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Cocaine self-administration and locomotor activity are altered in Lewis and F344 inbred rats by RTI 336, a 3-phenyltropane analog that binds to the dopamine transporter.

Lewis and Fischer 344 (F344) rats differ in responses to cocaine and characteristics of the mesolimbic dopamine system. Compared to F344 rats, Lewis rats have lower D2 receptor and dopamine transporter (DAT) levels in nucleus accumbens (NAc). We showed previously that altering D1 and D2 receptor levels pharmacologically had strain-dependent effects on cocaine self-administration. This study tests whether the phenyltropane analog, 3beta-(4-Chlorophenyl) tropane-2beta-[3-(4'-methylphenyl) isoxazol-5-yl] Hydrochloride (RTI 336), a potent and selective DAT inhibitor, differentially alters reinforcing, discriminative, and locomotor effects of cocaine in these strains. The effects of RTI 336 pretreatment on cocaine self-administration were assessed under a fixed-ratio (FR) schedule of reinforcement. Its effects on cocaine discrimination were conducted using a two-lever food-reinforced task. Finally, the effects of RTI 336 pretreatment on cocaine-induced locomotor activity were examined. RTI 336 increased cocaine self-administration in F344 rats, while Lewis rats showed reduced intake under the FR schedule. RTI 336 reduced cocaine-induced locomotor activity in Lewis rats but not in F344 rats. RTI 336 did not substitute for or antagonize cocaine's discriminative stimulus effects in either strain. Results show that a DAT inhibitor alters cocaine-induced behaviors in a strain-dependent manner. These effects may relate to inherent differences in NAc DAT levels between Lewis and F344 rats.

Analysis of Variance↗

Population distribution profiles of the activities of blood alanine and aspartate aminotransferase in the normal F344 inbred rat by age and sex.

Data on the blood enzyme activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were collected from control male and female F344 rats participating in toxicity studies at 17, 30, 56, 80 and 106 weeks of age. The data were skewed to the right with significant deviation from normality. Applying the Box-Cox transformation, it was concluded that approximately normal distributions could be obtained by using the reciprocal transformation. In general, the males showed a greater degree of heterogeneity for both enzymes. Enzyme activities at 17 weeks were lowest for both ALT and AST. There was a high correlation between the activities of blood ALT and AST, with some animals showing dramatic transient increases. Significant differences among studies with respect to the enzyme activities in rats of the same age were demonstrated.

Aging↗

[Establishment of a modified larynx transplantation model with inbred F344 rat].

BACKGROUND & OBJECTIVE: As a non-vital organ, transplantation of larynx lags behind that of the other organs, but it is supposed that if induction of immunologic tolerance of the host to the allograft comes true, larynx transplantation would be an optimal approach for management of advanced laryngeal cancer as well as functional reconstruction of the larynx. This study was designed to establish a modified rat model of larynx transplantation to improve survival rate of the recipients and vitality of the allografts, and provide an optimal rat model for further research on immunology and induction of immunologic tolerance in larynx transplantation. METHODS: A Strome's model of larynx transplantation was repeated with inbred F344 rats (40 rats in Stroma model A and 40 rats in Stroma model B). A modified model of larynx transplantation was developed (40 rats), in which both superior thyroid arteries and ascending pharyngeal arteries were preserved, combining with the hyoid, base of the tongue, hypopharynx, larynx, thyroid, part of the cervical trachea and cervical esophagus as an allograft complexity. The blood supply of the allograft was reconstructed through end-to-end anastomosis of the donors' carotid arteries with the recipients' carotid artery and anterior jugular vein. The recipients were injected with 15 ml of 5% glucose normal saline (GNS) through contralateral external jugular vein intraoperatively, and injected subcutaneously with 5 ml of 5% GNS daily for 3-5 days postoperatively. Morphology of the allografts and patency of the arteries and veins were observed under microscope 7 days after operation, and vitality of the allogafts was assessed pathologically. Survival of the recipients and vitality of the allografts in Strome model and modified model were compared. RESULTS: Survival rates of the recipient rats were 70% in Strome model A, 85% in Strome model B, and 95% in modified model; the survival rates of the allografts were 30% in Strome model A, 40% in Strome model B, and 80% in modified model, respectively. CONCLUSIONS: Compare with Strome models, the modified model of larynx transplantation reduces mortality of the recipients through enhancing perioperative care, improves vitality of the allografts through including both ascending pharyngeal arteries and superior thyroid arteries in the allograft complexity, which increases blood supply of the allografts and reduces micro-circulation resistance, therefore, reduces the micro-circulation malfunction of the allografts.

Anastomosis, Surgical↗

Chromatographic comparisons of heterotic rat liver histones.

Chromatographic comparisons of histones isolated by acid extraction of liver chromatin preparations from F344 inbred rats and their paternal heterotic F344 X H hybrid progeny reveal the presence of a number of age-and line-specific nonhistones also extractable in acid. The patterns of the core histones (H2A, H2B, H3, and H4) remain relatively constant during development, while histone H1 shows unusual chromatographic properties in the 30- and 35-day hybrid preparations. In general, the complexity of the nonhistone fraction decreases as the animal ages. Such variations may be a reflection of a prelude to altered genetic activity in organisms undergoing growth and development at different rates, and may have significant implications for transcriptional processes.

Age Factors↗

Strain differences in response to escapable and inescapable novel environments and their ability to predict amphetamine-induced locomotor activity.

RATIONALE: Locomotor response to novelty predicts locomotor and reinforcing effects of psychostimulant drugs in outbred rats. Among Lewis and Fischer 344 (F344) inbred rats this association is less clear, perhaps due to strain-selective differences in responses to novelty. OBJECTIVE: We examined responses to novel inescapable and escapable environments and to novel objects in these strains. METHODS: Experiment 1 utilized a place conditioning procedure. Rats were confined to one side for 8 days and then allowed access to both this (familiar) and the novel sides. Experiment 2 assessed locomotor response within an inescapable environment. On another occasion, contacts with novel objects within a novel environment were tabulated. Corticosterone levels and fecal boli were measured. Whether these responses predicted amphetamine-induced locomotor activity was determined. To further assess genetic contributions to this association, experiment 3 assessed novelty responses in F1 hybrid Lewis-F344 rats. RESULTS: Lewis rats showed greater novelty-seeking behavior in the escapable environment but lower locomotor activity in the inescapable environment compared to F344 rats. There were no strain differences in novel object contacts, corticosterone, or fecal boli responses. Baseline corticosterone levels and activity levels in the novel environment were positively correlated with amphetamine activity based on data from all rats. However, novelty and amphetamine-induced activity showed non-significant negative correlations in F344 and Lewis rats. Yet, F1 rats showed a significant positive correlation between these variables, even though some of their other responses were Lewis-like or F344-like. CONCLUSIONS: These data suggest that responses to different novelty situations are strain-dependent.

Amphetamine↗

HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats.

Much research supports a link between stress and its concomitant hypothalamic-pituitary-adrenal (HPA) axis responses with behavioral sensitivity to psychoactive drugs. Our research demonstrates that Lewis inbred rats more readily acquire drug self-administration than Fischer 344 (F344) inbred rats and, compared to this strain, Lewis rats have hyporesponsive HPA axis responses to stress exposure. This association appears to conflict with investigations using outbred rats and suggests that the relationship between drug sensitivity and HPA axis responsiveness is more complicated than originally thought. It is essential to better understand this relationship because of its relevance to vulnerability and relapse to drug abuse. Thus, this paper reviews the literature in which these two inbred strains have been compared. We discuss strain differences in HPA axis function, in characteristics of the mesolimbic dopamine system, and in behaviors thought to reflect emotionality. Strain differences in unconditioned and conditioned effects of psychoactive drugs are then reviewed. Next, we discuss the possible role of sex and gonadal hormones on responsiveness to psychoactive drugs in these strains. Finally, a comparison of results obtained from these strains to three other comparator groups (e.g., high and low responders) suggests that a non-monotonic relationship between behavioral sensitivity to drugs and HPA axis responsiveness can explain much of the discrepancies in the literature.

Animals↗

Electrophoretic comparisons of liver chromatin proteins isolated from heterotic rats during postweaning development.

Electrophoretic comparisons of histones and other acid-extractable chromatin proteins isolated from the livers of growing F344 inbred rats and a heterotic paternal hybrid derived by crossing F344 males with Holtzman females reveal significant heterogeneity among a class of nonhistone components soluble in acid. These variations appear to be age and line specific and show more variation in the inbred than the hybrid. Comparisons of the acid-insoluble nonhistone proteins by sodium dodecylsulfate gel electrophoresis reveal significant quantitative changes in a 28,600 dalton polypeptide present in large quantities at 30, 35, and 50 days of age in the hybrid and at 40 and 45 days only in the inbred. Other minor variations were noted in a class of proteins of 40,000--45,000 molecular weight and in those of very high molecular weight (100,000-200,000). Such variations could be a reflection of or prelude to changes in genetic activity and could ultimately be important in the control of growth patterns of developing heterotic animals.

Aging↗

EEG, EEG power spectral, and behavioral differences in response to acute ethylketocyclazocine administration in two inbred rat strains.

Differences in response to behavioral and electroencephalographic parameters were delineated between two inbred rat strains, Lewis (LEW) and Fischer 344 (F344), upon acute exposure to IV administration of ethylketocyclazocine (EKC) at doses of 1.25, 2.5, and 5 mg/kg. Duration of EKC-induced EEG slow-wave bursts and associated behavioral stupor increased in a dose-related manner, and was greater in duration for the LEW animals; a less robust, quadratic trend was displayed by the F344 group. For both rat strains, latency to onset of slow-wave sleep increased proportionately with EKC dose. Duration of EKC-induced EEG bursts and interbursts were greater in duration for the F344 rats. Assessment of six power spectral parameters (peak frequency, complexity, mobility, mean frequency, edge frequency, and total power) revealed no differences between groups when EKC-induced burst and interburst periods were analyzed simultaneously. Separation of the phases revealed rat strain differences; overall, the LEW animals displayed a greater dose-related EEG response. Except for total power, the F344 group displayed little variation across the three doses tested in the burst phase; the interburst phase reflected more dose-related differences for this group but to a lesser degree than the LEW animals. These results may reflect differences in opioid-related receptor populations between Lewis and F344 inbred rat strains.

Animals↗

Incidence of spontaneous neoplasms in F344 rats throughout the natural life-span.

The age-related incidence of spontaneously occurring neoplasms and degenerative diseases in the F344 inbred rat strain was established from the histologic examination of tissues from 160 male and 192 female rats kept throughout their natural life-span. The most common neoplasms were leukemias (25%), mammary tumors (females, 40.6%; males, 23.1%), pituitary adenomas (females, 35.9%; males, 23.8%), and testicular interstitial cell tumors (males, 85%). Various less common neoplasms were observed: thyroid interstitial cell tumors, adrenocortical adenomas, carcinomas of the genitourinary tract, representative central nervous system tumors, pheochromocytomas, and tumors of mesodermal origin including mesotheliomas, myoblastomas, fibromas, and fibrosarcomas. Multiple tumor types were found in 176 of the rats; metastatic tumors were uncommon. Degenerative diseases including myocardial degeneration and nephrosis were often observed. The incidence rate of these neoplasms and degenerative diseases generally increased with advancing age of the animals.

Adenoma↗

Genealogical memory to perinatal iodine-131 exposure in rats: I. Alteration in natural immunity.

A heritable alteration in the natural immunity as measured by changes in the natural killer (NK) cell activities of peripheral blood lymphoid-cells was found to occur in rats upon an in utero exposure to iodine-131. The model that was employed for the measurements consisted of Fischer F344 inbred rats exposed to iodine-131 (sodium) during their 16th to 18th day of gestation. The natural immunity of the animals was evaluated by determining the NK cell activities of peripheral blood lymphoid cells of the offsprings when they reached 2 months of age. Immediately following determination of the natural immunity, brother and sister matings were carried out for evolution of the families. Study of these pedigrees revealed an impairment in the natural immunity to persist through two generations (F1, and F2) of the male animals. The hematological profiles of the animals suggest that the insult may alter the numbers of red and white blood cells in the succeeding generations, but has little noticeable effect upon the percentage of lymphocytes. The interpretation of the results indicate that a perinatal insult by iodine-131 during late gestation can result in both somatic and germ cell changes in the immunological system. Thus, there appears to be a genealogical memory to an in utero radionuclide insult which may adversely affect the offspring's immunological competency to respond to subsequent insults.

Animals↗

Genetic profiles of morphine-induced EEG, EEG power spectra, and behavior in two inbred rat strains.

The purpose of the present study was to examine and compare the effects of morphine at doses of 3, 10, and 30 mg/kg, IV, on EEG, EEG power spectra, and behavior in two inbred rat strains, Lewis and Fischer 344. Duration of morphine-induced EEG slow-wave bursts and associated behavioral stupor was greater in Lewis rats. Latency to slow-wave sleep increased in a dose-related manner for both strains; differences were not significant between the two groups. The analog EEG signal was transformed by fast Fourier analysis; six power spectral quantities were examined: peak frequency, complexity, mobility, mean frequency, edge frequency, and total power. With the exception of peak frequency and edge frequency, all differed as a function of inbred rat strain. Regarding morphine dose, all spectral parameters differed except peak frequency. Factor analysis on morphine-induced EEG revealed a unique factor for each strain that was bipolar in nature and may be associated with the burst and interburst periods that occur in EEG after opiate administration. Genetic variability appears to play a role in the behavioral, EEG, and derived power spectral responses of both LEW and F344 inbred rat strains following acute morphine administration. These results may reflect differences in neurosensitivity and/or opioid receptor populations between Lewis and Fischer 344 inbred rat strains.

Animals↗

Maternal behavior modulates X-linked inheritance of behavioral coping in the defensive burying test.

BACKGROUND: Complex behavioral traits such as coping strategies in response to stress are usually formed by genetic and environmental influences. METHODS: By exploiting the phenotypic and genotypic differences between the Wistar Kyoto (WKY) and Fischer 344 (F344) inbred rat strains, we recently identified three X chromosome-linked quantitative trait loci contributing to differences in coping strategies in the defensive burying (DB) paradigm. In this article we study the influence of postnatal maternal environment in these behaviors by characterizing the maternal behavior of these strains and the effect of cross-fostering on DB behavior of male offspring from reciprocal crossing (F1). RESULTS: Maternal behavior of WKY rats can be quantitatively characterized by less contact and more periods of neglect of their F1 pups. In contrast, F344 mothers engaged in more active behaviors such as licking/grooming and arched-back nursing. Cross-fostering male F1 pups at birth did not influence the latency to bury measure in DB; however, duration of burying and prod approaches were influenced by both genotype and maternal environment in an additive manner. CONCLUSIONS: These results demonstrate that different measures of behavioral coping in the DB paradigm are influenced by maternal environment to differing degrees and in addition by genetic factors.

Aggression↗

Strain differences in mesotelencephalic dopaminergic neuronal regulation between Fischer 344 and Lewis rats.

Differences in the behavioral responses of Lewis and Fischer (F344) inbred rat strains to stress and psychoactive drugs have been related to differences in the expression of various regulatory proteins in regions containing mesolimbic dopamine (DA) neurons. The present study compared basal and stimulated neurochemical estimates of DA utilization and synthesis in mesocortical, mesolimbic and nigrostriatal DA terminal regions of these two strains. In unstressed control animals, the Lewis strain had lower DA concentrations in the dorsal striatum (ST; 80.3% of F344) and lower basal dihydroxyphenylalanine (DOPA) accumulation after m-hydroxybenzylhydrazine (NSD 1015) treatment in the medial prefrontal cortex (mPfx; 75.3% of F344). Similar differences were observed in vehicle-injected animals. No strain differences in basal neurochemistry were apparent in the nucleus accumbens shell (NAs) or core (NAc). In response to restraint stress, dihydroxyphenylacetic acid (DOPAC) to DA ratios in the mPfx, NAs and ST increased in the F344 but not the Lewis strain. However, restraint stress did not significantly increase DOPA accumulation in the F344 strain. This latter finding was not due to a deficit in synthesis capacity, as gamma-hydroxybutyric acid lactone (GBL) increased DOPA accumulation significantly more in F344 than Lewis animals. Finally, haloperidol increased DA utilization similarly in the two strains. Together these findings suggest that the inbred, behaviorally divergent F344 and Lewis rats have selective differences in mesocortical, nigrostriatal and mesolimbic DA neuronal regulation.

Animals↗

Nerve regeneration in rat composite-tissue allografts.

Reinnervation of composite-tissue allografts was examined in a rat hind-limb transplant model under Cyclosporin A (CyA) immunosuppression. Two groups of animals were studied. Group 1 consisted of 10 composite-tissue allografts using inbred Fisher rats (F344) as recipients and inbred Lewis rats (LEW) as donors. Recipient animals received 15 mg/kg/day CyA subcutaneously for three weeks and then twice weekly for three months. Group 2 consisted of 10 composite-tissue isografts undergoing no immunosuppression, and using F344 as both donors and recipients. Eight months after operation, electromyographic, histologic, and morphometric assessments of nerve regeneration were made. There were no significant electromyographic differences between these two experimental groups in amplitude and conduction velocity, but the levels were lower than in controls. The histologic patterns of nerve regeneration within the composite-tissue transfers were similar in the two groups. However, the fiber population in the regenerated nerves in the two groups was different from that in the normal sciatic nerve. This study confirmed the reinnervation of composite-tissue allografts under CyA immunosuppression. The quality of regeneration in allografts was similar to that in isografts, but the histologic and electromyographic properties of regenerated nerves were different from those of normal sciatic nerves.

Animals↗

Genetic control of indirect airway responsiveness in the rat.

Many of the airway responses to endogenous and exogenous stimuli are caused by indirect mechanisms such as the activation of neurons and/or inflammatory cells. In the present study we compare the bronchoconstrictor and the plasma protein extravasation response to adenosine and tachykinins in two highly inbred rat strains, F344 and BDE. BDE-rats have a bronchoconstrictor response to adenosine at lower doses. Challenge with the A3-adenosine receptor agonist APNEA demonstrates that the difference in airway responsiveness to adenosine between BDE- and F344-rats is probably related to a higher number of A3-receptors on the airway mast cells of BDE-rats. In contrast, F344-rats have a higher airway responsiveness to tachykinins than BDE-rats. Tachykinins cause bronchoconstriction in F344-rats mainly by an indirect mechanism, involving stimulation of NK1-receptors and mast cell activation. In BDE-rats they cause bronchoconstriction by a direct effect on airway smooth muscle via activation of NK2-receptors. Finally we also observed a difference between F344- and BDE-rats with regard to the mechanisms involved in the plasma protein extravasation in the airways caused by substance P or capsaicin. In F344-rats but not in BDE-rats mast cell activation and the release of 5-hydroxytryptamine is partly responsible for this plasma protein extravasation.

Adenosine↗

Behavior of male-specific minor histocompatibility antigen in skin and limb transplantation.

BACKGROUND: Although the role of male-specific minor histocompatibility antigen H-Y has been increasingly understood in both experimental and clinical organ transplantation, little has been investigated on musculoskeletal tissue transplantation. This study was performed to describe the behavior of male-specific minor histocompatibility H-Y antigen in rat skin and whole limb transplantation. MATERIALS AND METHODS: Using three different strains of inbred rats (Lewis, F344, and Dark Agouti), 75 donor hindlimbs and eighteen skin grafts were isogenically transplanted to the sex-mismatched recipients. Recipients were observed up to 48 weeks postoperatively. Rejection was monitored by the appearance of the skin of the grafted limb and histology. Systemic microchimerism was assessed by polymerase chain reaction using Y-chromosome specific primers. RESULTS: Skin rejection didn't occur in all limb transplant recipients and histology did not show any rejection findings in all components of the limb graft through 48 weeks. Successful functional recovery was expected. Stable and high level of chimerism (>1%) was detected in the lymphoid tissues in nontreated female recipients. Male skin grafts were rejected by Lewis and F344 female recipients within 6 weeks postoperatively. All female skin grafts survived in male recipients. CONCLUSION: Our results suggest that H-Y antigen can induce graft rejection in rat skin graft but causes no rejection reaction in whole limb transplantation. Systemic chimerism may play an important role for acceptance of sex-mismatched limb graft.

Animals↗

Morphological reaction in transplanted small intestines using immunogenetically defined rat strain combinations.

From the inbred rat stains F344, LEW and Brown-Norway (BN), the following combinations were formed: syngeneic (LEW--LEW), weakly allogeneic (F344--LEW) and strongly allogeneic (BN--LEW). A small intestine segment was transplanted using the by-pass technique; after 10 days the graft was removed and histologically investigated. The strongest rejection was found in the lymphatic tissue and the epithelium of the small intestinal transplant. The immunogenetical difference is significant for the survival of the graft: the greater the immunogenetical difference between donor and host, the more severe the morphologically demonstrable rejection reaction.

Animals↗

Colon epithelium. I. Light microscopic, histochemical, and ultrastructural features of normal colon epithelium of male Fischer 344 rats.

Although the colon of the inbred F344 rat is not distinctly demarcated into ascending, transverse, and descending segments as in the human colon, it can roughly be divided into ascending and descending portions that show distinct light microscopic, histochemical, and ultrastructural features. The ascending colon is characterized by a "herringbone" pattern of mucosal folds and test-tube-shaped uniform crypts that contain mucous cells (MC) with abundant mucin (acidic mucopolysaccharide--mostly sialomucin) in the lower one-third of the crypt, whereas the upper one-third contains two putative cell populations: 1) MC containing large globules of neutral mucopolysaccharide or sulfomucin and 2) columnar cells (CC), the full capabilities of which are unknown. The descending colon has longitudinal folds and contains sparse MC with small mucous granules at the lower one-third of the crypt, whereas the upper one-third contains numerous goblet cells. Neutral mucopolysaccharide is sparse and the acidic mucin is exclusively sulfated. Histochemically, the descending segment of the rat colon resembles the human descending colon in that the predominant type of mucus is sulfomucin. Ultrastructurally, the cell types observed in both the ascending colon and the descending colon are: a) MC, b) CC, c) endocrine cells, and d) undifferentiated cells.

Animals↗