on behaviour during 5 min social encounters with untreated partners were examined by ethological procedures, commencing at 30 min after injection. Behaviour was examined in an aversive and less aversive situation, an unfamiliar neutral cage and the home cage. Behavioural effects were then assessed in a two-compartment black and white test box. Quinpirole dose-dependently increased the frequency and duration of flight, including the specific element "retreat". At 0.5 mg/kg, the element, "freeze", was also increased during encounters in the neutral cage. Immobility (a flaccid sitting posture) and sniffing of the substrate were increased by quinpirole to a similar extent at all dose levels, while non-social activity and social investigation were reduced. The significance of the effects of quinpirole in the home cage and neutral cage were qualitatively similar; the only quantitative differences were a greater enhancement of the duration of immobility and the frequency of substrate sniffing in the home cage. In the light-dark box, quinpirole reduced the number of transitions between light and dark compartments and decreased line crossings and scans/unit time in the light compartment, although it increased the amount of time in the light compartment into which mice had been originally placed. The induction of immobility and decrease of several active behavioural responses may arise from a D2 autoreceptor inhibition of locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Conditioned taste aversion produced by 2-deoxy-D-glucose in rats and hamsters.

The glucose antimetabolite 2-deoxy-D-glucose (2DG) reliably causes hyperphagia in rats, but has consistently proven ineffective in producing overeating in golden hamsters. It was hypothesized that hamsters do not overeat following 2DG administration because of unusually strong aversive effects of the drug in this species. To test this hypothesis, rats and hamsters were tested in a conditioned taste aversion (CTA) paradigm, in which a novel 0.1% saccharin solution was paired on three occasions with intraperitoneal injections of either saline, lithium chloride (LiCl; 50 mg/kg), or 2DG (either 350 or 750 mg/kg). CTA was measured in 16 twenty-minute, two-bottle preference tests which were conducted at 2-3 day intervals following conditioning. LiCl and 2DG both produced strong and long-lasting aversions to saccharin solution in rats. However, 2DG was significantly less effective than LiCl in producing CTA in hamsters. It is unlikely, therefore, that the failure of 2DG to produce hyperphagia in hamsters is due primarily to an unusual sensitivity to the aversive effects of the drug.

Animals↗
PubMed1989

Glycolic acid and tryptophan effects on feed intake and hypothalamic indoleamines in chicks.

The effect of intraperitoneal injections of glycolic acid, glycine or tryptophan on feed intake and hypothalamic levels of 5-hydroxy-tryptamine (5-HT) and 5-hydroxy indole acetic acid (5-HIAA) was examined in chicks. Glycolic acid significantly depressed feed intake in a dose-dependent manner in comparison to saline or glycine, but only in birds injected with a level higher than 150 mg/kg body weight. The injection of glycolic acid or tryptophan but not glycine inhibited feed intake, and increased hypothalamic 5-HT and 5-HIAA 2 hr post-injection, as compared with saline injected controls. Blood plasma total lipids were elevated by all 3 compounds but plasma glucose was unaffected. The reduced feed intake obtained by injection of glycolic acid appears to result from an effect on the serotonergic system.

Animals↗
PubMed1993

A phase-response curve to the benzodiazepine chlordiazepoxide and the effect of geniculo-hypothalamic tract ablation.

The geniculo-hypothalamic tract (GHT) provides input to the mammalian circadian pacemaker in the suprachiasmatic nucleus. Several recent reports indicate that GHT ablation blocks phase shifts to the benzodiazepines triazolam and chlordiazepoxide at circadian times (CTs) 6 and 21. In this study we tested if GHT ablation blocks phase shifts to chlordiazepoxide at a wide range of circadian phases. Syrian hamsters were housed under constant dim light, and running-wheel activity rhythms were monitored. Intraperitoneal injections of either chlordiazepoxide (100 mg/kg) or saline were administered at various circadian times, and a phase-response curve was constructed. In intact animals, chlordiazepoxide produced phase-advance shifts at CTs 0, 4, 6, and 8, and phase-delay shifts between CTs 12-14. Although bursts of increased activity were sometimes observed on the day of injection, activity does not appear to mediate chlordiazepoxide-induced phase shifts. Hamsters with > 45% GHT ablation showed no phase shifts > 20 min to chlordiazepoxide. Our results indicate that the geniculo-hypothalamic tract is necessary for the phase-shifting effects of the benzodiazepine chlordiazepoxide throughout the circadian cycle.

Animals↗
PubMed1994

Exogenous cholecystokinin octapeptide in broiler chickens: satiety, conditioned colour aversion, and vagal mediation.

Intraperitoneal injections of 3.5, 7.0, 14.0, and 28.0 micrograms/kg of CCK-8 into free-feeding broiler chickens significantly reduced food intake and delayed feeding (p < 0.05). To determine whether CCK can condition preference or aversion and to investigate the latency and the reversal of the effect, a low (2 micrograms/kg) and a high (14 micrograms/kg) dose of CCK-8 were administered using the coloured food paradigm. One colour, the conditioning stimulus (CS+), was paired with injections of CCK-8; the other colour was paired with injections of saline (CS-). The 2 micrograms/kg dose of CCK-8 neither reduced food intake nor conditioned a colour aversion. The 14 micrograms/kg dose significantly reduced food intake and conditioned a colour aversion (p < 0.05). When vagotomy was performed, the 14 micrograms/kg dose of CCK suppressed feeding in sham-operated birds (p < 0.05) but not in vagotomized birds (p > 0.05). A significant aversion for the food paired with CCK was obtained in sham-operated birds (p < 0.001) but not in vagotomized birds (p > 0.05). It was concluded that IP injections of CCK-8 reduce food intake in broiler chickens and that chicks can learn to associate the colour of the food with injections of CCK, developing an aversion. It was also shown that the vagus nerve mediates the CCK satiety effects and that aversion conditioning to CCK is dependent upon intact vagal innervation of the viscera.

Age Factors↗
PubMed1991

Role of leukocyte depletion in noncholinergic bronchoconstriction of guinea pigs.

To test the role of leukocytes in the activation of afferent C-fibers in the lung, 33 guinea pigs, 18 control and 15 experimental or leukocyte depleted, were used. The leukocyte depletion was accomplished with an intraperitoneal injection of cyclophosphamide (100 mg/kg) 96 h prior to the study. On the day of the study, bronchial constriction was produced either by exsanguination (n = 17) or by capsaicin injection (16 micrograms/kg, i.v.) (n = 16) in anesthetized-paralyzed animals. Venous blood samples were collected for leukocyte counts. At 1-30 min following the above treatment, the maximal expiratory flow maneuver was performed and a decrease in the maximal expiratory flow at 50% baseline total lung capacity (Vmax50) was used as an index of bronchoconstriction. The leukocyte count decreased significantly following the pretreatment with cyclophosphamide [an average of 6217 +/- 612 (control) vs. 2242 +/- 334/mm3 (experimental)]. Exsanguination caused a gradual decrease in Vmax50 with time, indicating a temporal increase in bronchoconstriction. Capsaicin injection, on the other hand, caused an immediate (1 min) marked bronchoconstriction, which attenuated gradually with time. At a specific time point, leukocyte depletion did not produce any significant change in Vmax50 compared to the control group for both types of bronchoconstrictions. Based on these results, we conclude that leukocytes may play an insignificant role in the bronchoconstriction caused by the activation of afferent C-fibers in guinea pig lungs under our experimental conditions.

Animals↗
PubMed1988

Rat testis during 2,5-hexanedione intoxication and recovery. I. Dose response and the reversibility of germ cell loss.

The histopathology of the testicular injury induced by 2,5-hexanedione (2,5-HD) exposure was examined in the rat. Charles River CD rats (200 g) were intoxicated by consuming 1% 2,5-HD in the drinking water or by intraperitoneal injection of the toxicant. Both neurotoxic and subneurotoxic exposures were studied, the total dose ranging from 40 to 211 mmol/kg. The following results were obtained: (1) there was a time delay between administration of the toxicant and development of the testicular injury, (2) Sertoli cell vacuolation in stages associated with the meiotic metaphase was the first histological sign of cellular injury at all doses, (3) subneurotoxic doses produced selective defects in germ cells in stages I-VIII of the spermatogenic cycle, (4) both subneurotoxic and neurotoxic doses produced germ cell necrosis and generalized sloughing of germ cells, and (5) intensive intoxication followed by a 17-week recovery period resulted in an absence of all postspermatogonial germ cells from the seminiferous epithelium of three of five treated rats. These data demonstrate that 2,5-hexanedione-induced testicular atrophy occurs at exposure levels below those producing clinical neurotoxicity and that, within the time frame of this study, the testicular injury is at least partially irreversible.

Administration, Oral↗
PubMed1990

Chlordimeform-induced alterations in endocrine regulation within the male rat reproductive system.

The acaricide chlordimeform has been reported to have adverse effects in mammals that may be mediated by an interaction with alpha-adrenergic receptors. Since the hormonal signals involved in the regulation of reproductive function are themselves under hypothalamic adrenergic control, the present study was designed to investigate the effects of acute exposure to this compound on the hypothalamic-pituitary-testicular axis. Male rats given two intraperitoneal injections of chlordimeform-HCl (20 or 50 mg/kg) spaced 12 hr apart showed 24-hr declines in serum gonadotropins at 50 mg/kg that were paralleled by a drop in testosterone. These changes returned to control levels by 96 hr. Thyroid-stimulating hormone exhibited a dose-response decline that was accompanied by a similar decrease in serum thyroid hormone levels. The norepinephrine-stimulated secretion in vitro of gonadotropin-releasing hormone from hypothalamic explants was suppressed at the higher dose, while LH release from pituitary fragments in culture was unaffected. Although measurements of the in vitro release of other pituitary hormones suggest that there could be some direct pituitary effects of the compound, it appears likely that chlordimeform is able to influence endocrine regulation adversely within the reproductive system by interfering with hypothalamic alpha-adrenergic activity.

Amidines↗
PubMed1991

3-Methylindole-induced splenotoxicity: biochemical mechanisms of cytotoxicity.

3-Methylindole (3-MI) is a pneumotoxic metabolite of L-tryptophan that can form in the digestive tracts of humans and ruminants as a result of microbial protein metabolism. Alternatively, human lungs can be directly exposed to 3-MI formed during protein pyrolysis and inhalation of tobacco smoke. 3-MI has been shown to cause acute lung injury in both ruminants and rodents. The present studies demonstrate that the spleen is also a target for 3-MI-induced toxicity. A dose-dependent decrease in splenic weight (24-75%) and nucleated splenic cell number (22-68%) was observed 24 hr after intraperitoneal injection of 3-MI (50-300 mg/kg) to intact and adrenalectomized rats. These findings were associated with significant alterations in splenic histopathology. Mice appeared less affected by 3-MI than rats as no splenotoxicity was observed at doses less than 200 mg/kg. Other mono- and dimethyl-substituted indoles did not decrease mouse spleen cell numbers when administered in vivo. Phenobarbital pretreatment in vivo protected against 3-MI-induced splenotoxicity, suggesting a role for cytochrome P450-mediated metabolism of 3-MI in the splenotoxicity of this compound. Exposure of rat or mouse splenic cells to 3-MI (1 mM) in vitro resulted in toxic changes over 24 hr. However, equimolar concentrations of the structurally related mono- and dimethylindoles were also toxic in vitro, and preincubation with a variety of inhibitors of cytochrome P450 or prostaglandin synthase in vitro failed to protect against 3-MI-mediated toxicity to splenic cells in culture. These results suggest mechanisms of 3-MI splenotoxicity also exist that do not require bioactivation, and indicate a possible role for alkylindoles in suppression of immune function.

Adrenalectomy↗
PubMed1987

Distribution of tritiated tetrodotoxin administered intraperitoneally to pufferfish.

Tetrodotoxin was recoil-tritiated by the 3He(n,p)3H reaction and purified by gel filtration. The [3H]tetrodotoxin gave only one spot in both cellulose acetate strip electrophoresis and thin layer chromatography. The specific toxicity of tetrodotoxin did not decrease during the recoil tritiation and the [3H]tetrodotoxin showed a specific radioactivity of 25 x 10(-6) Ci/mmole. In spite of the low specific radioactivity, the [3H]tetrodotoxin was able to be used to investigate the anatomical distribution of tetrodotoxin in pufferfish. When intraperitoneally injected into 'torafugu' puffer, [3H]tetrodotoxin accumulated in most tissues, the level being highest in the skin, followed by the liver, intestines and muscle. With time, the [3H]tetrodotoxin radioactivity level in the injected pufferfish decreased in most tissues, except for skin and gallbladder. Based on these results, the metabolism of tetrodotoxin in pufferfish is discussed.

Animals↗
PubMed1989

Reduced thrombus formation in vivo after administration of pentoxifylline (Trental).

The hamster cheek pouch model of experimental thrombosis in which thrombi are induced in the microvasculature by iontophoretical administration of adenosine diphosphate (ADP) was used to test the antithrombotic potential of pentoxifylline (Trental). Single intraperitoneal injections of 5, 10 and 20 mg/kg pentoxifylline reduced thrombus formation by 20 to 50% from 30 to 105 min following drug administration. The effect of a single application of 10 mg/kg was exceeded significantly (p less than 0.05) by the higher rate of inhibition after repeated injections of the same dose given three times daily. This suggests a residual antithrombotic effect from the preceding administrations.

Adenosine Diphosphate↗
PubMed1978

Lordosis induction in the rat by prostaglandin E2 systemically or intracranially in the absence of ovarian hormones.

Within 20 minutes of an intraperitoneal injection, PGE2 induced lordosis responding to manual stimulation in 6 of 9 rats that were ovariectomized-hysterectomized and hormonally untreated. Similarly, intracranial application of PGE2, through guide cannulae that were chronically-implanted in the basal hypothalamus, induced lordosis responding to manual stimulation within 10 minutes in ovariectomized, hormonally-untreated rats.

Animals↗
PubMed1990

Photodynamic therapy of choriocarcinoma transplanted to the hamster cheek pouch. I. Intraperitoneal photosensitization.

Human choriocarcinoma (JEG-3) cells were transplanted into the cheek pouch of hamsters and treated with photodynamic therapy. Twenty-four hours after intraperitoneal injection of the photosensitizer dihematoporphyrin ether (DHE), 20 tumors were illuminated with 100 J/cm2 of 630-nm light from an argon pumped dye laser. Contralateral tumors served as controls. Dihematoporphyrin ether alone had no effect on tumor growth, while laser light in the absence of DHE resulted in complete regression in 3 tumors (17%), and partial regression in 4 of 18 tumors (22%), possibly due to hyperthermia, P greater than 0.10. Using the combination of DHE plus light (photodynamic therapy) complete tumor regression was noted after a single treatment in 11 of 20 tumors (55%, mean tumor volume 279 mm3) and in 7 of 7 tumors (100%) after a second treatment. Two of 20 tumors were not retreated. Therefore, 18 of 20 tumors (90%) were grossly destroyed by one or two photodynamic treatments. Contralateral control tumors continued to grow to a median volume of 990 mm3 (chi 2 = 26.30, P less than 0.0001). Choriocarcinoma transplanted into the hamster cheek pouch is highly responsive to photodynamic therapy.

Animals↗
PubMed1980

Kynurenines and audiogenic excitement in mice.

Adult male and female albino mice (SHR strain) responded to sound by locomotor excitement (73-81%), running fits (33-47%), clonic convulsions (15-25%), tonic extension (10-22%) and lethality (7-17%). Intraperitoneal injection of metabolites of tryptophan on the kynurenine pathway (Kynurenines): DL- and L-kynurenine sulfate, 3-hydroxyanthranilic, anthranilic, quinolinic, picolinic, nicotinic and xanthurenic acids (in doses of 200 and 400 mg/kg) decreased audiogenic excitement. Intraventricular injection of kynurenines (1-50 mcg), even in stimulating and convulsive doses, had no effect. Intraventricular injection did not induce an audiogenic response in C57 BL/6 and CC57BR mice which are not normally susceptible to sound. Pentylenetetrazol and strychnine injected intraventricularly in up to lethal dosages did not modify audiogenic excitement. Decrease of audiogenic excitement by kynurenines is suggested to be partially related to lowering of body temperature.

Acoustic Stimulation↗