Groups Of Gerbils Research Articles

Postnatal zinc deficiency due to giardiasis disrupts hippocampal and cerebellar development.

Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 μm; HGINV 37 ± 5 μm; WB 28 ± 3 μm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism.

Brush Border Membrane Vesicles from Rats and Gerbils Can Be Utilized to Evaluate the Intestinal Uptake of All-trans and 9-cis β-Carotene

Intestinal brush border membrane vesicles (BBMV) have previously been used to investigate the absorptive processes of a wide variety of nutrients. The first objective of this work was to develop a BBMV system to study carotenoid uptake using rat small intestine. The uptake of all-trans β-carotene by rat BBMV was linear up to 5.9 µmol/L, suggesting passive uptake at the concentrations used in this study. Both all-trans β-carotene and 9-cis β-carotene were taken up at a similar rate by the rat BBMV. The vesicle system was then utilized to investigate the uptake of retinol and β-carotene by BBMV isolated from Mongolian gerbils which had been subjected to three different vitamin A depletion and refeeding protocols. Three groups of gerbils (n = 10/group) were fed vitamin A-deficient diets for 8 wk. One group was killed at that point (marginally depleted), a second group was refed vitamin A for 5 d and a third group was further depleted of vitamin A for 5 d. Pooled BBMV from the marginally depleted group demonstrated greater uptake of all-trans β-carotene than pooled BBMV from the other two groups of gerbils while those from the group refed vitamin A for 5 d had greater uptake than the group that was depleted for 5 additional days (P < 0.01). In contrast, the uptake of retinol by BBMV was not significantly different among the three groups of gerbils. The results of the gerbil study suggest that as they become increasingly vitamin A deficient, impairment of all-trans β-carotene uptake by intestinal mucosal cells may be taking place. The BBMV system should prove valuable for the evaluation of the intestinal mucosal cell membrane uptake of carotenoids and retinoids under various nutritional conditions.

Outcomes of Radiotherapy for Osseous Echinococcosis of Meriones meridianus.

Background Osseous cyst echinococcosis (CE) is an infectious disease that causes disability and deformity in patients, yet there is still no satisfactory treatment. Focusing on the feasibility and prognosis of radiotherapy as an adjuvant or palliative treatment for osseous CE, this study investigated the outcome of Meriones meridianus with osseous CE after radiotherapy. Methods The study utilized a comparison control group design with three groups of gerbils, and 240 osseous CE gerbils were randomly divided into control, 40Gy/5times, and 50Gy/5times groups. Different doses of radiotherapy were given to the gerbils, and then, the effects of radiotherapy on gerbils and lesions were observed at 3 and 6 months after radiotherapy. Statistical analysis was done using χ2 test, unpaired t-test, and one-way ANOVA. Results Significant changes (P < 0.05) were achieved between the three groups in terms of seven parameters at 3 and 6 months, including the number of dead gerbils and lesion sites with ulceration and infection, number of dead scolices, protein content, Ca2+ concentration, the maximum diameter of lesion site, and wet weight of cysts. Except for the number of dead gerbils and lesion sites with ulceration and infection, all other parameters were observed a big difference between 3 months and 6 months in the 50Gy/5times group. Conclusion Radiotherapy at a dose of 50 Gy has inhibitory and therapeutic effects on osseous CE in gerbils, and radiotherapy could probably be a treatment option for persistent or recurrent osseous CE.

Proteomic responses of carotenoid and retinol administration to Mongolian gerbils.

Various health benefits of carotenoids have been described. However, while human observational studies generally suggest positive health effects, supplementation with relatively high doses of individual carotenoids (supplements) have partly produced adverse effects. In the present study, we investigated the effect of several carotenoids on the proteomic response of male Mongolian gerbils (aged 6 weeks). Five groups of gerbils (n = 6 per group) received either retinol (vitamin A/53 mg per kg bw), all-trans β-carotene (pro-vitamin A/100 mg kg-1), the non-pro vitamin A carotenoid lutein (100 mg kg-1), the acyclic carotenoid lycopene (100 mg kg-1) or vehicle (Cremophor EL), via oral single gavage. Gerbils were 12 h post-prandially sacrificed and blood plasma, liver, and white adipose tissue were collected. For liver and adipose tissue, a 2D-DIGE (difference gel electrophoresis) approach was conducted; for plasma, proteomic analyses were achieved by liquid chromatography-mass spectrometry. Compared to controls (vehicle), various proteins were showing significant abundance variations in plasma (66), liver (29) and adipose tissue (19), especially regarding structure (22), protein metabolism (15) and immune system/inflammation (19) functions, while proteins related to antioxidant effects were generally less abundant, suggesting no in vivo relevance. Surprisingly, a large overlap in protein regulation was found between lycopene and retinol exposure, while other carotenoids, including all-trans β-carotene, did not show this overlap. Mainly retinoid acid receptor co-regulated proteins may mechanistically explain this overlapping regulation. This overlapping regulation may be related to common nuclear hormone receptor mediated signalling, though further studies using synthetic ligands of retinoid receptors targeting protein regulation are needed for confirmation.

Detecção de ácidos nucleicos em tecidos de gerbils submetidos à infecção aguda por Neospora caninum

Neospora caninum é um protozoário de grande importância na pecuária, por determinar problemas reprodutivos principalmente em bovinos. Os gerbils (Meriones unguiculatus) podem atuar como modelos experimentais para reproduzir a neosporose aguda de bovinos. Neste trabalho, foram formados dois grupos de gerbils (n=10), inoculados com taquizoítos de N. caninum (cepa NC-1) nas doses de 5x10(6) taquizoítos ml-1 (G1) ou de 5x10(5) taquizoítos ml-1 (G2), doses capazes de induzir infecção aguda. Cérebro, medula espinhal, coração, pulmão, fígado, rins e baço foram coletados e a técnica de PCR foi realizada a partir das amostras de tecidos e órgãos. Na maioria dos animais, o DNA do N. caninum foi detectado pelo menos em cinco tecidos, considerando ambos os grupos (12/20; 60%). No grupo 1, a frequência de detecção de DNA, na totalidade das amostras, foi maior (52/70; 74,28%) quando comparada ao grupo 2 (38/70; 54,28%). A partir desses resultados, pode-se afirmar que o protozoário replicou eficientemente após inoculação e se disseminou pelos tecidos. Além disso, demonstrou-se que gerbils podem ser utilizados como modelo de infecção aguda pelo N. caninum, apresentando sinais clínicos da neosporose.

Anthelmintic effects ofProsopis laevigatan-hexanic extract againstHaemonchus contortusin artificially infected gerbils (Meriones unguiculatus)

The anthelmintic effect of Prosopis laevigata (mezquite) n-hexanic extract was evaluated against Haemonchus contortus endoparasitic stages in artificially infected gerbils (Meriones unguiculatus). Prosopis laevigata leaves were collected from the Sierra de Huautla, Ecological Reserve of the Biosphere, in Morelos State, Mexico; dehydrated under shade and macerated with n-hexane for 3 days, followed by distillation for 8 h. This procedure was repeated three times and the final extract was kept at 4 degrees C. The in vivo effect of the plant extract was evaluated in gerbils artificially infected with H. contortus. Plant extract concentration was 40 mg/ml. Three groups of gerbils were as follows: group 1 (n = 7), P. laevigata extract at 100 microl intraperitoneally (IP); group 2 (n = 6), control--Tween 20 in water at a single dose of 100 microl IP; group 3 (n = 8) also served as a control, receiving water only, to determine the mortality due to causes other than the plant extract. An additional group of seven gerbils (group 4) was administered fenbendazole, as a positive control. Five days later the animals were euthanized and stomach and mucosa removed to quantify the nematodes. Data were analysed using the Student's t-test to compare the mean of nematodes obtained in groups 1, 2 and 3. The parasite population in the plant extract treated group 1 was reduced by 42.5% (P < 0.05) with respect to the control group 2; and when control group 3 was used for comparison the parasitic reduction was estimated as 53.11%. This study shows the in vivo anthelmintic effect of P. laevigata n-hexane extract for the first time, using gerbils as an in vivo model, with potential use in sheep.

Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: Role of NADPH oxidase-derived ROS

Ethanol preconditioning (EtOH-PC) refers to a phenomenon in which tissues are protected from the deleterious effects of ischemia/reperfusion (I/R) by prior ingestion of ethanol at low to moderate levels. In this study, we tested whether prior (24 h) administration of ethanol as a single bolus that produced a peak plasma concentration of 42–46 mg/dl in gerbils would offer protective effects against neuronal damage due to cerebral I/R. In addition, we also tested whether reactive oxygen species (ROS) derived from NADPH oxidase played a role as initiators of these putative protective effects. Groups of gerbils were administered either ethanol or the same volume of water by gavage 24 h before transient global cerebral ischemia induced by occlusion of both common carotid arteries for 5 min. In some experiments, apocynin, a specific inhibitor of NADPH oxidase, was administered (5 mg/kg body wt, ip) 10 min before ethanol administration. EtOH-PC ameliorated behavioral deficit induced by cerebral I/R and protected the brain against I/R-induced delayed neuronal death, neuronal and dendritic degeneration, oxidative DNA damage, and glial cell activation. These beneficial effects were attenuated by apocynin treatment coincident with ethanol administration. Ethanol ingestion was associated with translocation of the NADPH oxidase subunit p67 phox from hippocampal cytosol fraction to membrane, increased NADPH oxidase activity in hippocampus within the first hour after gavage, and increased lipid peroxidation (4-hydroxy-2-nonenal) in plasma and hippocampus within the first 2 h after gavage. These effects were also inhibited by concomitant apocynin treatment. Our data are consistent with the hypothesis that antecedent ethanol ingestion at socially relevant levels induces neuroprotective effects in I/R by a mechanism that is triggered by ROS produced through NADPH oxidase. Our results further suggest the possibility that preconditioning with other pharmacological agents that induce a mild oxidative stress may have similar therapeutic value for suppressing stroke-mediated damage in brain.

Punishment Suppression: Some Effects on Alternative Behaviour:

Three experiments using a multiple response technique (Dunham, 1978) with Mongolian gerbils were designed to investigage die effect of different methods of producing response suppression on nonsupp...

Post-ischemic diazepam does not reduce hippocampal CA1 injury and does not improve hypothermic neuroprotection after forebrain ischemia in gerbils

The hippocampal CA1 sector is especially vulnerable to brief forebrain ischemia. Excitotoxicity is widely thought to contribute to this cell death. Accordingly, drugs that presumably counteract excitotoxicity, such as GABAergic agonists, have been repeatedly tested and found to reduce CA1 cell loss. Post-ischemic diazepam reduces CA1 injury. However, diazepam also causes hypothermia, which by itself is neuroprotective. Most studies fail to adequately control for this confound. In this study, we tested whether diazepam reduces injury in temperature controlled gerbils subjected to brief forebrain ischemia. Furthermore, we tested whether diazepam augments hypothermic neuroprotection. All gerbils were implanted with a core temperature telemetry probe and a cannula for the subsequent insertion of a thermocouple probe to measure ischemic brain temperature. Subsequently, they were given a 5-min normothermic ischemic insult. In Experiment 1, two groups of gerbils were given 10 mg/kg doses of diazepam (i.p.) at both 30 and 90 min post-ischemia. Temperature was maintained in one group by heating lamps. Another group was administered saline. Diazepam reduced cell death at 7 days post-ischemia when the drug-induced hypothermia was permitted, but not when it was prevented. In Experiment 2, four groups of ischemic gerbils were treated starting at 12 h post-ischemia with prolonged hypothermia, diazepam and the combination or saline treatment. Hypothermia, but not diazepam, provided partial neuroprotection and diazepam did not augment hypothermic neuroprotection. Thus, neuroprotection with diazepam is solely due to hypothermia. These data do not support the clinical use of diazepam as a neuroprotectant after global ischemia.

Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain.

L-Kynurenine and quinolinic acid are neuroactive L-tryptophan-kynurenine pathway metabolites of potential importance in pathogenesis and treatment of neurologic disease. To identify precursors of these metabolites in brain, [(2)H(3) ]-L-kynurenine was infused subcutaneously by osmotic pump into three groups of gerbils: controls, CNS-localized immune-activated, and systemically immune-activated. The specific activity of L-kynurenine and quinolinate in blood, brain and systemic tissues at equilibrium was then quantified by mass spectrometry and the results applied to a model of metabolism to differentiate the relative contributions of various metabolic precursors. In control gerbils, 22% of L-kynurenine in brain was derived via local synthesis from L-tryptophan/formylkynurenine versus 78% from L-kynurenine from blood. Quinolinate in brain was derived from several sources, including: local tissue L-tryptophan/formylkynurenine (10%), blood L-kynurenine (35%), blood 3-hydroxykynurenine/3-hydroxyanthranilate (7%), and blood quinolinate (48%). After systemic immune-activation, however, L-kynurenine in brain was derived exclusively from blood, whereas quinolinate in brain was derived from three sources: blood L-kynurenine (52%), blood 3-hydroxykynurenine or 3-hydroxyanthranilate (8%), and blood quinolinate (40%). During CNS-localized immune activation, > 98% of both L-kynurenine and quinolinate were derived via local synthesis in brain. Thus, immune activation and its site determine the sources from which L-kynurenine and quinolinate are synthesized in brain. Successful therapeutic modulation of their concentrations must take into account the metabolic and compartment sources.

Metabotropic glutamate receptor subtypes are differentially expressed after transient cerebral ischemia without, during and after tolerance induction in the gerbil hippocampus

Postischemic delayed neuronal death (DND) of hippocampal CA1 neurons can be prevented by a preconditioning sublethal ischemic stimulus. To check for possible participation of metabotropic glutamate receptors (mGluRs) in neuronal death or survival, we analyzed postischemic protein expression of subtypes 1b and 5 of group I mGluRs, which are thought to exert neurotoxic effects after pathological activation due to ischemia, and subtypes 2 and 3 of group II mGluRs, which in contrast are thought to be neuroprotective in this state, respectively. Therefore, three groups of gerbils with reperfusion intervals between 8 h and 4 days ( n=5 each) were investigated: one group was subjected to 5 min ischemia, resulting in DND of CA1 neurons, a second group to a tolerance inducing 2.5 min period of ischemia and a third group to 5 min ischemia after prior tolerance induction. The major finding was a transient postischemic reduction of mGluR1b and 5 expression in the ischemic tolerant CA1 subfield at 8 h. This downregulation of neurotoxic mGluRs may indicate a contribution to the survival of highly vulnerable CA1 neurons in the ischemic tolerant state.

Vulnerability of the gerbil cochlea to sound exposure during reversible ischemia.

Cochlear ischemia induces a sensorineural hearing loss, in part through a fast functional impairment of outer hair cellls. Assuming that the cochlea is rendered fragile during ischemia and reperfusion and that stimulation itself can jeopardize its functional recovery, we used a model of reversible selective cochlear ischemia in Mongolian gerbils to establish what type of sound exposure can be deleterious during and immediately after reversible ischemia. Several groups of gerbils were used, with different ischemia durations and levels of sound exposure. Control groups were only exposed to tones at 80 and 90 dB SPL during 30 min, while other groups underwent complete and fully reversible blockage of the labyrinthine artery, during 5.5 or 8 min, and were exposed to 60 or 80 dB SPL tones during 30 min. The amount of ischemia and reperfusion was measured by means of laser Doppler velocimetry, whereas outer hair cells' function was continuously monitored through distortion-product otoacoustic emissions (DPOAEs). The losses of DPOAE levels after 8 min transient ischemia and 60 dB SPL exposure were as large as those induced by 80 dB SPL exposures combined with 5.5 min ischemia, or 90 dB SPL exposures without ischemia, with a maximum loss around 25-30 dB, half an octave above the stimulus frequency. These results give evidence for an extremely high cochlear vulnerability to low-level sound exposure when associated with reversible ischemia. This vulnerability may have important clinical consequences in patients with cochlear circulatory disturbances.

5-( N-Ethyl- N-isopropyl)-amiloride, an Na +–H + exchange inhibitor, protects gerbil hippocampal neurons from ischemic injury

The effect of the selective Na +/H + antiporter inhibitor 5-( N-ethyl- N-isopropyl)-amiloride (EIPA) on cerebral ischemia/reperfusion injury was evaluated in the Mongolian gerbil. Ischemia was induced in unanaesthetized gerbils by a 5-min period of bilateral common carotid artery occlusion followed by reperfusion for 6 days. Two groups of gerbils were injected intraperitoneally with either dimethyl sulfoxide (DMSO; 10 μl) or EIPA (5 mg/kg in 10 μl DMSO) 30 min prior to ischemia. The increase in locomotor activity in the EIPA-treated group was significantly less than that of the control group at both 24 h and 6-day post-ischemia. The extent of CA1 pyramidal neuron loss was significantly reduced in the EIPA-treated group in comparison with that of DMSO treated controls. These results suggest that EIPA can protect cerebral neurons from ischemia/reperfusion injury and implicates acidosis and Na +/H + exchange as a causative factor in such injury.

Diazepam-induced neuroprotection: dissociating the effects of hypothermia following global ischemia

Global cerebral ischemia produces hippocampal CA1 neuronal loss which in turn leads to deficits in memory related tasks. Previous studies have shown that the benzodiazepine diazepam is effective at attenuating this cell death and the related behavioural impairments. However these studies have been confounded by diazepam-induced hypothermia. In this study we sought to determine the neuroprotective efficacy of diazepam in the absence of hypothermia. Diazepam (10 mg/kg) was administered to two groups of gerbils at 30 and 90 min following a 5-min ischemic insult. In one group the brain temperature was monitored for 24 h post-ischemically but not regulated. In the second group, post-ischemic brain temperature was maintained at 36.5°C to counteract the hypothermia produced by diazepam. Both behaviour (open field performance) and CA1 cell counts from these groups were compared to those from sham/normal, no drug ischemic and vehicle ischemic groups at 10 days survival. In animals treated with diazepam without temperature regulation, there was significant histological and behavioural protection at 10 days compared to untreated ischemic animals. Preventing hypothermia in diazepam-treated animals resulted in a decrease in the number of cells surviving (from 41.2 to 31.6% of sham) and abolished behavioural protection. Diazepam appears to have limited ability to attenuate neuronal loss and its neuroprotective efficacy is augmented by the concurrent hypothermic actions of the drug itself.

Discrimination learning of amplitude modulated tones in Mongolian gerbils

Discrimination learning of 100% sinusoidal amplitude modulated tones (AM) was investigated in adult Mongolian gerbils using a footshock motivated shuttle box avoidance go/no go paradigm. AM stimuli to be discriminated had identical carrier frequency (2 kHz) but differed in modulation frequency ( f m) by one octave. Six groups of gerbils were trained to discriminate AM-pairs with f m ranging from 10 to 640 Hz. Learning proceeded faster and discrimination performance was slightly better for low f m, up to 80 Hz, than for high f m, above 80 Hz. These results may be related to cortical AM encoding (Schulze, H. and Langner, G., J. Comp. Physiol. A, 181 (1997) 651–663), which is temporal for low f m (synchrony code) and spatial for high f m (rate-place code). This may implicate different neuronal learning strategies or distinct behavioral meanings influencing the discrimination training.

Discriminative stimulus functions of CNS sedative drugs assessed by drug versus drug discrimination procedures in gerbils

This study is concerned with dissecting out differences in the discriminative stimulus attributes between drugs from broader pharmacological categories such as sedative/hypnotics where generalization tests often indicate shared stimulus effects. To this end, the discriminative stimulus effects of three to five doses of either chlordiazepoxide (CDP), chlormethiazole (CMZ), ethanol (ETOH), and pentobarbital (P-barb) were studied with gerbils in a two-choice, T-maze task. When the discrimination was based upon the presence versus the absence of drug administration, speed of acquiring the discrimination increased dose-dependently for all four drugs with log of sessions to criterion being a linear function of log dose. The slopes of all four lines were similar. The acquisition of a discrimination based on different doses of the training drug was then examined. A two-to-one ratio of high to low doses was used. Discriminative control developed with CMZ, ETOH, and P-barb, but not with CDP. The side of the T-maze that correlated with the lower training dose was always selected in tests with saline. Gerbils were then trained to discriminate between two drugs using at least two different dose combinations. The CDP versus CMZ, CDP versus ETOH, CMZ versus P-barb, CMZ versus ETOH discriminations were acquired. The CDP versus P-barb discrimination was obtained across doses only after an additional training procedure was instituted such that the P-barb dose was incremented gradually from low to higher doses during discrimination training; the CDP training doses were 20 and 30 mg/kg in two different groups of gerbils, respectively and the dose of P-barb was incremented by 2.5 mg/kg until the final dose of 20 mg/kg was reached with the barbiturate. Thus, although often shown to share similar stimulus effects, members of the broad pharmacological class of CNS sedatives/hypnotics nonetheless were shown to be discriminable from one another. Non-drug tests (vehicle) were used to assess stimulus control between pairs of drugs, equal control being implicated when responding was evenly distributed across the two training conditions.

Acoustic isolation reduces degeneration of the ventral cochlear nuclei in mongolian gerbils

The role of auditory experience in the development of spongiform degeneration in the cochlear nuclei of Mongolian gerbils was studied by comparing results of animals exposed to either high or low levels of ambient noise. Gerbils reared in a typical vivarium experienced higher levels of ambient noise than animals reared in acoustic isolation chambers. Animals reared in the colony room showed a much greater number density and area density of spongiform lesions in the CN than did gerbils reared in acoustic isolation. The differences in the number and extent of spongiform lesions between the two groups of gerbils appeared to reflect their differences in exposure to ambient noise. These differences in lesion number and extent were most pronounced in the tonotopic regions of the PVCN which correspond to the greatest differences in the spectral characteristics of the ambient noise to which the animals were exposed. These results were compared with results previously obtained from gerbils with loss of hearing experimentally induced by a conductive block or by sensorineural damage. The lesion numbers and extent reflected the auditory experience of each group: in descending order, colony-reared, isolate, conductive-block, sensorineural loss. These results strongly support the hypothesis that this gerbilline encephalopathy is directly related to auditory functional activity.

Lethal effects of CCl 4 and its metabolism by mongolian gerbils pretreated with chlordecone, phenobarbital, or mirex

Gerbils are much more sensitive to the hepatotoxic and lethal effects of CCl 4 than rats as indicated by 48-hr LD50 values (0.08 vs 2.8 ml/kg). On the other hand, gerbils are refractory to chlordecone (CD) potentiation of CCl 4 toxicity. To investigate the possible mechanism underlying the high sensitivity of gerbils to CCl 4 lethality, the metabolism of CCl 4 was studied in gerbils pretreated with dietary CD, phenobarbital (PB), or mirex (M) at 10, 225, and 10 ppm, respectively. The hepatic content of 14CCl 4, the expiration of 14CCl 4 and 14CCl 4-derived 14CO 2, and lipid peroxidation were measured and the results were compared with the previous data for rats. After the 15-day dietary pretreatment, male gerbils (60–80 g) received 14CCl 4 (0.08 ml/kg; sp act 0.04 mCi/mmol) ip in corn oil and the radioactivity present in the expired air was collected for 6 hr. More than 80% of the parent compound as represented by the 14C-label in the toluene trap was expired in 6 hr regardless of the pretreatments. Expiration of 14CO 2 measured during the 6 hr after 14CCl 4 administration in control gerbils was 3.5-fold more than that in rats and was significantly increased in pretreated groups (M > PB > CD). PB and M pretreatments resulted in a significant increase of 14C-label bound to the nonlipid fraction of the liver as compared with CD-treated or control gerbils. The radiolabel present in the livers of control gerbils was 5-fold higher than that of rats. In vivo lipid peroxidation measured as diene conjugation in lipid extracts from the livers was lower in gerbils than in rats, and none of the pretreatments significnatly affected lipid peroxidation. The serum alanine aminotransferase and aspartate aminotransferase were significantly elevated at 6 hr after CCl 4 injection in all groups of gerbils. These data indicate that the more extensive metabolism of CCl 4, as represented by 14CO 2 formation and 14C-label bound to hepatic tissue, in gerbils as compared with rats, may partially explain the high sensitivity of gerbils to CCl 4 toxicity. However, the enhanced metabolism of CCl 4 found in CD-, PB-, or M-pretreated gerbils did not lead to amplified hepatotoxic and lethal effects of CCl 4. The reason gerbils may be refractory to CD amplification of CCl 4 injury might be associated with other factors yet to be investigated.

Cueing effects of anxiolytic benzodiazepines (DZP and Ro 11-3128): stereospecificity and antagonism by the convulsant benzodiazepine Ro 5-3663.

Two groups of gerbils were trained in a T-maze to discriminate between the vehicle condition (4 ml/kg) and either of the benzodiazepine (BDZ) agonists diazepam (DZP) and Ro 11-3128; administration (5.6 mg/kg) was IP 5 min prior to training onset. Once trained, novel doses and drugs were assessed in test sessions interposed between the regular training days. A dose-related generalization effect occurred with both compounds (range 0.1-5.6 mg/kg), the effect being similar at both the 5 and 15 min test intervals; the two intervals were evaluated after a single injection. The lack of generalization of Ro 11-3624 (range 5.6-56 mg/kg) indicates a stereoisomeric separation of BDZ agonist activity. Ro 5-4864 (range 17.5-56 mg/kg), an agent chemically/structurally related to DZP, did not produce DZP responding at either of the two test inverals; clear-cut convulsant activity occurred at the 15 min interval. The convulsant BDZ compound Ro 5-3663 (3 and 10 mg/kg) antagonized the DZP stimulus irrespective of whether Ro 5-3663 was given either prior to, simultaneously with, or shortly after the DZP injection.

Discrimination of Ro 11-6896, chlordiazepoxide and ethanol in gerbils: generalization and antagonism tests.

Separate groups of gerbils were trained in a T-maze to discriminate between either: (1) the 1,4-benzodiazepine Ro 11-6896 (1 mg/kg), (2) chlordiazepoxide (25 mg/kg) or (3) ethanol (2,000 mg/kg) and vehicle. Thus, the respective training condition served as a discriminative stimulus guiding choice behavior. A degree of generalization which was enhanced by increasing injection-test intervals occurred between ethanol and the benzodiazepines. Ro 15-1788 markedly attenuated the cue properties of the benzodiazepines, but not that of ethanol. Additional tests in the Ro 11-6896 group showed that this discrimination was stereoselective but not stereospecific in that the isomer Ro 11-6893 generalized to Ro 11-6896 at a dose of 10 mg/kg but not at 1 mg/kg; Ro 15-1788 attenuated this generalization. Diazepam (3 mg/kg) generalized to Ro 11-6896 whereas the structurally related Ro 5-4864 (3 mg/kg and 30 mg/kg) did not. In separate tests of open-field activity and temperature recording Ro 15-1788 significantly attenuated the effects of Ro 11-6896 (1 mg/kg) and Ro 11-6893 (10 mg/kg).