Long-acting neuroleptics used in wildlife management do not impair thermoregulation or physical activity in goats (Capra hircus)

Long-acting neuroleptics commonly are used in wildlife management to decrease stress-related mortality in wild animals, but with possible effects on thermoregulation, which may contribute to residual morbidity and mortality. We investigated the effects of haloperidol (0.01, 0.1, 1 mg kg(-1), n=4), zuclopenthixol (0.1, 1, 10 mg kg(-1), n=4) and perphenazine (0.1, 1, 10 mg kg(-1), n=8), as well as control injections of sunflower oil, on body temperature and physical activity of laboratory goats under hot, cold and thermoneutral ambient temperatures. Implanted data loggers continuously recorded abdominal temperature, and data loggers attached externally on the foreleg recorded movement of unrestrained goats, in a climatic chamber at 35 degrees C, 10 degrees C and 22 degrees C. Cycling ambient temperature between 35 degrees C in daytime and 10 degrees C at night time caused a significant increase in amplitude of the circadian rhythm of body temperature in goats given sunflower oil (P=0.0012, unpaired t-test, n=8), but the administration of zuclopenthixol or perphenazine did not affect this change in amplitude (P>0.05, two-way ANOVA, n=4). Mean daily body temperature after administration of zuclopenthixol or perphenazine, and mean daily activity after zuclopenthixol administration, were not significantly different to those after control injections, at any ambient temperature, for the expected duration of drug activity (all P>0.05, two-way ANOVA, n=4). Thermal response indices, and mean activity, during heat, cold or thermoneutral exposure, of goats for 7 h after haloperidol injection, were not significantly different, at any dose or any ambient temperature, to those following control injections (all P>0.05, repeated measures ANOVA, n=4). Long-acting neuroleptics did not impair activity or thermoregulation of goats subjected to inescapable thermal challenges.     

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.     

In hamsters dopamine D2 receptors affect ventilation during and following intermittent hypoxia

We tested the hypothesis that in golden Syrian hamsters (Mesocricetus auratus) carotid body dopaminergic D2 receptors modulate ventilation in air, during exposure to intermittent hypoxia (IH) and reoxygenation. Ventilation was evaluated using the barometric method and CO2 production was determined using the flow through method. Hamsters (n=8) received either subcutaneous injections of vehicle, haloperidol (0.5 mg/kg) or domperidone (0.5 mg/kg). Ventilatory and metabolic variables were determined 30 min following injections, after each of 5 bouts of 5 min of 10% oxygen interspersed by normoxia (IH), and 15, 30, 45 and 60 min following IH when hamsters were exposed to air. Haloperidol, but not domperidone decreased body temperature in hamsters. Neither treatment affected CO2 production. Vehicle-treated hamsters exhibited ventilatory long-term facilitation (VLTF) following IH. Haloperidol or domperidone decreased ventilation in air, during IH and eliminated VLTF due to changes in tidal volume and not frequency of breathing. Thus, in hamsters D2 receptors are involved in control of body temperature and ventilation during and following IH.     

Dopaminergic antagonists potentiate the adenohypophyseal growth reaction to oestrogen: thioridazine is less effective than perphenazine

The injection of oestradiol benzoate as an aqueous microcrystal suspension, in a dose of 1 mg twice a week, evokes a marked adenohypophyseal growth reaction in male rats. The reaction is potentiated by dopaminergic antagonists from the group of neuroleptics (specifically perphenazine and thioridazine). Elicitation of the same adenohypophyseal reaction required twice as much thioridazine (10 mg/rat per day) as perphenazine. Thyroxine inhibited the adenohypophyseal growth reaction to oestradiol. The serum polyphenol oxidase (ceruloplasmin) level rose after oestradiol and perphenazine and thioridazine slightly potentiated the increase.     

Kinetics of Drug-Induced Changes in Dopamine and Serotonin Metabolite Concentrations in the CSF of the Rat

Cerebrospinal fluid (CSF) was removed at a constant flow rate of 1 microliter/min from the third ventricle of anesthetized rats. Every 15 min, CSF dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined by direct injection of CSF into a liquid chromatographic system coupled with electrochemical detection. Mean CSF concentrations of DOPAC, HVA, and 5-HIAA were 1.29 microM, 0.88 microM, and 2.00 microM, respectively. In order to determine the turnover rates of dopamine (DA) and serotonin, experiments using monoamine oxidase (MAO) inhibition were performed. Tranylcypromine (20 mg/kg i.p.) induced a sharp exponential decrease of CSF DOPAC, HVA, and 5-HIAA, with respective half-lives of 15.60 min, 16.91 min, and 77.23 min. Their respective turnover rates were 3.74, 2.22, and 1.18 nmol X ml-1 X h-1. m-Hydroxybenzylhydrazine (NSD-1015, 100 mg/kg i.p.) and monofluoromethyl-DOPA (100 mg/kg i.p.), two decarboxylase inhibitors, induced a slow exponential decrease of all three CSF metabolites. alpha-Methyl-p-tyrosine (250 mg/kg i.p.) also induced a slow exponential decrease of DOPAC and HVA. These decreases of CSF DOPAC and HVA induced by DA synthesis inhibitors may reflect the turnover of DA in vivo. Haloperidol (0.5 mg/kg i.p.) considerably enhanced CSF DOPAC and HVA without affecting 5-HIAA, confirming that dopaminergic receptors modulate DA neurotransmission in vivo. Haloperidol administered 1.5 h after NSD-1015 did not increase DOPAC and HVA, in contrast to reserpine (5 mg/kg i.p.) injected under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of perphenazine to control cannibalism in DBA/1 mice

Maternal administration of perphenazine decreased the incidence of cannibalism in colonies of interferon-gamma, interleukin (IL-4, IL-10, and IL-12) knockout mice of the DBA/1 and C57BL/6 background strains. This colony had high incidence of neonatal death due to cannibalism in approximately 50% of the pups. Perphenazine was administered to the dams in the drinking water, beginning on the day before or the morning of parturition. The medicated water was supplied at two dosages: 0.5 mg/ml and 0.025 mg/ml, resulting in a dosage of 4 mg/kg of body weight and 2 mg/kg, respectively, to the dams. Dams that were treated with perphenazine weaned 76.4% of their pups, compared with nontreated dams that weaned only 59.4% of their pups. Timing of the administration of perphenazine did not have a significant impact on efficacy; also, both doses were equally effective at preventing cannibalism. These findings indicate that perphenazine can modify poor maternal behavior such as cannibalism, resulting in more efficient production of valuable knockout mice.     

GRF-induced feeding: Evidence for protein selectivity and opiate involvement

Growth hormone-releasing factor (GRF) is a hypothalamic peptide named for its ability to induce release of growth hormone from the anterior pituitary. GRF also acts as a neurotransmitter in the suprachiasmatic nucleus/medial preoptic area (SCN/MPOA) to stimulate food intake. The purpose of this series of experiments was to explore the nature of GRF-induced feeding, with a particular emphasis on macronutrient selectivity, and to examine the role of opiate activity in the paraventricular nucleus of the hypothalamus (PVN). Chow intake stimulated by GRF microinjection (1 pmol/0.5 μl) into the SCN/MPOA was blocked by injection of methyl-naltrexone (3 μg/0.5 μl) into the PVN. In animals habituated to macronutrient diets (Teklad, WI), GRF preferentially stimulated intake of protein at 2 and 4 h postinjection, whereas it had no effect on carbohydrate intake. Further, this effect was blocked by injection of naloxone (40 nmol/0.5 μl) into the PVN. Microinjection of morphine (0, 1, 10, and 17 μg/0.5 μl) into the PVN also specifically stimulated protein intake at 2 and 4 h postinjection. These results suggest that feeding derived from GRF actions in the SCN/MPOA is macronutrient selective, and is dependent on PVN opiate activity for expression.     

Peripheral ghrelin injections stimulate food intake, foraging, and food hoarding in Siberian hamsters

Fasting triggers many effects, including increases in circulating concentrations of ghrelin, a primarily stomach-derived orexigenic hormone. Exogenous ghrelin treatment stimulates food intake, implicating it in fasting-induced increases in feeding, a consummatory ingestive behavior. In Siberian hamsters, fasting also stimulates appetitive ingestive behaviors such as foraging and food hoarding. Therefore, we tested whether systemic ghrelin injections (3, 30, and 200 mg/kg) would stimulate these appetitive behaviors using a running wheel-based food delivery system coupled with simulated burrow housing. We also measured active ghrelin plasma concentrations after exogenous ghrelin treatment and compared them to those associated with fasting. Hamsters had the following: 1) no running wheel access, free food; 2) running wheel access, free food; or 3) foraging requirement (10 revolutions/pellet), no free food. Ghrelin stimulated foraging at 0-1, 2-4, and 4-24 h postinjection but failed to affect wheel running activity not coupled to food. Ghrelin stimulated food intake initially (200-350%, first 4 h) across all groups; however, in hamsters with a foraging requirement, ghrelin also stimulated food intake 4-24 h postinjection (200-250%). Ghrelin stimulated food hoarding 2-72 h postinjection (100-300%), most markedly 2-4 h postinjection in animals lacking a foraging requirement (635%). Fasting increased plasma active ghrelin concentrations in a time-dependent fashion, with the 3- and 30-mg/kg dose creating concentrations of the peptide comparable to those induced by 24-48 h of fasting. Collectively, these data suggest that exogenous ghrelin, similar to fasting, increases appetitive behaviors (foraging, hoarding) by Siberian hamsters, but dissimilar to fasting in this species, stimulates food intake.     

In vivo evidence that constitutive activity of serotonin2C receptors in the medial prefrontal cortex participates in the control of dopamine release in the rat nucleus accumbens: differential effects of inverse agonist versus antagonist

Control of the mesoaccumbens dopamine (DA) pathway by central serotonin_2C receptors (5-HT_2CRs) involves different 5-HT_2CR populations located within multiple brain areas. Here, using in vivo microdialysis in halothane-anesthetized rats, we assessed the role of medial prefrontal cortex (mPFC) 5-HT_2CRs in the control of basal and activated accumbal DA outflow, to identify the modalities of their recruitment and the role of 5-HT_2CR constitutive activity. Intra-mPFC injection of the 5-HT_2CR inverse agonist SB 206553 (0.5 μg/0.2 μL), without effect by itself, decreased accumbal DA outflow induced by morphine (2.5–10 mg/kg, s.c.), haloperidol (0.01 mg/kg, s.c.) or GBR 12909 (2.5 mg/kg, i.p.). Conversely, intra-mPFC injection of the 5-HT_2CR antagonist SB 242084 (0.5 μg/0.2 μL), without effect by itself, decreased the effect of 10 mg/kg morphine, the only drug enhancing basal 5-HT outflow in the mPFC. The inhibitory effect of SB 206553 on 2.5 mg/kg morphine-stimulated DA outflow was suppressed by the concomitant intra-mPFC injection of SB 242084. Finally, changes of basal DA outflow induced by the 5-HT_2CR agonist Ro 60-0175 (3 mg/kg, i.p.) or SB 206553 (5 mg/kg, i.p.) were unaffected by intra-mPFC injection of SB 242084. These results, showing that 5-HT_2CR antagonist and inverse agonist behave differently in vivo, demonstrate that mPFC 5-HT_2CRs facilitate activated accumbal DA outflow and that 5-HT_2CR constitutive activity participates in this interaction.     

原发性高血压患者红细胞抗高血压因子对高血压...

The effects of antihypertensive factor (AHF) from erythrocytes of essential hypertensive human subjects on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR), Wistar-Kyoto rats (WKY) and Wistar rats were examined. Single intraperitoneal injection of AHF (1.6 mg/kg body weight) resulted in a significant decrease in SBP of SHR and RHR. At 10 min postinjection, AHF lowered the SBP in SHR by 34.0 mmHg. SBP recovered to the original level at 3 h. The maximal decrease of SBP in RHR by 92.5 mmHg was at 24h postadministration and the SBP did not recover until the 9th day. When AHF was administered via femoral vein (0.8 mg/kg body weight), the maximal decrease values of the SBP and the DBP were 42.8 and 48.2 mmHg in SHR at 12 min and 38.3 and 42.5 mmHg in RHR at 25 min postinjection respectively. The DBP in Wistar rats decreased considerably (from 96.7 +/- 12.9 to 83.3 +/- 11.7 mmHg) at 5 min postadministration of AHF, but no effect on DBP in WKY rats was observed. The depressor effect of AHF on SBP in RHR was dose-dependent. AHF could also antagonize the pressor effect of norepinephrine in Wistar rats.     

Effect of hydrocortisone on peripheral blood phagocytic cells under beta-adrenoreceptors blockade

The effect of hydrocortisone (50 mg/kg body wt i.p.) under beta-adrenergic receptors blockade (four subcutaneous injections of propranolol in single dose of 5 mg/kg body wt with 3 h interval) on phagocytic activity and oxygen dependent microbicidal activity in NBT-test of peripheral blood phagocytic cells in male Wistar rats was investigated. It was established that hydrocortisone stimulated neutrophil phagocytic activity through 6, 24 and 48 h after hormone injection and decreased oxygen-dependent microbicidal activity of phagocytic cells in NBT-test. Hydrocortisone in vitro (500 ng/ml) decreased neutrophil phagocytic activity that indicated on realization of stimulating effect of hydrocortisone in vivo through complex of other indirect mechanisms. Administration of hydrocortisone led to depression of eosinophil phagocytosis and lesser decrease in monocyte phagocytic activity. Hydrocortisone effects were significantly modified under blockade of beta-adrenoceptors that indicated on its mediation by endogenous catecholamines through modulation of beta-adrenoceptor expression.     

Differential effect of polyherbal,antiobesity preparation,OB-200G in male and female mice and monosodium glutamate-treated rats

Effect of administration of different doses (0.25, 0.5, 1 and 2 g/kg, twice daily, po) of a polyherbal preparation, OB-200G and fluoxetine (10 mg/kg, ip) for 21 days was studied on food intake and body weight in male and female Laka mice. The study further investigated the effect of administration of 0.5 g/kg dose of OB-200G for 40 days on body weight, fat pad weights, locomotor activity and biochemical parameters in monosodium glutamate (MSG)-treated male and female Wistar rat pups. Administration of OB-200G produced dose dependent decrease in body weight in both male and female mice. On the other hand, fluoxetine decreased body weight only in female mice. The food intake was significantly (P < 0.05) increased in both fasted male and female mice after treatment with the lower dose (0.25 g/kg, po) of OB-200G. However, significant (P < 0.05) decrease in food intake was recorded with the administration of higher doses (0.5, 1 and 2 g/kg, po) of OB-200G and fluoxetine in fasted female mice on day 1, 7, 14 and 21. But in male mice differential effect on food intake was recorded at different doses on day 1, 7, 14 and 21. Further, OB-200G administration significantly (P < 0.05) decreased body weight and fat pad weights, increased serum glucose levels and ambulatory activity in MSG-treated female rats but not in MSG-treated male rats. The results suggest that OB-200G involves gender differences in mediating its antiobesity effect and may supplement the current armamentarium for the treatment of obesity.     

Effect of D,L-propargylglycine on cystathionine metabolism in rats

Hepatic gamma-cystathionase activity at 12 h after the intraperitoneal injection decreased in proportion to the amount of D,L-propargylglycine administered, but hepatic cystathionine beta-synthase activity did not change. Contents of cystathionine in the liver increased gradually from 0.25 mg to 30 mg/200 g body weight in proportion to the amounts of D,L-propargylglycine injected; in the kidney, 0.5 mg to 10 mg; in the brain, 5 mg to 20 mg; in the serum, 0.25 mg to 30 mg. Contents of N-acetylcystathionine in the liver and kidney also increased in parallel with the accumulation of cystathionine.     

Inhibition of peripheral adrenergic neurotransmission by lergotrile in spontaneously hypertensive rats

Intraperitoneal injection of lergotrile (0.5 mg/kg) produced arterial hypotension and bradycardia for 120 and 90 minutes, respectively, in anesthesized spontaneously hypertensive rats (SHR). During this time frame, lergotrile (0.5 mg/kg, i.p.) greatly attenuated diastolic blood pressure and cardiac rate responses to electrical stimulation (0.062-4 Hz) of the sympathetic outflow in pithed SHR, but had no significant effect on comparable increments in pressure and rate produced by exogenous norepinephrine (0.01–10 μg/kg, i.v.). Pretreatment of SHR with haloperidol (2 mg/kg, i.p.) prevented lergotrile-induced hypotension and partially reversed its inhibitory effect on neurogenic vasoconstrictor responses. Haloperidol alone had no significant effect on baseline arterial blood pressure or responses to sympathetic nerve stimulation. Administration of hexamethonium (20 mg/kg, i.v.) to SHR antagonized the hypotensive response to lergotrile (0.5 mg/kg, i.p.), although hydralazine (2 mg/kg, i.p.) still produced a marked reduction in pressure.These results suggest that lergotrile produces arterial hypotension and bradycardia primarily by inhibiting peripheral sympathetic nerve function through a dopaminergic mechanism. The probable site of action of lergotrile is at presynaptic (neuronal) dopamine receptors which are known to be inhibitory to neurogenic release of norepinephrine.     

Analgesic and antiinflammatory effects of chalcones isolated from Myracrodruon urundeuva allem?o.

The present work showed analgesic and antiinflammatory activities from a fraction containing three dimeric chalcones (chalcone enriched fraction - CEF), isolated from the stem-bark ethyl acetate extract of Myracrodruon urundeuva Allemao (Anacardiaceae). M. urundeuva is a popular medicinal plant used widely in Northeast Brazil, mainly as a topical female genital tract antiinflammatory. We observed that the CEF (5 and 10 mg/kg body wt., i.p. or p.o.) inhibited acetic acid-induced abdominal contractions in mice. In the formalin test, the CEF (5 and 10 mg/kg body wt.) was more effective intraperitoneally and inhibited predominantly the second phase of response. Naloxone reversed this effect, indicating an involvement of the opioid system. The CEF (10 and 20 mg/kg body wt.) also increased the reaction time to thermal stimuli in the hot-plate test in mice, after i.p. but not after p.o. administration. In the carrageenan-induced paw edema test in mice, the CEF (20 and 40 mg/kg body wt.) decreased paw volume significantly, after i.p. administration 2-4 hours after carrageenan injection. The CEF (40 mg/kg body wt.) was also active orally during the same period of time. The present work is the first report on peripheral and central analgesic effects and antiinflammatory activity of natural dimeric chalcones.     

Suppression of food intake by a complement C3a agonist [Trp5]-oryzatensin(5-9)

[Trp5]-oryzatensin(5-9) (WPLPR), an agonist peptide for complement C3a receptor, has been designed based on the C-terminal region of ileum-contracting peptide oryzatensin derived from rice protein. We previously reported that WPLPR has anti-analgesic and anti-amnesic activities after central or oral administration. In this study, we found a novel function of WPLPR on food intake. WPLPR suppressed food intake after intracerebroventricular or intraperitoneal (i.p.) administration at a dose of 3-30 nmol/mouse or 30-300 mg/kg, respectively, in fasted mice. Orally administered WPLPR at a dose of 300 mg/kg also decreased food intake. WPLPR decreased gastric emptying after i.p. injection at a dose of 300 mg/kg. The anorexigenic activity of WPLPR was blocked by cyclooxygenase inhibitor or antagonist for prostaglandin (PG) E receptor EP4 subtype. These results suggest that WPLPR decreases food intake through PGE2 production followed by EP4 receptor activation.     

Synthesis and 5-hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines

A series of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines was shown to exhibit 5-HT2C agonist binding and functional activity. Compound 21R inhibited food intake over 2 h in fasted, male Sprague Dawley rats with ED50 values of 2 mg/kg (i.p.) and 10 mg/kg (p.o.).     

Variability in development of tolerance to repeated injections of low doses of dl-amphetamine in rats

Male albino rats received injections of saline for 5 days before and 5 days after a series of 10 daily injections of dl-amphetamine, 1 or 5 mg/kg, sc. Core temperatures were measured every 30 min for 4 h after each injection and feeding activity (on a CRF operant schedule) every 30 min throughout. After amphetamine at either 0800 or 2000 h, a dose-related hyperthermia, stereotypic behavior, and an initial inhibition of feeding occurred. This anorexia decreased over the 4-h post injection period only in the evening-injected rats receiving 5 mg/kg. Mean body weights of all groups continued to increase during amphetamine administration. Mean 24-h food intake tended to remain below that in the control period and the hyperthermic response did not change significantly in any group. Initially on withdrawal from amphetamine all groups showed 'rebound' feeding. Taken with earlier reports, these results suggest that tolerance development to amphetamine-induced anorexia, hyperthermia, and stereotypic behavior occurs at different rates and is dependent upon frequency, route, dose, time, the amphetamine used, and whether the diet was restricted.     

Effects of anti-inflammatory drugs on fever and neutrophilia induced by Clostridium difficile toxin B

This study investigated the ability of Clostridium difficile toxin B, isolated from the VPI 10463 strain, to induce fever and neutrophilia in rats. Intravenous injection of toxin B (0.005-0.5 mug/kg) evoked a dose-dependent increase in body temperature. The febrile response to 0.5 mug/kg of the toxin started in 2.5 h, peaked at 5 h, and subsided fully within 24 h. Toxin B also induced a dosedependent neutrophilia. Pretreatment with indomethacin (2 mg/kg, i.p.) did not affect the neutrophilia induced by toxin B, but significantly reduced the febrile response measured 4 to 8 h after toxin B injection. Dexamethasone (0.5 mg/ kg) also markedly diminished the febrile response induced by toxin B. These results show that Clostridium difficile toxin B induced a febrile response susceptible to inhibition by dexamethasone and indomethacin. Furthermore, they suggest that prostaglandins are not involved in the neutrophilia caused by this toxin.