Effects of profadol on operant behavior in the pigeon

The effects of profadol were determined on the key pecking of pigeons under the control of a multiple fixed-ratio, fixed-interval schedule of grain presentation. The effects of naloxone and pentobarbital on the behavioral suppression produced by profadol were also determined. Profadol (0.64-10 mg/kg) decreased responding under both schedule components, and the decrease in responding could not be reversed by either naloxone or pentobarbital. A moderate dose of profadol (1.25 mg/kg) was ineffective as an antagonist of morphine (20 mg/kg). Profadol does not produce its behavioral effects in pigeons by an action with a naloxone-sensitive opioid receptor and its non-opioid behavioral effects are dissimilar to those of previously studied meperidine-like phenylpiperidine analgesics.     

Effects of feeding regimen on ethanol intake by guinea pigs

During daily two-hr sessions, guinea pigs licked a drinking tube filled with either 0 (tap water), 2, 4 or 8% (v/v) ethanol solution under three feeding regimens. Consumption of each solution was highest when sufficient food to maintain subjects at 90% of free-feeding weight was provided during sessions, lower when the same food ration was provided after sessions, and lowest when ad lib access to food was provided within and between sessions. However, this decrease in consumption across feeding regimens was inversely related to ethanol concentration. Under all feeding regimens, volume of solution consumed decreased with increasing ethanol concentration while milligrams ethanol consumed increased with ethanol concentration. These results are similar in some respects to previous findings with rats and monkeys, suggesting that further studies of oral ethanol self-administration by guinea pigs may be merited.     

Lung damage following whole body,but not intramuscular,exposure to median lethality dose of sarin: findings in rats and guinea pigs

Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxicity which includes hyper-salivation, respiratory distress, tremors, seizures, and death. Here we focused on the characterization of the airways injury induced by direct exposure of the lungs to sarin vapor and compared it to that induced by the intramuscularly route.

Materials and methods: Rats were exposed to sarin either in vapor (～1LCT50, 34.2?±?0.8?µg/l/min, 10?min) or by i.m. (～1LD50, 80?µg/kg), and lung injury was evaluated by broncho-alveolar lavage (BAL).

Results and discussion: BAL analysis revealed route-dependent effects in rats: vapor exposed animals showed elevation of inflammatory cytokines, protein, and neutrophil cells. These elevations were seen at 24?h and were still significantly higher compared to control values at 1?week following vapor exposure. These elevations were not detected in rats exposed to sarin i.m. Histological evaluation of the brains revealed typical changes following sarin poisoning independent of the route of administration. The airways damage following vapor exposure in rats was also compared to that induced in guinea pigs. The latter showed increased eosinophilia and histamine levels that constitutes an anaphylactic response not seen in rats.

Conclusions: These data clearly point out the importance of using the appropriate route of administration in studying the deleterious effects of volatile nerve agents, as well as the selection of the appropriate animal species. Since airways form major target organs for the development of injury following inhalation toxicity, they should be included in any comprehensive evaluation of countermeasures efficacy.     

Long-term,low-level exposure of guinea pigs and marmosets to sarin vapor in air: lowest observable effect level

Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. In order to expose animals to the lowest controllable concentrations of agent and to increase exposure times until a lowest observable effect level (LOEL) becomes measurable, a validated system was developed for exposing conscious animals to 0.05-1.0 microg/m(3) (8-160 ppt) of sarin and other nerve agents. Based on cold trapping of sarin from the exposure air, the concentration could be measured semicontinuously, at 4-min time intervals by means of gas chromatography. We found that the LOEL upon a 5-h whole body exposure of guinea pigs and marmosets to sarin vapor corresponds with the measurement of an internal dose by means of fluoride-induced regeneration of sarin from phosphylated binding sites in plasma, mostly BuChE. For guinea pigs the LOEL was observed at Ct = 0.010 +/- 0.002 mg/min/m(3), whereas a Ct of 0.04 +/- 0.01 mg/min/m(3) was established for the LOEL in marmosets. These levels are several orders of magnitude lower than those based on classical measurement of depressed cholinesterase activities. At low exposure levels of guinea pigs and marmosets (< or =1 microg/m(3)), a reasonable linearity was observed between exposure dose and internal dose. The data were addressed in the light of the recently recommended occupational exposure limits to sarin for workers without respiratory protection, which suggests that the exposure limits should be reconsidered if the slightest inhibition of cholinesterases should be prevented.     

Effects of nicotine on the shuttlebox behavior of trained guinea pigs

The comparative effects of three doses of nicotine (0.075, 0.15 and 0.3 mg/kg) were measured on the shuttlebox behavior of highly trained guinea pigs, using 50-trial sessions and a 15 sec CS-US interval. It was found that nicotine counteracted the characteristic intra-session performance decrement seen with this species and, in addition, that the various doses of nicotine could be differentiated from each other and the control (physiological saline) in this test. These results were obtained through the measurement of response latencies and the recording of intertriai responses which, for the purposes and conditions of this and future studies of this type, were shown to be more effective parameters than the measurement of avoidance frequency alone.     

火把花根片对哮喘豚鼠气道炎症的作用

目的探讨火把花根片对哮喘豚鼠气道慢性炎症的作用。方法建立哮喘豚鼠动物模型 :将豚鼠 2 6只随机分为 3组 ,A组为火把花根组 (9只 ) ,B组为地塞米松组 (9只 ) ,C组为哮喘对照组 (8只 ) ,观测豚鼠支气管肺泡灌洗液 (BALF)细胞总数、嗜酸性粒细胞、淋巴细胞、中性粒细胞数量以及蛋白浓度和肺组织病理学的变化。结果A组BALF细胞总数、以嗜酸性粒细胞为主的炎性细胞数量及蛋白浓度均低于C组 (P <0 0 1) ,其肺组织气道慢性炎症表现亦较C组减轻。结论火把花根片可显著抑制哮喘豚鼠的气道慢性炎症     

Behavioral evaluation of rats following low-level inhalation exposure to sarin

We evaluated the effects, in rats, of single and multiple low-level inhalation exposures to sarin. Rats were trained on a variable-interval, 56 s (VI56) schedule of food reinforcement and then exposed to sarin vapor (1.7-4.0 mg/m(3) x 60 min) or air control. The exposures did not produce clinical signs of toxicity other than miosis. Subsequently, performance on the VI56 and acquisition of a radial-arm maze spatial memory task was evaluated over approximately 11 weeks. Single exposures did not affect performance on the VI56 and had little effect on acquisition of the radial-arm maze task. Multiple exposures (4.0 mg/m(3) x 60 min/day x 3) disrupted performance on the VI56 schedule during the initial post-exposure sessions. The disruption, however, resolved after several days. Multiple exposures also produced a deficit on the radial-arm maze task in that sarin-exposed rats tended to take it longer to complete the maze and to make more errors. The deficit, however, resolved during the first three weeks of acquisition. These results demonstrate that in rats, inhalation exposure to sarin at levels below those causing overt signs of clinical toxicity can produce cognitive and performance deficits. Furthermore, the observed deficits do not appear to be persistent.     

Effect of quinidine on the intestinal secretion of digoxin in guinea pigs

Following i.v. injection of digoxin (10 μg kg^?1) the ratio between digoxin concentrations in the lumen of jejunal loops perfused in situ and in plasma (L/P) of guinea pigs increased linearily with time. After 3 h, L/P was 8·7, indicating net secretion of digoxin against a concentration gradient. In quinidine treated animals (100 mg kg^?1 p.o., 2h before experiment) both the L/P ratio (5·7; p < 0·01) and the digoxin content of jejunal tissue (– 32 per cent; p < 0·01) were markedly reduced. It is suggested that quinidine reduces the extrarenal clearance of digoxin at least in part by inhibiting the intestinal secretion of this glycoside.     

Effects on mitochondrial metabolism in livers of guinea pigs after a single or repeated injection of As2O3

Differences in the metabolite pattern were observed in previous experiments in guinea pig livers after a single injection or prolonged (5 days) treatment with AS₂O₃ (Reichl et al. 1988). To elucidate the underlying mechanism the effect of As₂O₃ on liver metabolism was therefore investigated. Male guinea pigs received either a single dose (s. d.) of As₂O₃ 10 mg × kg^–1 s. c. or repeated doses (r. d.) of 2.5 mg × kg^–1b. i. d. on 5 consecutive days. One hour after the s. d. or 1 h and 16 h after the last injection in the r. d. groups the animals were sacrificed in anaesthesia. The livers were removed by freeze clamping for the determination of various metabolites. In the s. d. group a significant decrease in hydroxybutyrate, acetylCoA, adenosinemonophosphate and in the ratio of hydroxybutyrate/acetoacetate and an increase in pyruvate, citrate, malate, and adenosinetriphosphate were observed. A significant decrease in glycogen, pyruvate, -ketoglutarate, acetylCoA, and acetoacetate and a significant increase in malate and in the ratios of lactate/pyruvate and hydroxybutyrate/acetoacetate were observed in the r. d.1-h group. In the r. d.16-h group a significant decrease in glycogen, pyruvate, lactate, and adenosinemonophosphate was found, but the values tended towards control values. The data are consistent with mechanisms of As₂O₃ toxicity in other species as PDH inhibition with consecutive citric acid cycle and gluconeogenesis inhibition and excessive carbohydrate depletion.     

Acute effects of physostigmine on complex operant behavior in rhesus monkeys

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001–0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or “cognitive” impairment.     

Environmental influences upon morphine or d-amphetamine induced suppression of operant behavior

Rats trained in an operant chamber to lever press for food on a FR-30 schedule of reinforcement were given 1.0 mg d-amphetamine sulfate (IP)/kg. Injection of the drug followed by immediate placement into the operant chamber resulted in a disruption of behavior, after a 10 min latency, which lasted for approximately 25 min. Removal of the animals from the chamber soon after the onset of behavioral disruption and replacement into the chamber as soon as 2.5 min later resulted in resumption of lever pressing almost immediately. Animals left in their home cages for 10 min after being injected with d-amphetamine and then placed in the operant chamber started to bar-press almost immediately, taking an average of 4 min to receive 5 reinforcers (150 responses). A second group of rats, maintained on the same schedule of reinforcement, showed similar striking effects of delayed placement after injection with 10 mg morphine sulfate/kg. The 10 min delay resulted in a significant reversal of the behavioral suppression observed at a comparable time after injection of morphine and immediate placement into the operant chamber.     

Protection of guinea pigs against soman poisoning with ferrocene carbamate

The protective effect of ferrocene carbamate pretreatment against soman poisoning was studied in guinea pigs. At doses corresponding to 1/20 x and 1/10 × LD₅₀ of this carbamate a 20% and 45% decrease of the acetylcholinesterase in blood and brain, respectively, was obtained. In combination with additional pretreatment, diazepam, and therapy, HI-6 and atropine, the protective ratios (LD₅₀ of soman in treated animals/LD₅₀ of soman in untreated animals) were around 20 and 40, respectively. Animals pretreated with the high dose of the ferrocene carbamate that survived 10 x and 15xLD_50s of soman showed no remaining signs of poisoning after 24 h. Thus, the ferrocene carbamate afforded a better protection against soman than physostigmine. The explanation for this could be due to the properties of the ferrocene carbamate, not correlated to its cholinesterase inhibiting activity. This hypothesis is discussed.     

复方苍耳子滴鼻剂对豚鼠变应性鼻炎的影响

目的观察复方苍耳子滴鼻剂对变应性鼻炎模型豚鼠症状的变化和血清组胺含量的影响。方法以甲苯-2,4-二异氰酸甲苯酯(TDI)作为致敏因子建立豚鼠鼻黏膜变态反应模型,以模型组、阳性药物组与空白组为对照,测定各组豚鼠鼻黏膜内组胺的含量及形态组织学的改变。结果 ①鼻部症状的改善情况:复方苍耳子滴鼻剂高、低剂量组药前总评分与药后总评分比较差异有统计学意义(P<0.05),能显著性改善慢性鼻炎模型动物的整体症状;②对血清组胺含量的影响:复方苍耳子滴鼻剂高、低剂量组血清组胺含量均显著低于模型组(P<0.05或0.01),能显著降低慢性鼻炎模型动物的血清组胺含量;③形态组织学的改变:复方苍耳子滴鼻剂高、低剂量对鼻黏膜上皮化生、腺体增生、血管增生或扩张及炎性细胞等方面均能显著改善慢性鼻炎模型动物的形态组织学。结论复方苍耳子滴鼻剂对豚鼠实验性变态反应性鼻炎有显著的改善作用。     

Effect of arsenic on carbohydrate metabolism after single or repeated injection in guinea pigs

Divergent pattern in pyruvate efflux from livers perfused with As₂O₃ and livers of animals previously repeatedly treated with the toxicant was observed in earlier experiments (Reichl et al. 1987, 1988). Further studies of the effect of As₂O₃ on carbohydrate metabolism were therefore performed. Male guinea pigs received either a single dose of As₂O₃ 10 mg· kg^–1 s.c. or repeated doses of 2.5 mg·kg^–1 bis in die (b.i.d.) on 5 consecutive days. One hour after the single dose or 1 h and 16 h after the last injection in the repeated treatment group the animals were sacrificed under anaesthesia. The livers were removed by a freeze-stop technique and the contents of glycogen and glycolysis intermediates were measured. In the single dose group a decrease in fructose-1,6-diphosphate and glycerolaldehyde-3-phosphate and an increase in phosphoenolpyruvate and pyruvate was observed. In the repeat dose, 1-h group a significant decrease in glycogen, glucose-6-phosphate, fructose-6-phosphate, glycerolaldehyde-3-phosphate, dihydroxyacetonephosphate, 2-phosphoglycerate and pyruvate was found. In the repeat dose, 16-h group the contents of glycogen, glucose-6-phosphate, pyruvate and lactate were diminished. The most prominent finding after repeated As₂O₃ administration was a marked depletion in total carbohydrate content. This was due mainly to depletion of glycogen.     

Cyclazocine disruption of operant behavior is antagonized by naloxone and metergoline

Male-Sprague-Dawley rats were trained to press a lever on a fixed ratio-40 (FR-40) schedule for food reinforcement. Doses ranging from 0.5 to 16 mg/kg of the mixed narcotic agonist-antagonist cyclazocine (30-min pretreatment) resulted in a dose-dependent decrease in the number of reinforcements obtained and a reciprocal increase in “pausing” (IRT's greater than 10 sec). A 5-min pretreatment with 4 mg/kg of the narcotic antagonist naloxone attenuated the cyclazocine disruption. The 5-HT antagonist metergoline (1 mg/kg; 180-min pretreatment) also blocked cyclazocine effects to approximately the same degree as did naloxone. However, the shift of the dose response pattern of cyclazocine was not parallel for either antagonist. A greater degree of attenuation of the cyclazocine effects was observed when naloxone (4 mg/kg) and metergoline (0.1 mg/kg) were given together, indicating that cyclazocine disruption may be antagonized by either a narcotic antagonist or a 5-HT antagonist, and that these antagonists may operate synergistically. Thus, the behavioral effects of cyclazocine may relate to both opioid and serotonergic components.     

Serum and lung levels of thiamphenicol after administration of its glycinate N-acetylcysteinate ester in experimentally infected guinea pigs

Thiamphenicol is an analogue of chloramphenicol and is characterised by a broad spectrum of action. In this study, serum and lung levels of thiamphenicol (TAP) were studied in infected guinea pigs after the administration of thiamphenicol glycinate N-acetylcysteinate (TGA). Animals received a single dose of TGA (15 mg/kg, subcutaneously) immediately after intra-tracheal infection with Haemophilus influenzae (about 10⁷ CFU/animal). Serum and lung concentrations of TAP were determined at 0, 1, 3, 6, 12 and 24 h after drug administration by means of HPLC. TAP serum levels were elevated at 1 h and remained detectable for 24 h after drug administration. Tissue lung levels were comparable to peak serum concentrations but remained higher and decreased more slowly than serum concentrations.     

Effects of intracerebroventricular injection of naloxone on operant feeding and drinking in pigs

Operant feeding and drinking to satiation were studied in prepubertal pigs deprived of food or water for 18 hours and then given intracerebroventricular (ICV) injections of a solution of naloxone hydrochloride. In feeding tests there was no difference in the amount of food consumed, or in the rate at which reinforcements were obtained, between pigs given ICV injections of 0.4 or 0.8 mg naloxone and those receiving a control injection of saline. However, in drinking tests, injection of both 0.2 and 0.4 mg naloxone significantly (p less than 0.01) reduced the quantity of water drunk and slowed the rate at which reinforcements were obtained. No significant effects on operant water intake were seen after intravenous injection of 0.4 mg naloxone.     

Differential sensitivity to the effects of albuterol on locomotor activity and operant behavior

The purpose of the present study was to determine the effects of the beta-2 selective adrenergic agonist albuterol on three behaviors, locomotor activity, behavior maintained under a differential-reinforcement-of-low-rate (DRL) schedule, and behavior maintained under a multiple fixed-interval, fixed-ratio (FI-FR) schedule of reinforcement. Albuterol reduced response rate under the DRL schedule in a manner that resulted in an increase in reinforcement rate. Similarly, albuterol reduced response rate under both components of the multiple FI-FR schedule in a dose-dependent manner. The ED₅₀ values for the effects of albuterol on these two operant behaviors were calculated to be approximately 1 mg/kg and the minimal effective doses were 0.3–1 mg/kg. In addition to affecting operant behavior, albuterol also reduced locomotor activity; the ED₅₀ values and minimal effective doses were 0.05 and 0.03 mg/kg, respectively. The effects of albuterol on DRL behavior, FI-FR behavior and locomotor activity were antagonized by the beta adrenergic antagonist propranolol; this suggests that the behavioral effects of this agonist were mediated, at least in part, by beta adrenergic receptors. The differential sensitivity of locomotor activity and operant behavior to albuterol suggests that the actions of this drug on locomotor activity may be mediated predominantly by peripheral beta adrenergic receptors and that its effects on operant behavior may be mediated by beta adrenergic receptors in the central nervous system.     

太子健对哮喘豚鼠白细胞介素-5 P-选择素的影响

目的　观察太子健 对反复诱发哮喘的哮喘豚鼠血中白细胞介素 (IL) - 5、黏附分子 P-选择素的影响。方法　将豚鼠随机分为正常组、模型组、地塞米松组、太子健 高剂量和低剂量组 5组 ,后 4组分别用卵蛋白致敏 15 d后 ,再用卵蛋白反复诱发哮喘 ,正常组用生理盐水代替 ,同时 ,正常组和模型组灌服生理盐水 ,其余 3组分别灌服地塞米松、高剂量和低剂量太子健 ,予以治疗 ,连续 15 d。结果　太子健 可减少血中 IL- 5、黏附分子 P-选择素的含量。结论　太子健 可以影响 IL- 5、P-选择素对炎症细胞的调节作用 ,从而减轻气道慢性变应性炎症 ,具有一定的抗哮喘复发的作用。     

Stimulant actions of histamine H1 antagonists on operant behavior in the squirrel monkey

Squirrel monkeys were studied under fixed-interval schedules of reinforcement in which the first response (lever press) after a fixed period of time resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. Benztropine mesylate (0.03–1.7 mg/kg), promethazine HCl (0.3–10 mg/kg), and diphenhydramine HCl (0.3–17 mg/kg) all produced marked increases in responding at intermediate doses. The increases in responding were at least as great as those observed with psychomotor stimulants, such as amphetamine, in this species under similar behavioral conditions. Benztropine was most potent and diphenhydramine was least potent in most monkeys and, in some, promethazine and diphenhydramine were about equipotent. The order of potency and the magnitude of potency differences among the drugs suggest that the behavioral effects were due to antagonist actions at histamine H₁ receptors, rather than to effects on dopamine uptake or on muscarinic receptors.