Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions

Effects of cocaethylene on dopamine and serotonin synthesis in Long–Evans and Sprague–Dawley brains

We examined the behavioral and neurochemical effects of cocaethylene treatment in Long–Evans (�LE). and Sprague–Dawley� (SD) rats. Cocaethylene-induced behaviors were significantly less in LE rats. Cocaethylene caused an inhibition of dopamine synthesis in the caudate nucleus and nucleus accumbens that was equivalent in both rat lines. Serotonin synthesis was also suppressed by cocaethylene treatment, however this phenomenon was less pronounced when compared with the effects on dopamine synthesis

The brattleboro rat displays a natural deficit in social discrimination that is restored by clozapine and a neurotensin analog.

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported

Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

The finding of more severe steatohepatitis in alcohol fed Long Evans (LE) compared with Sprague Dawley (SD) and Fisher 344 (FS) rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories) ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation

Successful islet allotransplantation in diabetic rats immunosuppressed with FK506: A functional and immunological study

The effect of a novel immunosuppressive agent, FK506, on fresh islet allografts was evaluated in diabetic rats across major histocompatibility complex (MHC) barriers with respect to the transplantation (TR) site, islet source, treatment regimen, and antidonor antibody (Ab) titers of the recipients after TR. The functional periods of Wistar (Wi) islets transplanted under kidney capsule (KC) or intraportally (IPo) and of a mixture of Wi and Lewis (Le) islets under KC or IPo in nonimmunosuppressed ACI rat recipients were 6.9 ± 0.4 (n = 7), 6.4 ± 0.5 (n = 7), 5.6 ± 0.4 (n = 7), and 6.2 ± 0.4 (n = 5) days, respectively. FK506 treatment at 1 mg/kg/d intramuscularly (IM) for 2 weeks (protocol I) following islet TR under KC and IPo significantly prolonged the allograft function to more than 71.8 ± 11.3 (n = 10) and 161.7 ± 18.6 (n = 11) days, respectively. Additional treatment with FK506 at 1 mg/kg/wk (protocol II) further increased the islet survival under KC to more than 212.6 ± 22.3 (n = 8) days. With this FK506 treatment protocol, the Wi + Le mixed-islet allograft function was extended to more than 106.1 ± 10.5 (n = 7) and 167.9 ± 28.6 (n = 7) days under KC and IPo, respectively. Nephrectomy in 8 8 ACI rats with long-term-functioning Wi (n = 6) and Wi + Le (n = 2) islet allografts resulted in their return to hyperglycemia. Immunohistochemical staining showed abundant insulin-positive cells at the graft site, with small numbers of CD4- and CD8-positive cells present in the vicinity of the normal-appearing islets. Macrophages were not detected. The immunosuppressive effect of FK506 was further tested in ACI rats presensitized by a previous Wi islet TR. When the duration between the first and second TR under KC was 114.3 ± 20.5 days, protocol II treatment significantly prolonged the graft function to more than 152.9 ± 28.7 (n = 8) days. However, with a short duration of about 2 weeks between the two TRs, the same FK506 protocol achieved islet graft function of 14.0 ± 3.8 days (n = 7). Additional immunosuppression with cyclophosphamide did not further improve the survival time. Antidonor Abs detected in ACI recipients of Wi islet allografts were significantly lower in the FK506-treated animals compared with the nontreatment group. Wi and Le skin grafts performed in three ACI rats with long-term-functioning Wi islets IPo caused the rejection of the islet allografts. Skin grafts were also rejected in the first-set fashion. Six ACI recipients with long-term-functioning IPo Wi islet allografts were rendered hyperglycemic by streptozocin (STZ) injection. Long-term normoglycemia without further FK506 immunosuppression was achieved following retransplantation with fresh Wi islets IPo (n = 2), but not under KC (n = 2). The results of the present study indicate that FK506 was an effective immunosuppressant for islet allotransplantation in diabetic ACI rats across MHC barriers with islets from two donor strains, as well as in sensitized recipients whose antidonor activities had subsided. The efficacy of the immunosuppression was influenced by the FK506 treatment protocol and the site of the islet transplant. The results suggest that FK506 could be useful in clinical islet TR. © 1994

Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague–Dawley and Long–Evans rats

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague–Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60–120 ms) and less sensitive to their PPI-enhancing effects at short (10–30 ms), compared with Long–Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors. The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats. PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF). As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains. Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux

Mercury accumulation in kidney lysosomes of proteinuric rats

Mercury accumulation in kidney lysosomes of proteinuric rats. The purpose of the present study was to determine whether lysosomal accumulation of mercury in the kidney is due to a leakage of protein-bound mercury through the glomerular filtration barrier followed by reabsorption into the lysosomal system of the proximal tubule. The subcellular distribution of mercury in the kidney was studied in four different groups of rats with and without proteinuria: normal young rats, young rats With amino-nucleoside nephrosis, old rats with spontaneous proteinuria, and old rats with chronic mercury intoxication and proteinuria. Radioactive mercuric chloride (203HgCl2) was injected s.c. into the rats 72 hours before sacrifice. Cell fractionation experiments were carried out on homogenates of the renal cortex by differential centrifugation. Determination of radioactive mercury in the subcellular fractions revealed that mercury was concentrated in the lysosomal fraction of all rats with proteinuria. In contrast, normal rats without proteinuria had the highest concentration of mercury in the supernatant, and there was no enrichment of mercury in the lysosomal fraction. Gel filtration chromatography performed on urine samples from proteinuric rats demonstrated that excreted mercury was associated with the albumin fraction. The accumulation of mercury in renal lysosomes of proteinuric rats and the demonstration of mercury bound to albumin in the urine support the hypothesis that mercury bound to plasma proteins passes the glomerular filtration barrier in proteinuric conditions and enters the lysosomal system of the proximal tubule by way of endocytosis.Accumulation de mercure dans les lysosomes rénaux de rats protéinuriques. Le but de ce travail a été de déterminer si l'accumulation lysosomale de mercure dans le rein est due à une fuite de mercure lié aux protéines à travers la barrière de filtration glomérulaire suivie d'une réabsorption dans le système lysosomal du tube proximal. La distribution subcellulaire du mercure a été étudiée dans quatre groupes de rats : des jeunes rats normaux, des jeunes rats atteints de néphropathie de l'aminonucléoside, des rats âgés avec une protéinurie spontanée et des rats âgés avec une intoxication mercurielle chronique et une proteinurie Du mercure radioactif (203HgCl2) a été injecté par voie sous-cutanée à des rats 72 heures avant le sacrifice. Le fractionnement cellulaire a été réalisé sur des homogénats de cortex rénal par centrifugation différentielle. La détermination du mercure radioactif dans les fractions subcellulaires a révélé que le mercure est concentré dans la fraction lysosomale de tous les rats protéinuriques. Les rats normaux sans protéinurie au contraire, ont une concentration de mercure plus élevée dans le surnageant et il n'y a pas d'enrichissement en mercure de la fraction lysosomale. La chromatographie par filtration sur gel réalisée sur les échantillons d'urine de rats protéinuriques a démontré que du mercure excrété est associée à la fraction albuminique. L'accumulation de mercure dans les lysosomes rénaux des rats protéinuriques et la mise en évidence de mercure lié à l'albumine dans l'urine sont en faveur de l'hypothèse selon laquelle le mercure lié à des protéines plasmatiques passe la barrière de filtration glomérulaire dans les situations où il existe une protéinurie et entre dans le système lysosomal du tube proximal par endocytose

L’effet thérapeutique de l’huile de lin « linumusitatissimum » sur l'hypertriglycéridémie et l'hypercholestérolémie chez des rats obèses âgés

L'obésité, un des problèmes de santé les plus courants, est associée àdes anomaliesdu glucose etdu métabolisme des lipides; le vieillissement est aussiassociée à des troubleslipidiques.Le rôle del'huile de lina été étudiéà 2,5% et 5% dans la modulation del'altérationdu métabolisme des lipideschez les rats âgésobèses. Des rats mâles âgés Wistar sont répartis en six groupes de 10 rats chacun: Groupe contrôle, groupe contrôlehuile de lin 2,5%, groupe contrôlehuile de lin5%, groupe cafétéria, groupe cafétéria lin2,5%, groupe cafétéria lin 5%. Le régime enrichi en huile de Lin est administré pendant 2mois. Apres sacrifices la glycémie est mesurée, ainsi le cholestérol au niveau sérique, hépatique et au niveau des HDL. Les triglycérides ont été également dosés. Nos résultats montrent que le régime cafeteria induit une hyperphagie et une obésité chez les rats âgés sous régime cafeteria comparés aux rats témoins.L’augmentation de la masse grasse est accompagnée de modifications notables des paramètres lipidiques, avec une augmentation des teneurs plasmatiques et tissulaires en cholestérol et triglycérides et une diminution de taux de HDL-C. La glycémie est élevée au niveau du plasma chez le groupe cafeteria comparé aux rats témoins. L’effet bénéfique de l’huile de Lin est marqué par une augmentation de HDL-C des rats expérimentaux comparé aux rats témoins, diminution significative de la glycémie du Triglycerides et cholestérol au niveau de plasma et du foie chez les rats âgés rendu obèse par le régime cafétéria. L’huile de lin a des effets bénéfiques sur les troubles lipidiques et diminue de manière significative l’hyperglycémie et présente une protection contre ces anomalies lie à l’obésité et le vieillissement en termes d’apport en oméga-3.Mots-clés : cholestérol, triglycéride, huile de lin, obésité, omega 3, vieillissement

Strain specific effects of low level lead exposure on associative learning and memory in rats.

Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) rats. The present study examined the extent to which this differential effect of Pb on hippocampal gene expression might influence behavior. Animals (males and females) were tested in a trace fear conditioning paradigm to evaluate effects of Pb exposures (perinatal (PERI; gestation to postnatal day 21) or early postnatal (EPN; postnatal day 1 to day 21)) on associative learning and memory. All animals (Pb-exposed and non-Pb-exposed controls) showed normal acquisition of the conditioned stimulus (tone)-unconditioned stimulus (footshock) association. Long Evans rats showed a significant deficit in short- and long-term recall, influenced by sex and the timing of Pb exposure (PERI or EPN). In contrast, Pb exposure had no significant effect on memory consolidation or recall in any SD rats. These results further demonstrate the important influence of genetic background to the functional outcomes from developmental Pb exposure

Biotoxicité Rénale, Hépatique Et Splénique Du Sulfate De Cadmium Chez Les Rats Wistar

International audienceHeavy metals (lead, mercury and cadmium) cause problems of public health. Studies undertaken in Côte d'Ivoire within the framework of the environmental monitoring made it possible to apprehend the state of the cadmium pollution of the sediments, of the market garden grounds. Six (6) batches of rats Wistar males and females were made up. These rats were contaminated with cadmium sulfate by daily during 30 days with various proportion respectively 4; 5; 6.66; 10 and 20 mg/kg body weight (bw). The rats were weighed each week. At the end of the experiment, the serum was used for proportioning of the enzymes and of the substrates using Cobas C311 ROCHE HITACHI. Work completed made it possible to determine the LD 50 of cadmium sulfate which is of 200 mg/kg bw. The weight of the rats of the batches treated with cadmium decreased significantly compared to the batch untreated (control). Transaminases, creatinine and the urea were increased significantly (p<0.05) when the bilirubin and cholesterol were decreased at the two sexes. However, the effect on cholesterol is not significant. Cadmium caused liver and kidney dysfunction and it decreased the weight of rats of both sexes.Les métaux lourds (plomb, mercure et cadmium) posent des problèmes de santé publique. Les études entreprises en Côte d'Ivoire dans le cadre de la surveillance de l'environnement ont permis d'appréhender l'état de la pollution par le cadmium des sédiments, des terrains maraîchers. Six (6) lots de rats mâles et femelles Wistar ont été constitués. Ces rats ont été contaminés par le sulfate de cadmium quotidiennement pendant 30 jours avec des proportions variables, respectivement 4; 5; 6,66; 10 et 20 mg / kg de poids corporel. Les rats ont été pesés chaque semaine. À la fin de l'expérience, le sérum a été utilisé pour le dosage des enzymes et des substrats à l'aide de Cobas C311 ROCHE HITACHI. Les travaux ont permis de déterminer la DL 50 du sulfate de cadmium qui est de 200 mg / kg de poids corporel. Le poids des rats des lots traités au cadmium a diminué de manière significative par rapport au lot non traité (témoin). Les transaminases, la créatinine et l'urée ont augmenté significativement (p <0,05) lorsque la bilirubine et le cholestérol ont diminué chez les deux sexes. Cependant, l'effet sur le cholestérol n'est pas significatif. Le cadmium provoque un dysfonctionnement du foie et des reins et diminue le poids des rats des deux sexes