Toxic effects of subacute inhalation exposure to trichloroethylene on serum lipid profile,glucose and biochemical parameters in Sprague–Dawley rats

Abstract

The current study evaluated the inhalation toxicity of trichloroethylene (TCE) at 0, 10, 100, 250 and 400?ppm in Sprague–Dawley rats for 10 day period, because the subacute inhalation toxicity of TCE on serum lipid profile, glucose and some biochemical parameters has not been previously reported. TCE vapors were generated using the dynamic generation system based on evaporation method in the exposure chamber. On the basis of the results, mean serum low-density lipoprotein (LDL) and albumin (ALB) decreased significantly in all the groups exposed to TCE compared with the control group (p?<?.005), but there was a significant increase for parameters: fasting blood glucose (FBG) and alkaline phosphatase (ALP) (p?<?.005). Rats exposed to 400?ppm TCE showed a significant decrease in serum cholesterol (CHOL) and protein (Pr) compared with the control group (p?<?.005). A negative relationship was found between triglycerides (TG), very low density lipoprotein (VLDL), CHOL, LDL, Pr, ALB and urea levels and the subacute exposure to concentrations of TCE (R²?=?–0.26, p?<?.05), but there was a direct correlation for parameters FBG, ALP and alanine aminotransferase (ALT) (R²?=?0.42, p?<?.05). In conclusion, studies with Sprague–Dawley rats demonstrated that subacute inhalation exposure to TCE (≥ 100?PPM) is associated with biochemical and lipotoxicity in the form of decreased serum ALB and LDL and raised ALP and glucose levels. The present study also provides additional evidence relating to decreased serum CHOL and Pr after subacute inhalation exposure to 400?ppm TCE.     

Effects of carnosine on amygdaloid kindled seizures in Sprague - Dawley rats

The effects of carnosine （ -alanyl -L -histidine） on amygdaloid kindled seizures were investigated in rats. Intraperitoneal injection of carnosine （500, 1000, 1500 mg/kg, i. p. ） significantly decreased seizure stage, afterdischarge duration and generalized seizure duration, and significantly prolonged generalized seizure latency of amygdaloid kindled seizures, in a dose - dependent, and time - related manner. The protective effect of carnosine （ 1500 mg/kg） was completely antagonized by histamine H1 -antagonists pyrilamine （2, 5 mg/kg, i. p. ） and diphenhydramine （5, 10 mg/kg, i. p. ）,     

Anxiolytic-like profile in Wistar, but not Sprague–Dawley rats in the social interaction test

Rationale The social interaction test is a valuable behavioural model for testing anxiolytic drugs in rodents, quantifying the level of social behaviour between pairs of rats.Objective The aim of the present study was to assess the appropriateness of the social interaction test for use with a Sprague–Dawley rat line, because of increasing use of this strain in targeted mutagenesis research.Methods Sprague–Dawley and Wistar rats received either diazepam or mCPP or were exposed to different environmental conditions (lighting, social isolation prior testing, habituation, testing-time). General anxiety-related parameters measured were: duration of active social contact, frequency of active social contact, latency to first contact. Different forms of active social contact were recorded: number of crawls, follows and sniffs. Secondly, aversion-induced hippocampal serotonin release and serotonin content in brain regions were measured.Results In Wistar rats habituation to the test substantially increased the time of social contact, an effect comparable with treatment with diazepam (1 mg/kg), whereas changes in the lighting level had less impact. Latency to the first contact increased under anxiety-reducing conditions, the frequency of contacts did not change consistently. Sprague–Dawley rats behaviour did not change under varying environmental conditions, and treatment with diazepam had only sedating effects at higher doses (5 mg/kg). Anxiogenic doses of mCPP caused reduced social interaction in both strains. Serotonin release and serotonin content were higher in the anxious Wistar rats.Conclusions Different rat strains as well as differing test conditions have a major impact on the outcome of this animal test for anxiety.     

Effect of food restriction on cocaine locomotor sensitization in Sprague–Dawley rats

Rationale

The interaction between repeated cocaine exposure and food restriction on sensitization to the stimulatory effects of cocaine has not been characterized.

Objectives

To compare cocaine sensitization in rats free fed and food restricted, and begin to explore the role of the stress-responsive dynorphin/kappa opioid system.

Methods

Male rats were maintained for 10 days on two feeding conditions: free fed or food restricted (85 % of free fed weight). Test 1 of locomotor reactivity to cocaine (3, 9, or 15 mg/kg, IP) was followed by a sensitizing regimen of cocaine exposure (0 or 30 mg/kg/day × 5 days, IP), by a 10-day drug-free period, and by Test 2 of reactivity to the same cocaine dose. In a second experiment, rats received an injection of norbinaltorphimine (nor-BNI; 0, 5 or 20 mg/kg, SC) 10 days prior to each locomotion test, and plasma corticosterone (CORT) was assessed after Test 2.

Results

On Test 1, it was found that food restriction enhanced locomotor responses to all doses of cocaine. On Test 2, it was found that free fed and food restricted animals displayed similar sensitized responses to cocaine. This, however, was not observed in nor-BNI-treated rats. Furthermore, 20 mg/kg nor-BNI reduced both the locomotor response to cocaine on Test 2 and the effect of cocaine and food restriction on CORT plasma levels.

Conclusions

These results indicate that the interaction between cocaine sensitization and food restriction is not synergistic, and that it involves activation of kappa-opioid receptors.     

The comparative study of Sprague–Dawley and Lewis rats in adjuvant-induced arthritis

The outbred Sprague–Dawley (SD) rats, similar to the inbred Lewis (LEW) rats, have been recently demonstrated to be highly susceptible to adjuvant-induced arthritis (AIA). We herein compared AIA in SD and LEW rats in terms of clinical, histological, radiological, and immuno-inflammatory features. The results showed that, following inoculation with a ground Mycobacterium tuberculosis (MT) suspension, SD and LEW rats manifested closely similar disease progression, with 100% incidence and similar severity. The development of arthritis was accompanied by significantly higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels than in control rats. Radiographic examination of the hind paws showed that both SD and LEW AIA rats manifested conspicuous soft tissue swelling, bone matrix resorption, periosteal new bone formation and bone erosion, while histopathological analysis of the synovial joints revealed marked cellular infiltration, angiogenesis, synovial hyperplasia, pannus formation, narrowing of joint space, and cartilage and bone destruction. Moreover, in relation to disease progression, serum tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels were markedly overexpressed in both SD and LEW AIA versus control rats, and SD and LEW AIA rats exhibited divergent profiles for the expression of TNF-α and IL-1β. Taken together, these results demonstrated that the SD rat AIA model shares several arthritic features with the comparable model in LEW rats. Hence, given the more favorable characteristics of SD rats than LEW rats (i.e., lower cost, wider availability, and heterogenic background), this SD rat AIA model is more cost effective and advantageous for screening and testing novel anti-arthritic agents.     

Effects of the food contaminant semicarbazide following oral administration in juvenile Sprague–Dawley rats

Semicarbazide (SEM) is an azodicarbonamide by-product present in glass jar packaged foods including babyfoods, in bleaching steps and flour treatment. Experimental data showed SEM acting as osteolathyrogen agent, but few toxicological data are available in susceptible life-stages. This study aimed to evaluate effects of SEM oral administration for 28 days at 0, 40, 75, 140 mg/kg bw day during the juvenile period in Sprague–Dawley rats. Histopatological examinations of: epiphyseal cartilage – potential target of SEM lathyrogen action - testes, ovary, uterus, thyroid, thymus, spleen, adrenals, representative of the main developing organs relevant to juvenile toxicity, and neurobehavioural tests in males, were performed. Mortality at high and mid dose levels and significantly decreased body weight gain were observed in males even at the lowest dose. Lack of mineralization in cartilage at all dose levels was present. Marked alterations of spontaneous motor and exploratory behaviours were evident even at 40 mg/kg. Histological alterations were observed in all tissues; thyroid and ovary effects were present also at 40 mg/kg. The present study indicate that the NOAEL in juvenile rats is lower than 40 mg/kg for SEM oral administration. SEM administration during juvenile period exerted pleiotropic effects and further studies are suggested to elucidate mechanisms.     

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

Rationale 3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”) use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT).Objectives This study investigates whether sex differences in the acute and long-term effects of MDMA exist.Methods Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment.Results Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later.Conclusions MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females. Funding: DA 09079. Christina N. Williams was supported by an RJR-Leon Golberg postdoctoral fellowship and ES07031.     

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Rationale

Fendiline is a GABA_B receptor-positive allosteric modulator and L-type Ca²⁺ channel blocker that is safe for human use. Based on these pharmacological properties, fendiline may be useful to disrupt associative memories that can drive relapse to drug use in drug-addicted individuals

Objective

The current study evaluated the potential of fendiline to inhibit the maintenance and expression of learned associations between methamphetamine (meth) and an environmental context using conditioned place preference (CPP) in rats, to model for the associative learning that occurs during drug abuse by humans

Methods

Following meth conditioning (1 mg/kg), fendiline (5 mg/kg) was administered at various post-conditioning times to ascertain if there was a temporal window during which fendiline would be effective.

Results

Two once-daily injections of fendiline did not influence the maintenance of CPP regardless of the post-conditioning treatment time while 10 once-daily fendiline treatments inhibited CPP maintenance (p?<?0.05). Fendiline administered immediately prior to the CPP test inhibited expression of meth-induced CPP in rats with a fendiline treatment history of 10 once-daily injections (p?<?0.05) or those that received two injections that corresponded to the last 2 days of the 10-day treatment (p?<?0.05). Fendiline did not produce preference or aversion on its own, nor did it alter motivated motor behavior.

Conclusion

Maintenance and expression of meth CPP is mitigated by repeated fendiline treatments when administered during the days that precede CPP testing. Reduction in the significance of meth-associated cues can reduce relapse; therefore, fendiline may be of value for addiction therapy in abstinent, meth-addicted humans.     

The metabolic fate and effects of 2-Bromophenol in male Sprague–Dawley rats

Abstract

1. The metabolic fate and urinary excretion of 2-bromophenol, a phenolic metabolite of bromobenzene, was investigated in male Sprague–Dawley rats following single intraperitoneal doses at either 0, 100, or 200?mg/kg.

2. Urine was collected for seven days and samples analysed using ^1?H NMR spectroscopy, inductively coupled plasma (ICP)MS, and UPLC-MS.

3. ^1?H NMR spectroscopy of the urine samples showed that, at these doses, 2-bromophenol had little effect on endogenous metabolite profiles, supporting histopathology and clinical chemistry data, which showed no changes associated with the administration of 2-bromophenol in this study.

4. The use of ICP-MS provided a means for the selective detection and quantification of bromine-containing species and showed that between 15 and 30% of the dose was excreted via the urine over 7?days of the study for both the 100 and 200?mg doses, respectively.

5. The bulk of the excretion of Br-containing material had occurred by 8?h post administration. UPLC-MS of urine revealed a number of metabolites of 2-bromophenol, with 2-bromophenol glucuronide and 2-bromophenol sulphate identified as the major species. A number of minor hydroxylated metabolites were also detected as their glucuronide, sulphate, or O-methyl conjugates. There was no evidence for the production of reactive metabolites.     

The effects of extended intravenous nicotine administration on body weight and meal patterns in male Sprague–Dawley Rats

Rationale

Increased appetite and weight gain after cessation is a deterrent for quitting smoking. Attempts to understand the mechanism for these effects using animals have been hampered by the difficulty or inconsistency of modeling the effects seen in humans.

Objective

To examine the effects of extended daily access to intravenous nicotine, via programmed infusions, on body weight and meal patterns in rats.

Methods

Intravenous (IV) nicotine infusions (0.06 mg/kg/inf) were administered noncontingently, every 30 min throughout the dark cycle and the last 3 h of the light cycle, to emulate self-administration. The effect of these infusions on food intake, meal patterns, and weight change were examined relative to a control group during treatment and in a post-nicotine phase.

Results

Nicotine-treated rats gained half the weight that vehicle treated animals gained and ate approximately 20 % less food overall than vehicle-treated rats. Whereas a compensatory increase in meal frequency occurred during the dark period to account for smaller meals, no compensation was observed throughout the light period. In a post-nicotine phase, the nicotine group maintained a lower weight for 1 week and then gained weight back to control levels. The rate of weight gain post-cessation was faster in animals that had received nicotine compared to controls.

Conclusion

Compared to previous studies examining the effects of minipump or intraperitoneal injections of nicotine on food intake, the present study was able to detect previously unknown circadian differences in meal patterns which will be important in the development of smoking cessation and weight gain prevention drugs.     

Comparative 90-day dietary study of paraffin wax in Fischer-344 and Sprague–Dawley rats

Highly refined mineral hydrocarbons (MHCs) such as low melting point paraffin wax (LMPW) and low viscosity white oils can cause inflammatory changes in the liver and mesenteric lymph nodes (MLNs) of the Fischer-344 (F-344) rat. In contrast, only minimal MLN changes are seen in the Sprague–Dawley (S–D) rat with no changes in the liver. In this study, the response of female F-344 and S–D rats was compared after 90 days dietary treatment with 0%, 0.2% or 2% LMPW. Effects in the F-344 rats were significantly greater than in the S–D rats: increased liver and splenic weights and inflammatory changes (hepatic microgranulomas) in these tissues were observed only in the F-344 rats. Microgranulomas in the MLNs were observed in both strains but the effects were substantially greater in the F-344 rats. Cellular markers of inflammation were examined in a subset of rats from each group using immunohistochemical staining. An increase in staining for CD3 (T-cells), CD8a (suppresser/cytotoxic T-cells) and CD4 (helper T-cells) correlated with an increase in lymphoid cells in the livers of treated F-344 rats. The majority of macrophages in the hepatic microgranulomas of treated F-344 rats were negative for the ED2 marker, indicating a likely origin from non-resident macrophages. Electron microscopy showed Kupffer cell hypertrophy and hyperplasia in treated F-344 rats. However, lysozyme staining (indicating activation of epithelioid macrophages) decreased with increasing granuloma size. Non-ED2 expressing cells may have been recruited but not sufficiently activated to be lysozyme positive. Inflammatory changes in the cardiac mitral valve noted in previous studies of LMPW were also seen in the F-344 rats in this study but not in the S–D rats. Chemical analysis showed that MHC accumulated in livers from treated F-344 but not S–D rats and the concentration was more than 2-fold greater in MLNs from the F-344 than from the S–D rats. The F-344 appears to be more immunologically sensitive to a number of agents than other rat strains and the results of this study suggest that this may contribute, along with pharmacokinetic differences, to the inflammatory response of F-344 rats to dietary MHCs.     

Acute and developmental toxicity assessment of erincine A-enriched Hericium erinaceus mycelia in Sprague–Dawley rats

This study aimed to establish an in vitro model to confirm the efficacy of erinacine A-enriched Hericium erinaceus (EAHE) mycelia and investigate its potential adverse effects in a preclinical experimental setting, including an assessment on the oral administration of EAHE mycelia in acute and prenatal developmental toxicity tests. At a single dose of 5000?mg/kg body weight, EAHE mycelia elicited no death or treatment-related signs of toxicity in ten Sprague–Dawley rats of both sexes during the 14?days of the experimental period. After considering the recommended dose range of EAHE mycelia from the acute toxicity test as well as the therapeutic doses, EAHE mycelia was administered to 66 pregnant rats in the low, medium, and high-dose groups by gavage at 875, 1750, and 2625?mg/kg body weight, respectively. All dams were subjected to a Caesarean section on the 20th day of pregnancy, and the fetuses were examined for any morphological abnormalities. Results indicated that weight of uterus, fetal body weight, number of corpora lutea, implantation sites, pre-implantation loss, and post-implantation loss of the treatment groups and the control group exhibited no statistical difference. In addition, no significant differences were observed in the fetal external, organ, and skeletal examinations. Taken together, it can be concluded that EAHE mycelia is considered safe and practically nontoxic for consumption within the appropriate doses and investigation period in this study.     

Enhancing effect of heroin on social recognition learning in male Sprague–Dawley rats: modulation by heroin pre-exposure

Rationale  There is evidence that pre-exposure to drugs of abuse can induce sensitization to several of their effects. Objective  Four experiments were conducted to investigate the effect of heroin pre-exposure on modulation of memory consolidation as indexed by heroin's action on rate of learning. Materials and methods  Male Sprague–Dawley rats were tested on a social recognition learning task which assesses changes in investigation during repeated exposure to the same rat (habituation training: four sessions) and during exposure to a novel rat (dishabituation test). In the first experiment, rats received 0, 0.3, or 1 mg/kg heroin s.c. immediately following each training session, or 1 mg/kg heroin 2 h post-training. In experiments 2 and 3, rats received 1 mg/kg heroin post-training after a 7-day drug-free period from heroin pre-exposure achieved through conditioned place preference (1 mg/kg s.c., 1 injection/day × 4 days) or intravenous self-administration (0.05 mg/kg/infusion i.v., 3 h/day × 9 days) training. In experiment 4, rats received 0, 0.03, 0.3, or 3 mg/kg heroin post-training after a 7-day drug-free period from a regimen of heroin administration (i.e., 1 mg/kg heroin/day s.c. × 7 days) that induced locomotor sensitization. Results  Post-training administration of heroin enhanced social recognition learning in a dose- and time-dependent manner. Importantly, no regimen of heroin pre-exposure significantly altered this effect of heroin. Conclusions  These results do not support the hypothesis that heroin pre-exposure leads to sensitization to its effect on memory consolidation of non-drug-related learning. However, this requires further testing using alternative heroin pre-exposure regimens, a wider range of post-training heroin doses, as well as other types of learning tasks.     

Effects of stress modulation on morphine-induced conditioned place preferences and plasma corticosterone levels in Fischer, Lewis, and Sprague–Dawley rat strains

Rationale There is a direct relationship between hypothalamic–pituitary–adrenal axis (HPA) reactivity and susceptibility to drug use in outbred rats. Specifically, manipulations that increase or decrease HPA activity also increase or decrease drug intake, respectively. Interestingly, this relationship has not been established in the inbred Fischer (F344) and Lewis (LEW) rat strains that are often used as animal models of susceptibility to drug use.Objective The present study investigated the effects of manipulations known to affect HPA activity on morphine-induced conditioned place preference (CPP) in male LEW, F344, and Sprague–Dawley (SD) rats.Materials and methods In experiment 1, animals were exposed to an injection of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and 2-h restraint stress prior to the conditioning of a morphine-induced place preference (1, 4, or 10 mg/kg subcutaneous). In experiment 2, animals were chronically exposed to corticotropin-releasing hormone type 1 receptor antagonist, antalarmin, prior to CPP training. The effects of DMCM/restraint and antalarmin on corticosterone levels were examined in experiments 3 and 4.Results In outbred rats, DMCM/restraint increased both HPA activity and morphine-induced CPP, while antalarmin decreased CPP and produced a slight, but nonsignificant, decrease in corticosterone levels. In the inbred rats, however, DMCM/restraint increased plasma corticosterone yet decreased place preferences in the LEW strain, and antalarmin treatment decreased plasma corticosterone but increased place preferences in the F344 strain.Conclusions These data suggest that the relationship between stress and drug use may be nonmonotonic. The use of these inbred strains in genetic analysis of drug addiction may require reexamination.     

Effects of in utero through lactational exposure to dicyclohexyl phthalate and p,p′-DDE in Sprague–Dawley rats

Anti-androgenic chemicals alter sexual differentiation by a variety of mechanisms, and the mechanisms between phthalate esters and p,p′-DDE are considered to be different. We performed an in utero through lactational exposure assay using dicyclohexyl phthalate and p,p′-DDE to investigate the sexual differentiation of these chemicals. Pregnant CD (SD) IGS rats were given dicyclohexyl phthalate or p,p′-DDE orally from gestational day (GD) 6 to postnatal day (PND) 20, and the endocrine-mediated effects in dams and their offspring were examined. The reproductive performance of offspring was also examined. The doses of dicyclohexyl phthalate were 0, 20, 100, and 500 mg/kg/day, and those of p,p′-DDE were 5, 15, and 50 mg/kg/day. Using the dicyclohexyl phthalate, a dam in the 500 mg/kg group showed dystocia and died. The viability index of offspring on PND 4 decreased in the 500 mg/kg group. Prolonged preputial separation, reduced ano-genital distance, increased areolas/nipple retention, hypospadia, decreased ventral prostate and levator ani/bulbocavernosus muscle weights and decreased testicular germ cells were observed in male offspring in the 500 mg/kg group. In the assay using p,p′-DDE, decreased viability index of offspring on PND 21, prolonged preputial separation in male offspring and early vaginal opening in female offspring were observed in the 50 mg/kg group. The copulation and fertility indices decreased in the reproductive performance of offspring in the 50 mg/kg group. The endocrine-mediated effects were detected in offspring of dams given 100 mg/kg dicyclohexyl phthalate, and in offspring of dams given 20 mg/kg p,p′-DDE. Our results suggest that the in utero through lactational exposure assay is a useful method to detect endocrine-mediated effects and that further comparative study between this assay and two-generation reproductive test are necessary when this assay becomes one of the definitive tests.     

An evaluation of the effects of nonselective and cardioselective ��-blockers on wound healing in Sprague Dawley rats

Objectives:

To investigate the effect of a nonselective β-blocker (propranolol) and cardioselective β-blocker (metoprolol) on wound healing in rats using incision and excision wound models and to compare the effect of these drugs on wound healing.

Materials and Methods:

Propranolol and metoprolol were given orally. Sprague Dawley rats of either sex were used. Incision and excision wound models were used to evaluate the wound-healing activity. Effects of metoprolol and propranolol on tensile strength, period of epithelialization, and hydroxyproline content were observed. Histological analysis was done to see collagen deposition and inflammatory infiltrate.

Statistical Analysis Used:

The data was subjected to analysis of variance (ANOVA) followed by Scheffe''s test. P < 0.05 was considered to be statistically significant. Statistical analysis was done using SPSS software version 15.0.

Results:

Administration of propranolol or metoprolol was shown to decrease tensile strength, delay wound contraction and re-epithelialization, increase inflammatory infiltrate, and reduce collagen density and hydroxyproline levels.

Conclusions:

The results suggest that nonselective and cardioselective β-blockers delay wound healing and these effects are mediated by β1-receptors.KEY WORDS: Excision wound model, incision wound model, metoprolol, propranolol     

Inter-individual diversity and intra-individual stability of amphetamine-induced sensitization of frequency-modulated 50-kHz vocalization in Sprague–Dawley rats

Rationale

Propensity for drug dependence shows great diversity that is related to intrinsic neurobiological factors. This diversity is important both for the understanding of these traits and for the development of therapies.

Objectives

The goals of the study were (1) to define, using ultrasonic vocalization characteristics, inter-individual differences in rats’ propensity for sensitization to amphetamine, (2) to test whether possible resistance to this effect could be overcome with repetitive treatment, and (3) to seek useful predictors of the propensity.

Methods

Rats were subject to tests meant to characterize their anxiety, pain sensitivity, and responses to novelty and natural rewards. Then they were subject to the so-called two-injection protocol of sensitization (using amphetamine) followed by 2?weeks of daily amphetamine treatment, 2-week withdrawal, and final amphetamine challenge. The development and outcome of sensitization were monitored by measuring 50-kHz vocalization.

Results

The two-injection protocol yielded three patterns of changes in the frequency-modulated 50-kHz vocalization response to amphetamine. These patterns persisted after completion of the extended drug treatment. Rats with lower sensitivity to pain or with longer latency of their vocalization response to the first drug exposure showed an increased propensity for ultrasonic vocalization sensitization.

Conclusion

Vulnerability to sensitization of frequency-modulated 50-kHz vocalization response of Sprague–Dawley rats to amphetamine, which supposedly reflects rats’ propensity for amphetamine dependence, shows large inter-individual diversity. Resistance to this effect, which is evident in a majority of the rats, cannot be overcome even with prolonged intermittent drug treatment under the conditions (novelty) that promote sensitization.     

Respiratory safety pharmacology: Positive control drug responses in Sprague–Dawley rats,Beagle dogs and cynomolgus monkeys

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.